A great paper in Cell (full text freely available for now) dives into the role of mitochondria in relation to aging, calorie restriction (CR) and sirtuins: "CR can exert a positive effect on mitochondria, boosting mitochondrial activity and hence providing at least some of the salutary effects of CR. ... CR and sirtuins upregulate the activity of mitochondria in different organisms. ... There is ample evidence that damage to mitochondria increases progressively with age. This has been observed in the form of the accumulation of mutations in mitochondrial DNA and a decline in the activity of mitochondrial enzymes and components of the electron transport chain. ... A higher pool of functional mitochondria may ameliorate tissue damage simply by buffering [cells] against the gradual decline in the ability to produce energy as mitochondria become damaged during aging. One may well wonder why mitochondrial number is not normally set to a higher level during ad libitum feeding to forestall this decline. It is important to remember that aging occurs postreproductively and is nonadaptive. Thus, under normal conditions, mitochondrial number and function will only fall sway to selective pressure until the reproductive period has been completed. ... By this logic, CR and perhaps other stressors may impose a new selective landscape in which robust somatic maintenance, rather than reproduction, is now at a premium and mitochondrial biogenesis favored."
A look at one particular type of objection to healthy life extension in this New American Media piece: the person who agrees with the goal of defeating age-related suffering and death, but nonetheless feels that even wonderfully positive change must be slow and socialized - discussed, debated, funneled through the polical and regulatory sausage machine. "It deserves a long and wide-ranging effort of serious deliberation - not just debates, which rarely change anybody's mind, but dialogues in which people actually listen to one another and consider deeply all the issues and scenarios. Such an effort will take time and money, but certainly no more than it will take to figure out how to turn old geezers into young geezers. It could run concurrently with life-extension research, and it would inevitably deepen our understanding of the complexities of human life." To which I usually respond: "well then, just how many people - at the rate of 100,000 lives lost each day - are you willing to condemn to death by aging for the sake of your delicate sensibilities?" There is no other moral choice beyond as much freedom of research as possible, and as great a speed as can be mustered.
The latest issue of the Journal of Internal Medicine focuses on aging. Some interesting material in there, and you'll note that the publisher is allowing free access to the full text of some papers. For example:
Increasing age in mammals correlates with accumulation of somatic mitochondrial DNA (mtDNA) mutations and decline in respiratory chain function. The age-associated respiratory chain deficiency is typically unevenly distributed and affects only a subset of cells in various human tissues, such as heart, skeletal muscle, colonic crypts and neurons. Studies of mtDNA mutator mice has shown that increased levels of somatic mtDNA mutations directly can cause a variety of ageing phenotypes, such as osteoporosis, hair loss, greying of the hair, weight reduction and decreased fertility. Respiratory-chain-deficient cells are apoptosis prone and increased cell loss is therefore likely an important consequence of age-associated mitochondrial dysfunction.
Mitochondrial dysfunction is clearly involved in the human ageing process, but its relative importance for mammalian ageing remains to be established.
A belief that ageing and longevity are governed by genetic factors has led to growing excitement that research on the human genome will soon uncover the genes for ageing and perhaps open new paths to longer life and health spans. Even if direct gene modification is remote, a clearer understanding of the pathways regulated by such genes may point the way to nongenetic interventions that exploit this knowledge. But what is the evidence that genes do control ageing and how realistic is it to expect that the 'new genetics' can secure for us a modern-day elixir of youth? And how can we accommodate the genes responsible for ageing within the framework of natural selection, when surely the decline in vitality that results from the ageing process would appear to run counter to the principle of maximizing Darwinian fitness?
Although the evolutionary theory of ageing is by now well established, there has continued to be a tendency to seek explanation of ageing in terms of some kind of adaptive genetic programme. The attractions of this concept are easily understood. First, ageing is phylogenetically a very widely distributed trait and in species where senescence occurs, it affects every individual that lives long enough to experience its adverse impacts on fertility and vitality. Secondly, there are clear genetic effects on longevity and this leads naturally to supposing that the relevant genes specify some kind of 'ageing clock'. In spite of these attractions, the programme theory, as a general explanation for ageing, is both logically and empirically unsound.
About the most profound thing I've read in the past few months on the nature of aging research - and I forget the source, so apologies to whomever I'm lifting this from - is that most gerontologists believe that the only viable way to extend healthy life span is to slow aging by re-engineering the complexities of metabolism and genetics. This is generally agreed to be very hard; it's a long, long road and we stand at the very beginning, barely assembling the necessary knowledge to build a roadmap. Thus most gerontologists think that major changes to human life span within our lifetime are extremely unlikely, even in the scenario of muliple, large-scale, coordinated research and development initiatives
Fortunately, engineering a better human is not the only way to greatly extend the healthy human life span. It's not even plausibly the fastest, most efficient way to do it. Instead of engineering new biochemistry, we can focus on repairing the biochemistry we have today. Don't slow aging, but rather reverse it by fixing the damage that is aging as it occurs. Significant near-term progress in this endeavor is more plausible than significant near term progress in metabolic re-engineering, and it will also benefit those people who are already damaged by aging.
We don't need to walk the long road to better, engineered humans, and see all of us alive today die along the way. We can walk the much shorter road to medical technology to repair the aged, learning to better maintain the biology we have today.
Researchers continue to make solid progress in detailing the biochemical mechanisms by which calorie restriction extends healthy life: "Calorie restriction (CR), the only non-genetic intervention known to slow aging and extend life span in organisms ranging from yeast to mice, has been linked to the down-regulation of Tor, Akt, and Ras signaling. In this study, we demonstrate that the serine/threonine kinase Rim15 is required for yeast chronological life span extension caused [by] calorie restriction. ... Deletion of stress resistance transcription factors Gis1 and Msn2/4, which are positively regulated by Rim15, also caused a major although not complete reversion of the effect of calorie restriction on life span. ... Notably, the anti-aging effect caused by the inactivation of both pathways is much more potent than that caused by CR." Enumerating the required parts of the chain, one by one, is an early step in the process of building a full understanding - and then reproducing and improving upon natural longevity-inducing biochemistry. Interestingly, Rim15 is also required for the recently demonstrated set of genetic tweaks that boost yeast life-span ten-fold - even though that did not involve calorie restriction.
It seems there is a whole business ecosystem out there revolving around very short, single-topic educational video clips. In addition to the VideoJug question and answer sessions with biomedical gerontologist Aubrey de Grey - collected on the Methuselah Foundation website - you can find more of the same at Big Think. From the perspective of an advocate, I certainly see the value of collected short answers to many pertinent questions about healthy life extension, the science of repairing aging, and plans to develop real anti-aging therapies. It remains to be seen whether any of these businesses find enough profit in this venture to build a sustaining architecture dedicated to this sort of educational content.
Evidence to date suggests that we retain diverse populations of stem cells - and the resulting processes by which new cells and tissue are generated - throughout our lives. Stem cells don't go away as we age, but rather age-related changes in our biochemistry act to suppress the action of those cells. When we better understand these biochemical changes, it may be possible to restore the regenerative capacities of the aged through comparatively simple manipulation of signaling processes in the body. Here are a couple more papers to add to the weight of science behind this supposition:
Neurogenesis, or the birth of new neural cells, was thought to occur only in the developing nervous system and a fixed neuronal population in the adult brain was believed to be necessary to maintain the functional stability of adult brain circuitry. However, recent studies have demonstrated that neurogenesis does indeed continue into and throughout adult life in discrete regions of the central nervous systems (CNS) of all mammals, including humans. Although neurogenesis may contribute to the ability of the adult brain to function normally and be induced in response to cerebral diseases for self-repair, this nevertheless declines with advancing age. Understanding the basic biology of neural stem cells and the molecular and cellular regulation mechanisms of neurogenesis in young and aged brain will allow us to modulate cell replacement processes in the adult brain for the maintenance of healthy brain tissues and for repair of disease states in the elderly.
In healthy individuals, skin integrity is maintained by epidermal stem cells which self renew and generate daughter cells that undergo terminal differentiation. It is currently unknown whether epidermal stem cells influence or are affected by skin aging. We therefore compared young and aged skin stem cell abundance, organisation, and proliferation. We discovered that despite age associated differences in epidermal proliferation, dermal thickness, follicle patterning, and immune cell abundance epidermal stem cells were maintained at normal levels throughout life. These findings, coupled with observed dermal gene expression changes, suggest that epidermal stem cells themselves are intrinsically aging resistant and that local environmental or systemic factors modulate skin aging.
Cancer is the big potential problem associated with any "put the stem cells back to work" strategy. It is probable that evolutionary pressures have led to biochemistries in which generative processes diminish with age, thereby reducing the risk of cancer due to damaged stem cells. It's a balanced trade-off between losing capacity and the harm caused by runaway, damaged cells. But we have to fix cancer anyway, if we'd like to live much longer, healthier lives - and the near-term for cancer medicine is very rosy, even if complete prevention and absolute cures are still decades in the future.
As this New York Times article points out, the most obvious reason for not banking your stem cells - now that you can - is that it seems likely science will quickly progress far past their utility: "some experts say consumers should think twice before spending hundreds or thousands of dollars on such services, because it is not clear how useful such cells will be. ... Some people buying the services say there is little to lose from doing so except money, even if the chance that the cells will be needed or useful is slim. ... Scientists say it is quite unlikely a person will ever need such cells. And the technology could change so much that cells stored now may not be needed if a person falls ill in 10 or 20 years. Recently, scientists found a way to turn skin cells into cells that behave like embryonic stem cells. That might allow a person of any age to have customized tissue created on the spot." So it's a rational decision of risk, reward and chance. How long before aging catches up with you, and how long before science masters the biology of regeneration with no need for those stem cells from your past history?
We live in an era close to artificial eyes, to regrowth of complex organs, and to a full melding of technology and biology. So you'll see things like this on the way to where we're going: "The technique could enable sufferers of retinitis pigmentosa, age-related macular degeneration and diabetic retinopathy to see. In the advanced stages, retinas with these disorders can no longer detect light, which means they no longer have usable rods and cones, but all their remaining neurons, such as the ganglion cells, survive. This raises the possibility that a retinal prosthetic could bypass the diseased tissue and stimulate the remaining healthy cells. ... A discreet prosthetic in front of the patient's eyes would capture images with a camera and process the information. It would then stimulate ganglion cells by outputting a series of bright, intense light spots to them. ... With gene therapy, a patient's entire population of ganglion cells could be turned into light-sensitive neurons. ... The prosthetic will also use retinal algorithms to replace the visual processing lost in the diseased retinal tissue. ... So essentially we've put all the engineering outside the eye, and the device will attempt to talk to the retinal ganglion cells through optical communication."
I pointed out a paper in passing a few weeks back, in which researchers put forward a model to explain how some species can evolve extreme longevity, or even agelessless (or negligible senescence).
How can evolution, biased to early reproductive success at all reasonable cost, produce such a species?
As it turns out, there may be some plausible scenarios - which is a good thing, given the fact that many extremely long-lived animal species exist, and that some might indeed be ageless. Problems arise for any theory that cannot explain the outliers. Chris Patil has given this work a great deal more attention over at Ouroboros, and you should take look.
The authors describe in detail two organisms - the Bristlecone pine and Arctic quahog - that exhibit density-dependent recruitment. In both species, sessile adults live in crowded but stable conditions in which new opportunities for maturation arise rarely. In such situations, it behooves an individual organism to outlive its neighbors, so that when they die its seedlings or larvae have a place to dig in and grow up. In such contexts, the authors argue, natural selection can trigger an anti-aging arms race that results in negligible senescence as a consequence of runaway selection.
But does the evolutionary theory that explains the emergence of negligible senescence in trees and clams have anything to teach us about how long-lived species arise from short-lived stock? If so, are those lessons in any way portable to mammals? Possibly.
One famous example of a species with far greater longevity than similarly sized species of comparable body plan, the naked mole rat, is also territorial and eusocial. It is tempting to speculate that mole rat queens, like their peers among the harvester ants, have evolved long lifespans in order to wait out their competitors in other burrows.
Mole rats are no less similar to humans than lab mice are. Therefore, biogerontologists are very interested in learning the detailed mechanisms by which mole rats have delayed senescence, since it’s likely (more likely than for clams and trees, anyway) that these details might be of some practical use to us.
The most important lesson to learn from an examination of the huge range in animal - even mammal - longevity is that it is possible to design better humans with the biotechnology of tomorrow. Longer lived, less diseased, less prone to aging. That is the driving goal behind much of the mainstream work in metabolism, genetics and aging these days. It'll be a long time in the making, however - a truly massive undertaking of great scope and complexity.
While that great work is underway, we should devote more resources to the easier path to longevity: learning how to repair the humans we have now.
The groundwork continues to be laid for the use of autologous stem cell therapies to regenerate more varied types of damage in the aged. Via EurekAlert!: bone marrow stromal cells (BMSCs) "were injected into animals 24 hours following [a stroke] ... researchers found that within seven days of the injection the BMSCs had migrated through the region of the middle cerebral artery into the scar area and border zone of the ischemic region. ... We evaluated vascular density in the ischemic region in all animals seven days after cell transplantation. The animals exhibited significant reductions in scar size and cell death and improvements in neurological function when compared to controls that received no BMSCs ... the intravenous delivery of bone marrow-derived cells may enhance tissue repair and, in turn, functional recovery after a stroke. While the potential mechanisms for this recovery are unclear, among the possibilities are that the brain microenvironment early on following a stroke may mimic brain development. Subsequent elevated levels of growth factors might enhance homing of BMSCs to the injured area and induce cell proliferation." Greatly enhanced regeneration through manipulation of stem cells and cellular environments will be commonplace a decade from now.
From EurekAlert!, more on the aging-exercise connection: "Individuals who are physically active during their leisure time appear to be biologically younger than those with sedentary lifestyles ... Regular exercisers have lower rates of cardiovascular disease, type 2 diabetes, cancer, high blood pressure, obesity and osteoporosis ... Inactivity may diminish life expectancy not only by predisposing to aging-related diseases but also because it may influence the aging process itself ... Men and women who were less physically active in their leisure time had shorter leukocyte telomeres than those who were more active .... Oxidative stress - damage caused to cells by exposure to oxygen - and inflammation are likely mechanisms by which sedentary lifestyles shorten telomeres, the authors suggest. In addition, perceived stress levels have been linked to telomere length. Physical activity may reduce psychological stress, thus mitigating its effect on telomeres and the aging process." If you want to maximize your chances of living into the era of radical life extension medicine, it pays to take care of the health basics.
My attention was drawn to a Spanish article on one of the many research groups investigating the role of p53 in aging and cancer. There has been a great deal of interest in finding ways around the "cancer or aging, choose one" limitation to this set of biochemical mechanisms, thought to apply until recently. This Spanish article is somewhat in advance of the scientific publication; I'm not sure why that is the case.
The translation via Google is fair (suggestions taken on a better translation automaton):
In this line, Serrano said that the genomes of a chimpanzee and humans are virtually identical at 99.8%. However, the maximum life of a chimpanzee is 60 years and the human rarely exceeds 110. The average of a chimpanzee is 40 years and that of a human, 80. There must be something in our genes very subtle changes made to live 50 years to live 100. Then, along with the team of Mary Blasco, we are going to make some genetic manipulation to see if we can increase longevity in mice much more. That is our challenge If we get a mouse in the privileged environment of a laboratory comes to live three years to live six passes, it would be proof that longevity is flexible and would know how to enlarge it.
So it seems compelled to ask the molecular biologist in this battle if they have undertaken together against cancer and aging, it is just a matter of putting telomerase a mouse to make it immortal. The answer is no, because telomerase makes more cancer. To ensure a tumor, which has activated telomerase, and if a mouse has more telomerase than normal, for example, on transgenic mice, we know that you have more tumors. What we have done is to use the superratones Manuel, because p53 protects cancer and a 18% lengthens the life of mice, and if we add to this the gene of immortality, telomerase, which got these mice [to] live an average of 50% more, without cancer, which are words older. That is what we have discovered now.
Because this extension of life, 50% in superratones is the longest that has been described in mammals.
You get the gist, despite the breakdown of translation in the last few sentences: there are combinations of metabolic and genetic states in mammals not selected for by evolution that nonetheless lead to a clearly superior beast, from our perspective at least. Well, more or less. If you head over to the Methuselah Foundation forums, you'll find that Michael Rae wrote a long piece on this research back in mid-2007, before the life span studies were complete:
The standard reading is that the "Super p53" mice are getting less cancer, but are having their [life spans] restrained by lack of tissue replenishment due to stem cell loss, while the telomerase transgenics are on the opposite horn of the same dilemma. It seems at least possible that if one overlaid the strong cancer resistance conferred by the former, with the increase in stem cell mobilization and proliferative capacity of the latter, you'd wind up with a long-lived, slow-aging mouse.
There are a lot of caveats and details both prior and after that statement, many of which still apply even with these final life span study results. It's not all completely clear-cut, as is often the case, but I can see this impressive work garnering a great deal of attention in the popular press once it jumps the language gap for the English-speaking world.
Aging is molecular damage: how much faster can we progress to repair technologies with a detailed map of that damage? "One of the most fundamental molecular aspects of aging is accumulating oxidative damage caused by reactive oxygen species (ROS) as proposed by the free radical theory of aging. These unwanted chemical side products of normal metabolism lead to the formation of altered, less active and potentially toxic species of DNA, RNA, proteins, lipids, and small molecules. Due to gradually accumulating small contributions of irreversible reactions during ageing, uncatalyzed chemical side reactions occur with increasing frequencies and repair functions decline. Eventually key biochemical pathways are impaired by increasingly less efficient cellular stress management. In this review, we describe the chemical nature of nonenzymatic age-related modifications of proteins and provide an overview of related analytical challenges and approaches, with a focus on mass spectrometry. We include the description of a strategy to rapidly exploit the wealth of mass spectrometric information [for] the characterisation of age-related oxidative amino acid modifications."
This Times Online columnist gets it; wrong in the details of the science that will most likely liberate us from age-related degeneration, but right in the grand scope of what is possible: "Until 1828 it was believed that life, with its so-called 'vital forces', owed nothing to science, but in that year Friedrich Wohler synthesised urea in the test tube. Since then, chemistry's invasion of biology has been unstoppable. So it is not science fiction, it is inevitable, that within our children's lifetimes, molecular biologists will tweak the human genome. If we can re-create existing bacterial genomes, we will be able to create new improved human ones. The ills that flesh is heir to are many, but thanks to DNA chemistry they will be abolished. Diseases such as cystic fibrosis or muscular dystrophy will be eliminated as thoroughly as smallpox. And the greatest ill of all - ageing - will also be conquered. It was Sir Francis Bacon, the Father of the Scientific Method, who wrote in his Valerius Terminus of 1603 that the purpose of science was the 'discovery of all operations and possibilities of operations from immortality (if it were possible) to the meanest mechanical practice' - and immortality is possible."
The full content of the December 2007 issue of Rejuvenation Research is presently freely available. These promotions don't last too long, so take a look while it's available - there's a lot of good reading in there. For example, Aubrey de Grey's piece on the balkanization of gerontology (PDF):
In my view, the divide between biogerontologists and other gerontologists concerning the desirability of combating aging is a symptom of the pitifully limited amount of communication between these subfields. Though they study facets of the same phenomenon, these researchers' actual contact is very nearly nil. It is thus no surprise that such fundamental differences of opinion persist. Whether anyone is really to blame for this "balkanization" of the field is debatable: it exists in a more limited way even within biogerontology, and the reasons are probably the same, revolving around the much higher priority (in career terms) of maintaining prestige among those who know and understand one’s work best than of disseminating it to others.
There has long been a recognition that this balkanization is regrettable, and token measures have been taken to diminish it: for example, the Gerontological Society of America (GSA) brings together all the gerontological specialties under one roof every November. But token is all these measures are: as anyone who has attended the GSA’s annual meeting will tell you, the event is indistinguishable from a coincidence of three or four conferences going on in the same building at the same time.
Alternately, William Bains' pointed commentary on views of death and aging (PDF):
no one will ever be in a position to ask, "Should I live forever?" We will be asked another, harder question. It is my contention that we should debate that question, and yes debate it in terms of its possible, long-term, science fictional implications if you like, but do not pretend the debate is ‘about’ whether people should seek physical immortality. It is about something more complicated, less black-andwhite, and much more immediate.
The question is not, "Do you want to live forever?" The question is, "Do you want to die tomorrow?" Replacing "should we live forever" with "do you want to die tomorrow?" strips away the sheer nonsense that is spouted about what 'might be,' and brings us back to specifics. Many people state firmly that they do not want to live forever. Many say they would not want to live beyond 100. Usually they are less than 60 years old when they say it (few 95-year-olds hold this view; very few 99-year-olds). But these people appear genuinely to feel that they do not want to live to be 100. So they do not want to live another 50 years. Do they want to die tomorrow? No. If I ask again tomorrow, will they want to die the day after? No.
In our view, aging research is drastically underfunded. Promising opportunities must be pursued, such as the emergence of stem cell research, which offers the possibility of new therapies for treating or renewing diseased tissues or organs.
The growth of an aging population will bring treasury-breaking healthcare costs unless health can be maintained and age-related diseases delayed or cured. Human suffering that accompanies age-related disease is not just a financial burden.
It's a pity that all this more broadly interesting content ends up behind the paid firewall. I can imagine that all parties involved in publishing Rejuvenation Research would be better served by a journal in which the content above - very interesting and accessible to the layperson - is open while the research publications remain as paid access only. If you want more people to see what you have to say, open access is the way to go, and those in the research community who pay for the journal will pay for it regardless of the non-research content.
As a companion piece to the clinical trial noted yesterday, here's more stem cell research aimed at blood vessel repair and regrowth: "Multipotent adult progenitor stem cells extracted from bone marrow, and known as MAPCs, have proved to be effective in the regeneration of blood vessel tissue and also in muscle tissue when treating peripheric vascular disease. ... Acute peripheric vascular disease involves the obstruction of the blood circulation in a determined area of the organism, as a consequence of the occlusion of the artery supplying blood to it, with the consequent reduction in blood flow. ... The most important finding from the research was that adult MAPC stem cells are more effective when injected without pre-differentiation, not only because they contribute in increasing the quantity of arteries and veins generated in the new area, but also because they manage to enhance muscle regeneration [as] a consequence of secreting a series of substances. The research thus concluded that the MAPC progenitor cells implanted in mice achieved an indirect improvement of the muscle and a direct enhancement of the vessels."
As good a definition as any in this paper: "Aging at the molecular level is characterized by the progressive accumulation of molecular damage. The sources of damage act randomly through environmental and metabolically generated free radicals, through spontaneous errors in biochemical reactions, and through nutritional components. However, the occurrence of damage on a macromolecule may depend on its structure, localisation and interactions with other macromolecules. Damages in the maintenance and repair pathways comprising homeodynamic machinery lead to age-related failure of homeodynamics, increased molecular heterogeneity, altered cellular functioning, reduced stress tolerance, diseases and ultimate death." This means that any therapy capable of effectively intervening in aging must "incorporate means to minimize the occurrence and accumulation of molecular damage." At the high level, the most important debate in biogerontology today is over whether to work to slow the damage or repair the damage. I favor the latter course.
Far too much is going on in the field of stem cell research to give more than a flavor of progress in any document of a reasonable length, but here are a few interesting items that caught my eye today.
Just as many scientists had given up the search, researchers have discovered that the pancreas does indeed harbor stem cells with the capacity to generate new insulin-producing beta cells. If the finding made in adult mice holds for humans, the newfound progenitor cells will represent "an obvious target for therapeutic regeneration of beta cells in diabetes"
If the past couple of years have made anything clear, it's that an absence of stem cells in a particular organ or tissue means that researchers aren't looking hard enough. A steady stream of newly identified stem cell populations flows through the popular science press, sometimes one a month. An identified population is raw material for first generation stem cell therapies, often based on autologous transplantation, that aim to kick-start existing regenerative and growth processes to heal what the body will not heal on its own.
Meanwhile, the existing drug research and development community is giving rise to a hybrid school aiming to produce (or repurpose) drugs that can manipulate stem cell behavior in desired ways, controlling growth or regrowth in damaged or wasted tissue:
These studies raise the possibility that drug-induced progenitor/stem cell differentiation could be used in vivo to therapeutically modulate bone formation from a primitive reservoir of cells and that an existing clinical-grade drug can be "repurposed" to modulate stem biology. This strategy may be applicable to increase bone volume in the osteolytic disease of malignancy or in osteoporosis, where the function of more mature populations of cells has been compromised.
Aiding the variety of paths presently followed to manipulate stem cell behavior are those researchers who untangle stem cell biochemistry. You can get a machine to do the job if you only have half the instructions, but it's a lot easier with the full set.
Like fine china and crystal, which tend to be used sparingly, stem cells divide infrequently. It was thought they did so to protect themselves from unnecessary wear and tear. But now new research from Rockefeller University has unveiled the protein that puts the brakes on stem cell division and shows that stem cells may not need such guarded protection to maintain their potency.
"It seems like the resting phase isn't as necessary as was once thought," says Horsley. "Even though these stem cells are highly proliferative, they still maintain their stem cell character."
This particular immediate application - restoration of hair growth - isn't all that interesting for someone who cares about whether their organs are aging them to death. It will no doubt garner intense interest and investment from the hair restoration industry (which is larger and more involved in fundamental research than you might imagine) and people whose priorities are not quite so in line with healthy longevity. You can live without hair - it's harder to do so with the other degenerations of age, and repairing those other degenerations should be higher on everyone's priority list.
An overview: "Ample evidence from model organisms has indicated that subtle variation in genes can dramatically influence lifespan. The key genes and molecular pathways that have been identified so far encode for metabolism, maintenance- and repair mechanisms that minimize age related accumulation of permanent damage. Here, we describe the evolutionary conserved genes that are involved in lifespan regulation of model organisms and humans, and explore the reasons of discrepancies that exist between the results found in the various species. In general, the accumulated data has revealed that when moving up the evolutionary ladder, together with an increase of genome complexity, the impact of candidate genes on lifespan becomes smaller. ... currently used methodologies may have only little power and validity to reveal genetic variation in the population. In conclusion, although the study of model organisms has revealed potential candidate genetic mechanisms determining aging and lifespan, to what extent they explain variation in human populations is still uncertain." Genetic and metabolic manipulation in humans - changing our biology - is not the way ahead for the near term. Rather, we need to learn how to repair the damage of aging in the biology we have today.
EurekAlert! notes that stem cell therapies continue to show promise as a way to regrow damaged blood vessels: researchers have "launched the first U.S. trial in which a purified form of subjects' own adult stem cells was transplanted into their leg muscles with severely blocked arteries to try to grow new small blood vessels and restore circulation in their legs. ... Severely blocked arteries in the leg and sharply diminished blood flow can result in wounds that don't heal, the breakdown of tissue and gangrene. This painful condition is called critical limb ischemia (CLI) and results in the amputation of more than 100,000 limbs every year in the United States. ... An estimated 15 percent of the population will have this disease by the time they reach age 70. ... The stem cells themselves can assemble into blood vessels. They can also secrete growth factors that stimulate and recruit other stem cells to come into the tissue and help with the repair. It's an amazing biology we're trying to leverage in these folks. ... transplanting stem cells into the limbs have shown this approach to be effective in mice and rats. ... Based on that, we think it has a good chance of helping humans."
You might recall I posted on the work of Skulachev back in 2006, lamenting the language barrier that causes interesting Russian research to fail to appear in the popular science press. A high level view of the research in question:
The life time of such mice increased by one third on average as compared to that of the reference group mice. Even more demonstrative are experiments with mutant rats, where accelerated ageing - progeria - was observed. SkQ prolonged their life span by three times, besides, it cured them from a large number of senile diseases. They include infarctions, strokes, osteoporosis, hemogram abnomality, reproductive system disorders, behavior change, visual impairment.
Skulachev's past results appear to lead to similar life span extension in mice to the work of Rabinovitch in gene engineering antioxidant catalase into mitochondria. All this adds to the general weight of evidence suggesting that antioxidants are spectacularly useless unless carefully directed in our biochemistry. Of all the places you can target antioxidants, it seems that the mitochondria is the most effective discovered to date: not too surprising considering the role of mitochondria in oxidative damage related to aging.
Your mitochondria are a source of a whole lot of biochemical trouble as the years go by. Damaged mitochondria proliferate in some cells and, like damaged factories, pollute those cell with excess reactive oxygen species and free radicals produced as metabolic byproducts. Each damaged cell then tries to maintain itself by exporting more reactive oxygen species and free radicals from its cell membrane structures, spreading the damaging pollution far and wide in the body.
I noticed a more recent paper from Skulachev while meandering through PubMed today:
Antioxidants specifically addressed to mitochondria have been studied for their ability to decelerate aging of organisms. For this purpose, a project has been established with participation of several research groups from Belozersky Institute of Physico-Chemical Biology and some other Russian research institutes as well as two groups from the USA and Sweden, with support by the "Mitotechnology" company founded by "RAInKo" company (O. V. Deripaska and Moscow State University). This paper summarizes the first results of the project and estimates its prospects.
In mammals, the effect of SkQs on aging is accompanied by inhibition of development of such age-related diseases as osteoporosis, involution of thymus, cataract, retinopathy, etc. ... Thus, it seems reasonable to perform clinical testing of SkQ preparations as promising drugs for treatment of age-related and some other severe diseases of human and animals.
Investment and further outside scientific collaboration are afoot: it looks like we'll be hearing more of this approach in the years to come.
There's nothing like a good divide to get the press interested. Here's a view from the Independent of the two ends of biogerontology: "Valter Longo is one of the small but influential group of specialists in this area who believes that an 800-year life isn't just possible, it is inevitable ... We're very, very far from making a person live to 800 years of age. I don't think it's going to be very complicated to get to 120 and remain healthy, but at a certain point I think it will be possible to get people to live to 800. I don't think there is an upper limit to the life of any organism ... The attitude of most mainstream gerontologists towards the idea that people may one day live for many centuries - or even 1,000 years, as one scientific maverick has suggested - is best summed up by Robin Holliday ... Like many experts on the science of ageing, Holliday is deeply sceptical about the idea that the ageing process can somehow be circumvented, allowing people to extend their lives by decades or even centuries. ... The whole [anti-ageing] movement not only becomes science fiction; it is also breathtakingly arrogant, Holliday says. An immense hinterland of biomedicine suggests that death at a maximum age of about 125 is inevitable." In other words, sensible people who know how science and progress works versus the flat-earthers who don't. The article is actually somewhat wrong in that respect: the majority of the community these days is much closer to Longo than to Holliday in outlook.
The weight of research into the biomechanisms of fat tissue continues to grow. It just isn't sensible to be overweight - at least if long-term health and longevity happen to be on your list of goals. Here's the latest update on one of the ways in which excess fat tissue slowly destroys you from the inside:
a team of University of Michigan Cardiovascular Center scientists reports direct evidence of a link between inflammation around the cells of visceral fat deposits, and the artery-hardening process of atherosclerosis.
The discovery came partly by chance. He and his colleagues had been studying mice that lack the gene for leptin, a hormone generated by fat cells that plays a role in appetite and metabolism as well as reproduction. In an effort to get these obese mice to produce some leptin, the team developed a technique to transplant clusters of fat cells from normal mice of the same strain, into the leptin-deficient mice.
The result surprised them. “In addition to producing leptin and preventing obesity, the fat transplants became inflamed, attracting immune cells called macrophages” Eitzman explains. “Since the mice were genetically identical except for leptin, this shouldn’t have happened. But the inflammation was there, and it was chronic.”
The inflammation occurred around individual fat cells, or adipocytes. Further tests showed it was regulated by the same factors that regulate the inflammation that other researchers have seen in the naturally occurring fat deposits of obese mice - specifically a chemokine called MCP-1.
But because the fat was transplanted, the inflammation could be attributed directly to the fat, and not to overfeeding of the mice, or the metabolic problems that overfeeding and obesity bring, such as diabetes. Armed with this discovery, the researchers set out to see what was causing inflammation to occur, and what implications it had.
“There appeared to be an interaction between the macrophages causing the inflammation in the visceral fat, and the process of atherosclerosis,” says Eitzman, who notes that blood vessels far from the site of the fat transplant developed increased atherosclerosis.
All that excess fat hanging around over the years generates atherosclerosis, which then kills you:
Most commonly, soft plaque suddenly ruptures, [causing] the formation of a thrombus that will rapidly slow or stop blood flow, that is, within 5 minutes, leading to death of the tissues fed by the artery. This catastrophic event is called an infarction. One of the most common recognized scenarios is called coronary thrombosis of a coronary artery, causing myocardial infarction (a heart attack). Another common scenario in very advanced disease is claudication from insufficient blood supply to the legs, typically due to a combination of both stenosis and aneurysmal segments narrowed with clots. Since atherosclerosis is a body-wide process, similar events occur also in the arteries to the brain, intestines, kidneys, legs, etc.
According to United States data for the year 2004, for about 65% of men and 47% of women, the first symptom of atherosclerotic cardiovascular disease is heart attack or sudden cardiac death (death within one hour of onset of the symptom).
This is one of the many reasons why people who keep in shape and stick to the health basics tend to live longer, healthier lives.
From the Methuselah Foundation blog: "We wanted to provide a view of this recent fundraising for all supporters of the Methuselah Foundation - and of our work on the Mprize for longevity science and Strategies for Engineered Negligible Senescence (SENS) research - so we've pulled together a list of the high points, and an overview of where these new resources will be put to use. ... all of this wind was in our collective sails when Foundation chair Aubrey de Grey and SENS program director Jeff Hall met with Peter Thiel for the latest of our periodic updates. Peter was so pleased and excited by this very strong, broad show of support for longevity research that he decided on the spot to donate the full remaining balance of his $1,000,000 matching pledge for 2007! We're still doing the calculations, but it looks like this will add more than $750,000 in new funding, cash in hand and ready to be used in the laboratory, for the Foundation. So, what's the bottom line? $1,860,000 received or pledged within the last 60 days! ... these additional funds will more than double the amount that we can spend on SENS research in 2008 relative to 2007. We plan to put this money to work by increasing the manpower on both our existing SENS projects (LysoSENS and MitoSENS), and by initiating at least two new projects."
Matters have certainly moved along in the past decade. The conservative view in gerontology is now that greater human longevity is desirable and can be engineered through metabolic manipulation - a great improvement over the previous state of affairs, but still a way to go yet towards the SENS model of repair and radical life extension. This In the Pipeline post typifies the mainstream view, I think, including a knee-jerk labeling of ongoing SENS longevity research as "fringe": "first, it's increasingly clear that there are deep connections between metabolism and lifespan. All sorts of genes related to food intake and insulin signaling affect how long model organisms live, and there's every reason to expect that the same is true of us. Second, the settings for our lifespans may not be optimal - or what we'd now consider optimal. ... there's no reason that we necessarily have to accept whatever tradeoffs were made during the development of our species. ... ever since our brains became large and complex enough for language and culture, and ever since we started growing our own food, we've been altering the evolutionary bargains that all other species have had to make - predator/prey relationships, availability of food, and so on. We may yet be able to draw a black line through another paragraph of the contract, and make it stick."
I think this piece from Global Pensions is representative of the way the behemoths of the insurance and other capital markets are viewing the prospects for increasing longevity: "Could longevity experience a spike if there was a dramatic breakthrough in medical science, if someone found a cure for cancer for example? ... That would not change mortality statistics suddenly. It would take a long time to filter through. If some of the drugs being tested at the moment come on stream between now and 2020 then you would not see a significant impact until the middle of the century. Our model factors in the impact of significant medical advances and the key point for investors is that longevity is nevertheless a trend exposure rather than a spike, or event risk as is the case with mortality - and yet mortality bonds have nevertheless found a fairly broad marketplace." This sort of thinking - in any market - is why disruptive innovations are disruptive. The behemoths are right in that onerous regulatory burdens greatly slow advances in medicine, but success in Strategies for Engineered Negligible Senescence (SENS) or SENS-like work will be the disruption here. I'd say that betting vast sums against greatly increasing longevity in in the midst of a biotechnology revolution isn't such a good idea.
Change is the one constant you can count on; radical, ongoing change driving and in turn being driven by the relentless advancement of technology. So if you're planning on placing yourself into cryonic suspension on death, how best to ensure that the provision of that storage will continue for the unknown length of time it will take for revival technologies to be developed?
Cryonics, for those new to the party, is a form of low temperature storage of the body, vitrified rather than frozen to preserve the fine structure of your brain and all the information it contains - preserve your self, in other words, waiting for the likely technology of the 2040s or later that can repair and revive a cryopreserved individual. It is very plausible, very sensible and less supported than it should be. Just like serious research into rejuvenation technology, cryonics suffers from the mass acceptance of - and even impassioned advocacy for - aging and death we see in the world today.
But back to the question: how to best ensure the continuation of an organization and its resources such that cryopreservation of vitrified customers continues solidly for half a century or longer? For added value, you'd want an organization that contributes to and helps to build the research communities developing revival technologies. You can be sure that a lot of thought has gone into this matter over the decades that cryonics providers have already existed:
For persons entering cryonic suspension in the twentieth century, and for some decades beyond, the success of their venture will be determined primarily by two contingent future circumstances: the development of repair technologies; and the survival of the organizational vehicle which they selected to transport them into the future when those technologies will exist.
A fundamental rationale for selecting the self perpetuating Board structure was its ability to provide continuity of purpose over a long period of time. Existing Board members select those new Board members who they believe are best able to preserve Alcor's core values and carry out its mission.
Board members have a strong incentive to choose carefully because the success of Alcor and the survival of our members - including our Board members - is heavily dependent on the abilities and character of future Boards of Directors.
One of the original rationales for Alcor's self perpetuating Board was to prevent a takeover of Alcor. Because the Patient Care Trust Fund has significant assets, and is growing, the incentive for such a takeover continues to be present today. This argument seems most effective against a member elected Board if all members - even recent members or members whose motives might be viewed as suspect by the majority of established cryonicists - are allowed to vote. Various limitations might be imposed which would significantly reduce this risk. It is clear, though, that this issue would need to be thoroughly explored before making any significant change in Alcor's structure. It is essential that the risk of a takeover - a catastrophic failure mode - be held to a minimum.
Change is like water; it tends to flow along the paths of incentive. Humans are incented by the prospect of obtaining resources, and looting is as much a part of modern society as it ever was in ancient times. The forms are more baroque these days, but the thievery as just as real. You have to do your best to ensure the continuation of resources - and the intent to protect those resources - while you are not going to be there to help out. That has always been a challenge:
Putting your body and brain into cryonic suspension is an educated gamble, we must recognize that much. I think it's a good gamble, since technology is advancing rapidly and comparatively few interests are aligned against you in the matter of revival and returning to a place in society. Trying to put your resources, your wealth, on ice strikes me as a much more risky endeavor - the long history of human attempts to take action or enforce a decision after death should amply demonstrate the futility of attempting to preserve post-mortem vision and wealth from the predations and honest choices of your fellow human beings.
The present Alcor managers recently posted an update that reflects some of their philosophy and intent in these matters. It's well worth reading:
When the Alcor management changed in September 2005 to the current team, we developed a new policy of not talking about what grand plans we have for the organization, instead choosing to talk about things that we have completed. We implemented this policy change because the management team (consisting of Steve Van Sickle, Jennifer Chapman, and myself) were disappointed members. We were all weary of the empty promises, the distinct lack of improvement in technical capability and the lack of responsible fiscal oversight. We very deliberately set out to rebuild Alcor into an organization of which we could be proud, and we were enthusiastic about bringing positive change. Though it is a lengthy process, in my opinion we are succeeding, and we’d like to present a little perspective on the changes of late and on the challenges yet ahead.
Our staff is highly motivated and productive. We have an internal plan of action that the staff has been implementing for the last eighteen months. This plan relates directly to the two things Alcor needs most in order to transition beyond the tiny startup company it has been for the past 35 years: better evidence and professionalism. It presents a plan for developing an infrastructure to meet both technical and administrative requirements that are necessary to a growing membership.
It is good to see management at Alcor, as the leading light of the cryonics industry, saying the right things. Transition from volunteerism to professionalism is vital - it is the good form of change for an organization set on growth. Equally important is the continual critique and improvement of core assumptions, marketing, technology and business models. Alcor has suffered in the past for its failure to generate growth as an organization, but it is encouraging to see the potential for the industry - in terms of investment for research and spin-off technologies, public acceptance, and growth into professional status - to be far greater now than in past years.
For all too many of us, cryonics providers will be the only shot at a much longer, healthier life in the future. It's an ugly reality that we have to face up to and do our best to overcome through work, resources and research.
Ouroboros looks at recent longevity research in the context of DNA damage and other genomic instability - a good follow-on to a recent post on that subject at Fight Aging!: "Earlier this week we learned that mutations in the kinase SCH9, combined with intervention in the RAS and TOR pathways, can extend the chronological lifespan of yeast by as much as tenfold. ... Mutation of SCH9, which extends lifespan on its own, suppresses the longevity-shortening phenotype of SGS1 deletion. Since calorie restriction (CR) has no effect on chromosomal rearrangements in the SGS1 mutants, this study has parsed the contributions of SCH9 and CR to at least one molecular correlate of aging (specifically, genome stability). The authors argue that their results further demonstrate the importance of genome stability to the aging process, a point on which certain researchers focusing on mammalian aging would agree. The question remains, however: Does genomic instability shorten lifespan by increasing transcriptional noise, as suggested by the Vijg lab's stochasticity experiments, or via another mechanism?" A good question indeed. The precise relationship between damage to the genome and aging is up for debate.
A number of groups are working to engineer replacement neurons for those gradually destroyed by Parkinson's disease. Here's another, noted at EurekAlert!: the "team studied the development of [dopaminergic] neurons in animals to determine the important biological molecules in the brain that were necessary for the cells to grow and function efficiently. The scientists identified one particular molecule that seemed to be key, a protein called Wnt5a. They showed that when this molecule, together with a second protein called noggin, was included in cultures of stem cells, far more [dopaminergic] neurons were produced than when these ingredients were not present. ... they used neural stem cells - which are programmed to develop only into nerve cells. ... When the researchers transplanted the cells into laboratory animals whose substantia nigra region of the brain was damaged, the results were promising. ... We reversed almost completely the behavioural abnormalities, and neurons differentiated, survived and re-innervated the relevant part of the brain better. Furthermore we do not see the kind of proliferation of the cells that has occurred in the past and we get very little clustering."
There have been repeated rumblings on the topic of longevity insurance in the past few years:
Here is a knee-jerk response: unless these products are stunningly bad value for money under very conservative estimates for growth in life expectancy in the old, those companies to offer longevity insurance packages will be taking a bath twenty to thirty years from now. You might recall that the actuaries are wavering on their estimates for life expectancy, and a healthy debate is taking place in the actuarial community as to just how to account for the ongoing revolution in biotechnology and medicine. An insurer that offers fair valued, competitive products today based on the actuarial trends of the past few years will find themselves in trouble down the line if the efforts of groups like the Methuselah Foundation succeed, or even if the systems biologists have their more modest way.
In general, betting against increasing longevity seems to be a fool's game. But even the venerable tontine is making a comeback as the vast - and consequently archly conservative - insurance industry grapples in slow motion with uncertainty brought on by radical change and progress in biotechnology and aging science:
If you die earlier than your scheme's age range, your family receives your original lump sum without any investment gains. But if you live, you will be paid an income which goes up every year depending initially on your investment growth - this is offshore in Ireland so tax is minimised - but also on how many others in the plan die.
The clever part, according to the company, is the so-called "birthday units" - although "deathday units" would be more accurate, as survivors get a regular investment boost from the funds of plan holders who die. Helped by the death of others, a man on an 80 to 100 plan with £50,000 originally invested would get £19,600 a year at 80, rising to £30,600 at 90 and increasing to £257,000 a year 10 years later when he reaches 100. But do its figures stack up? And is it the only solution? "It sounds like a tontine to me," says retirement income expert Nigel Callaghan at Hargreaves Lansdown. A tontine is an old-fashioned form of life insurance where everyone pays in but the last one living scoops the pool.
Looking at the Wikipedia entry for "tontine", I note:
Tontines were the first government bonds issued anywhere in the world, and the British government first issued tontines in 1693 to fund a war against France. However, tontines soon caused problems for their issuing governments, as they would increasingly underestimate the longevity of the population.
Sound familiar? The monolithic, regulated insurance industry of today, faced with the potential of true rejuvenation medicine in the next few decades, isn't looking much better than 17th century governments. It just isn't smart to bet against healthy longevity in the midst of revolution in biotechnology. A great many people will wind up losing their shirts - make sure you aren't one of them.
ScienceDaily brings news of more potentially common biomechanisms of cancer: "The gene, USP22, encodes an enzyme that appears to be crucial for controlling large scale changes in gene expression, one of the hallmarks of cancer cells. ... USP22 was part of a group of 11 genes that are overexpressed in a variety of cancers and that overexpression of USP22 predicts which tumors can go on to spread elsewhere in the body. This group of genes is collectively called the 'cancer stem cell signature.' ... Since USP22 is an enzyme, the type of protein that is easiest to target with drugs, our new findings may help extend these earlier discoveries to the point where therapeutics can be developed. There are already drugs being used in cancer patients that attack other enzymes in this pathway, and there are companies interested in extending this to find USP22 inhibitors." If it turns out that less than 20 key mechanisms can be used to shut down 80% of cancers, few of you reading this today will ever suffer from cancer. That is one of the many promises of the biotechnology revolution: knowledge is power.
A profile of Andy Grove and his initiatives and views can be found at Forbes: "before [Parkinson's disease] debilitates him, Grove is going to fight. Over the past eight years Grove has immersed himself in the minutiae of the disease and has used his money and his stature to agitate for more and faster research on the neurology of Parkinson's. ... You can't go close to this and not get angry. There are so many people working so hard and achieving so little. ... Grove criticized research funding at the U.S. National Institutes of Health, the unwillingness of researchers to share data and the lack of urgency in translating basic science into treatments that can help people. ... What is needed is a cultural revolution that values curiosity, follow-through and a problem-solving orientation and also puts the data being generated in full view, scrutinizable by all." This is the same story for all us - just change Parkinson's to aging and add a couple more decades before the clock ticks down. We're in exactly the same position otherwise, and the mainstream research community is just as disinterested in progress and goal-setting.
Does the accumulation of DNA damage in the cellular nucleus contribute to significantly to aging? How, if so? It is a topic for debate, with a weight of papers behind many of the consensus interpretations, but most of the community would answer "yes" with some variety of qualifications. On the other side, biomedical gerontologist Aubrey de Grey argues that DNA damage - mutations to the DNA contained in the chromosomes - is not important over a normal human life span, except where it causes cancer:
we don't actually need to fix chromosomal mutations at all in order to stop them from killing us: all we need to do is develop a really really good cure for cancer.
Looking back in the Fight Aging! archives, you'll find plenty of theories on how DNA damage might contribute to degenerative aging. A short selection:
- Double strand breaks are the real problem
- Cancer stem cells arise from DNA damage
- DNA damage causes disarray in gene expression, which contibutes to aging
- DNA damage causes age-related reduction in stem cell capacity
And so forth - it isn't hard to find academic arguments for the role of DNA damage in most of the better known age-related degenerations. It's a matter of time, resources for research and scientific debate as to which pan out. Here's another different point of view from a recent paper, focusing on longevity genes and metabolic changes - such as those brought on by calorie restriction - that lead to greater longevity:
Aging represents the progressive functional decline and increased mortality risk common to nearly all metazoans. Recent findings experimentally link DNA damage and organismal aging: longevity-regulating genetic pathways respond to the accumulation of DNA damage and other stress conditions and conversely influence the rate of damage accumulation and its impact for cancer and aging. This novel insight has emerged from studies on human progeroid diseases and mouse models that have deficient DNA repair pathways. Here we discuss a unified concept of an evolutionarily conserved 'survival' response that shifts the organism's resources from growth to maintenance as an adaptation to stresses, such as starvation and DNA damage. This shift protects the organism from cancer and promotes healthy aging.
It's a broad, interesting topic for study, I think you'll agree that much.
Progress in biological engineering via the Telegraph, this time in repair strategies for the macula: "More than 500,000 people in the UK have irreversible blindness caused by macular degeneration ... The disease is marked by a progressive loss of central vision due to degeneration of the macula - a pigmented spot at the back of the retina. ... Using surgical instruments introduced through three one millimetre holes in the eye, the team goes under the retina, a translucent layer, then inflate it so it separates from the underlying cells. The human eye cells derived from embryonic cells were then introduced on a rolled up patch and injected through a one millimetre hole, where the patch of human cells unfolded under the retina. ... The results are really encouraging. We plan to do the first patient within three years ... As a human trial run for the operations, the team has also repaired the vision of four out of 12 patients with the wet form of macular degeneration by moving around their own tissue within the eye." A decade from now, this sort of early regenerative medicine will be commonplace and widely available.
The Telegraph looks at a representative initiative aimed at the targeted elimination of cancer stem cells: researchers "have found a strategy that selectively targets these cancer stem cells for destruction, successfully halting the spread of one of the deadliest cancers - melanoma - in mice. ... Not every cell in a cancer are the same. There is a population of cancer stem cells. But it has never been shown that targeting them can halt tumour growth. This is a very important study when it comes to validating this approach for future treatments ... The team took mice that were growing human tumour cells from melanoma patients, then injected the rodents with monoclonal antibodies - proteins designed only to bind with the ABCB5 protein and thus the melanoma stem cells. They found that this stimulated an immune response that killed tumour cells and significantly inhibited melanoma growth as compared with untreated mice. ... It is of course preliminary and it would be wrong to raise false hopes but many are trying to turn cancer stem cell targetting into therapy."
Your mitochondria are a source of a whole lot of biochemical trouble as the years go by. Damaged mitochondria proliferate in some cells and, like damaged factories, pollute those cell with excess reactive oxygen species and free radicals produced as metabolic byproducts. Each damaged cell then tries to maintain itself by exporting more reactive oxygen species and free radicals from its cell membrane structures, spreading the damaging pollution far and wide in the body. See the Fight Aging! archives for a more detailed explanation:
Free radicals, and reactive oxygen species (ROS) in particular, play an important part in aging. These are (usually small) molecules lacking an electron needed for stability; they will steal an electron from the first thing they bump into. Like pulling a cog out from clockwork, stealing an electron from a protein or enzyme is usually not good for the finely-tuned biochemical machinery of our cells. The free radical might be rendered safe in the process, but it has left some form of chaos and damage in its wake.
So you have the Rube Goldberg system outlined above whereby a few free radicals have caused a cell to become an ongoing, major exporter of free radicals into the surrounding environment.
Free radicals mean damage to molecules and cells, vital processes sabotaged one chemical reaction at a time. Over the years this adds it - it is a part of aging. Repairing or replacing damaged mitochondria is one way to strike at the root of this process, and a number of groups are working on that:
Today our team confirmed our previous preliminary data showing that we can achieve robust mitochondrial transfection ... This achievement has important implications for medicine: protofection technology works in vivo, and should be capable of replacing damaged mitochondrial genomes.
The SENS research program identifies a different and even more fundamental way forward: create a backup in the cell nucleus for specific mitochondrial processes that cause all these problems when damaged.
Mitochondria make energy from food available for cellular processes. To do this they need a small amount of their own DNA. For over 30 years mutations in mitochondrial DNA [mtDNA] have been suspected to be important contributors to aging. If we can incorporate working copies of that mtDNA into our nuclear DNA, the mtDNA will be rendered superfluous and any mutations it suffers will be inconsequential.
Another approach that's out there in the field is to target antioxidant chemicals to the mitochondria, where they can be effective in soaking up some fraction of the excess free radicals before they wreak havoc. Antioxidants in general don't seem to be terribly effective when simply thrown at our biochemistry. While making a difference, targeted antioxidants are clearly only a delaying tactic - as opposed to repair strategies that can be performed indefinitely:
Instead of gene therapy, Skulachev's group has found a viable biochemical strategy for effectively localizing ingested antioxidants in the mitochondria; clever. ... The life time of such mice increased by one third on average as compared to that of the reference group mice.
The concept of targeting chemicals to specific types of cell or specific cellular components is gaining ground in the broader biology and biotechnology research community. A great deal of money is flowing into this field of research. Here's a recent paper illustrating that many more people than just the SENS researchers are very interested in targeting mitochondria, and are actively engaged in engineering new methodologies:
Our approach is based on conjugating nitroxides to segments of natural products with relatively high affinity for mitochondrial membranes. For example, a modified gramicidin S segment was successfully used for this purpose and proven to be effective in preventing superoxide production in cells and [lipid] oxidation in mitochondria.
This is what medicine looks like at the base layer these days - a lot of organic chemistry, building molecules that tweak other molecular machinery in a particular way. Manipulating mitochondria to reduce their contribution to aging and age-related disease is a growth field; you'll be seeing a lot more of it in the years ahead.
An interesting review paper connecting a few previously published links in the chain: "Aging is inevitably associated with a progressive loss of muscle mass and strength, a condition also known as sarcopenia of aging. Although the precise mechanisms underlying this syndrome have not been completely elucidated, recent studies point toward several key cellular mechanisms that could contribute to age-associated muscle loss. Among these, mitochondrial dysfunction and deregulation of apoptotic signaling have emerged as critical players in the onset and progression of sarcopenia. Interestingly, calorie restriction, a well-known antiaging intervention, and, more recently, exercise training have been shown to beneficially affect both mitochondrial function and apoptotic signaling in skeletal muscle from young and old animals. Preliminary observations also indicate that even a small (8%) reduction in food intake may still provide protective effects against sarcopenia and cellular remodeling in aging skeletal muscle, with the advantage of being more applicable to human subjects than the traditional 30-40% restriction regimen." This is the era of understanding - at the deepest level - why good health practices extend healthy longevity.
As we continue to raise awareness and support for healthy life extension science, it is important to expand the public dialog. Some thoughts from researcher Attila Chordash: "One strategy (call it Life Extension Gets Personal) to raise awareness for the idea and technology of healthy life extension is to publicly encourage life extension 'coming outs' on behalf of mainstream celebrities ... As a first target Craig Venter, the genomics pioneer seemed unconventional and free minded enough to approach with the idea of a LE blogterview. On the other hand I found definite signs of his interest in longevity and life extension suggesting that if Craig Venter had been given a technological-medical chance to extend his healthy lifespan significantly he would definitely not like to die due to accumulating functional declines associated with aging within the next, say hundred years. Maybe I am wrong here, maybe I am not but to figure this situation out I translated these signs into the following blogterview questions and tried to contact him in early December, 2007. So far I reached only his nice and diplomatic PR agent, who said that maybe we have a chance to get the blogterview done in the near future." Making this sort of modest effort is more than most people are doing - an excellent initiative.
A thought for the day, from a recent FuturePundit post:
Brain aging is gradual brain damage. Some people think aging is wonderful and natural. That's tantamount to saying that brain damage is wonderful and natural.
While progressive brain degeneration with age is not wonderful, it most certainly is natural - just like anthrax, parasites, suffering, living in caves and having a life expectancy of somewhere south of 30. Our present human condition is, thankfully, far removed from those past natural states. The reason it is far removed from that is, of course, because many, many people have labored to make it so through the advancement of medical science and other enabling technologies. The present human condition deserves its label by virtue of having been manufactured by humans, not because it is something that happens to humans.
We're not done with that manufacturing process, however, not by a long chalk. Anything and everything we don't like about the human condition is up for engineering in the years ahead. The purpose of that engineering is to provide choice: the choice not to live in caves, not to host parasites, not to suffer and die.
People who think aging is wonderful have their heads stuck in the sand; given the choice, almost all would opt to avoid suffering, degeneration and mandatory death by aging on a schedule other than their own. It's a damn shame we don't have that choice today, and so we see people strive to convince themselves that the ugly state of affairs they're stuck with is the best of things. In doing so, however, they shut off discussion about engineering a better future, cutting off their lives to save a little existential angst in the present.
Now that we're entering the era of rapidly advancing biotechnology, and there is a clear path ahead to producing medical technologies capable of rejuvenation of the old, the biggest obstacle to progress is a world of people convinced that aging and dying is the only option - indeed, that it is wonderful and noble. The more people we can win away from that cliff, the faster progress in the science of rejuvenation will advance. At the largest scales and over decades, widespread public support and understanding is what drives research onward.
A good, long introduction to the way in which normal metabolic processes push you into aging and disease can be found at DiabetesHealth. Along the way, the article heaps praise on the practice of calorie restriction, which is usually a good way to know the writer has their head screwed on right: "At first glance, human centenarians would appear to have very little in common with calorie-restricted animals. After all, humans can eat what they want when they want, and many centenarians did just that. There is no evidence that centenarians followed a particular diet or even had particularly healthy life styles. Some centenarians smoked, some did not; some exercised regularly, some did not; and some were careful eaters, and some ate whatever they felt like. Despite the obvious differences, there are some striking similarities between caloric-restricted laboratory animals and free-living centenarians. Centenarians and calorie-restricted animals share a particular bio-metabolic profile that distinguishes them from their peers who die younger and sicker. We now know the common denominators that are found in almost all living beings - whether they are worms, mice, monkeys or humans - that defy the odds and live beyond their expected life span."
Point of Inquiry interviews biomedical gerontologist Aubrey de Grey: "Aubrey de Grey, PhD, is a biomedical gerontologist and Chairman and Chief Science Officer of The Methuselah Foundation. His major research interests are the role and etiology of all forms of cellular and molecular damage in mammalian aging, and the design of interventions to reverse the age-related accumulation of such damage. He has published extensively on these and other areas of gerontology, and is also Editor-in-Chief of Rejuvenation Research, the only peer-reviewed academic journal focusing on intervention in aging. He is the organiser of an ongoing series of conferences and workshops that focus on the key biomedical research relevant to SENS, and he also oversees the Methuselah Foundation's growing sponsorship of SENS research worldwide. In this conversation with D.J. Grothe, Aubrey de Grey explains aging, and the SENS (Strategies for Engineered Negligible Senescence) program that seeks to reverse aging in our lifetime. He explains how his work is, and is not, continuous with 'transhumanism.' He addresses challenges the medical and scientific establishment have brought against his work, and how his project is different than the quackery so widespread in the anti-aging movement. He also discusses some of the social and existential problems that ending aging may create for our civilization."
You've all probably heard about the latest advance in tissue engineering:
The researchers removed all the cells from a dead rat heart, leaving the valves and outer structure as scaffolding for new heart cells injected from newborn rats. Within two weeks, the cells formed a new beating heart that conducted electrical impulses and pumped a small amount of blood.
With modifications, scientists should be able to grow a human heart by taking stem cells from a patient’s bone marrow and placing them in a cadaver heart that has been prepared as a scaffold, Dr. Taylor said in a telephone interview from her laboratory in Minneapolis. The early success "opens the door to this notion that you can make any organ: kidney, liver, lung, pancreas - you name it and we hope we can make it," she said.
Todd N. McAllister of Cytograft Tissue Engineering in Novato, Calif., said, "Doris Taylor’s work is one of those maddeningly simple ideas that you knock yourself on the head, saying, ‘Why didn’t I think of that?’ "
Very clever - and simple, obvious in hindsight, as all the truly clever ideas are. It's a measure of the investment made in regenerative medicine and tissue engineering in the past decade that research groups are beginning to find very promising paths around the complexities involved in growing replacement organs from scratch.
One such complexity is the placement of cells; if you don't happen to have a complete guide to where cells must go, and a map of chemical signals released in various regions of the growing organ, you must perform all that work yourself. How else to guide the cells to form the right sort of tissue in the right place? Blood vessels in particular are a thorny, crucial problem.
Personally, I anticipate much of the work of the next decade will go towards developing the knowledge, techniques, industry and infrastructure to mass produce nanoscale-featured, tailored, biochemical-laced scaffolds for the regrowth of entire organs, ready to be seeded with stem cells. That will still be the course, I've no doubt - but a model to hand in the form of an existing organ turned into such a scaffold will speed the work.
Biology is diversity; while the rule on predation and the evolution of longevity seems to hold for most species, there are always outliers: "mice are low on the food chain and rather likely to meet a bad end; consequently, there’s very little opportunity for genes that enhance longevity to benefit the animal (or even get expressed in the first place). Based on examples of this kind, biologists of aging generally predict that lower extrinsic mortality from predation is a positive influence on the evolution of longevity. Hence, it is surprising that guppies exposed to predation actually appear to live longer (and age more slowly) than similar fish from a similar environment without predators. ... This is an exception to two classical predictions of evolutionary theory: that low extrinsic mortality should be associated with longer life span, and that higher fertility should be associated with shorter life span. Some theorists have tried to accommodate this and other anomalous results within the standard framework, but we argue that the exceptions they carve out do not explain the results at hand. In fact, the findings suggest that population regulation has been selected at the group level, though this is a mechanism that most theorists regard with suspicion."
As noted at Biosingularity, researchers are greatly improving the degree to which they can extend the life spans of simple organisms: "Biologists have created baker's yeast capable of living to 800 in yeast years without apparent side effects. The basic but important discovery, achieved through a combination of dietary and genetic changes, brings science closer to controlling the survival and health of the unit of all living systems: the cell. ... Longo's group put baker's yeast on a calorie-restricted diet and knocked out two genes, RAS2 and SCH9, that promote aging in yeast and cancer in humans. ... We got a 10-fold life span extension that is, I think, the longest one that has ever been achieved in any organism." It is interesting to see methods that are additive - this result in and of itself is going to spur a great deal of combinatory experimentation in mice over the decade ahead, I'll wager.
There are any number of plausible theories as to why women enjoy a longer life expectancy than men. Differing smoking rates, stem cell effectiveness, mitochondrial effectiveness, and the possible effects of hormones on the immune system are all on the list.
Here's another viewpoint - that hormones influence the expression and activity of known longevity genes:
We have shown that the higher levels of estrogens in females protect them against aging, by up-regulating the expression of antioxidant, longevity-related genes such as that of selenium-dependent glutathione peroxidase (GPx) and Mn-superoxide dismutase (Mn-SOD). Both estradiol and genistein (the most abundant phytoestrogen in soy beans) share chemical properties which confer antioxidant features to these compounds.
This antioxidant protection is reflected in the lower peroxide levels found in cells treated with estrogens or phytoestrogens when compared with controls. The challenge for the future is to find molecules that have the beneficial effects of estradiol, but without its feminizing effects. Phytoestrogens or phytoestrogen-related molecules may be good candidates to meet this challenge.
It's never as straightforward as saying that more antioxidants are always a positive thing, of course. It matters greatly where those antioxidants are directed, and how else they affect metabolism. But the present state of biotechnology and biological knowledge is ripe for theorizing - this is a grand era of discovery, barnstorming and experimentation when it comes to the minutae of our biochemistry. It is promising to see so many new papers in aging research leaping directly from "here it is" to "and here is what we could do," even if I might not agree with the importance of the work at hand.
The great curse of aging research in past decades has been the lack of will to manipulate, influence and intervene in aging. With that passivity gone, it's only a matter of time before the best methods of action and progress win out.
Somewhere out there in the world, some few, scattered scientists are working on projects that none of us would recognize, and which will prove vitally important to the future of engineered healthy life extension. Perhaps one of these lines of research will spring directly from the ongoing analysis of metabolism and genetic determinants of human longevity. Perhaps not - I am skeptical on that count. But it always pays to hedge a little against yourself.
If you want to help yourself live a longer, healthier life, you have to keep up with the basics. From EurekAlert!: "Studying a group of healthy, overweight but not obese, middle-aged men and women, the researchers found that a yearlong regimen of either calorie restriction or exercise increase had positive effects on heart function. Their analysis revealed that heart function was restored to a more youthful state so that during the heart's filling phase (called diastole) it took less time for participants' hearts to relax and fill with blood. ... By the end of the yearlong study, both the calorie restriction and exercise groups of volunteers lost 12 percent of their weight and 12 percent of their body mass index (BMI), a measurement considered to be a fairly reliable indicator of the amount of body fat. In both groups, participants' hearts responded to this weight loss by gaining the ability to relax more quickly, recovering some of the elasticity characteristic of younger heart tissue. Those in the calorie restriction group achieved slightly more reduction of heart stiffness. ... By looking at filling function in healthy, non-obese [people], the researchers in the current study were able to understand in more detail how normal hearts react to moderate weight loss."
The Wall Street Journal looks at ongoing research into the secrets of bear biochemistry: "Why don't bears suffer from osteoporosis during hibernation, he asked himself during one wilderness encounter nearly a decade ago? Even a few weeks of inactivity for humans, and most animals, are enough to soften and weaken bones. But bears snooze as much as six months a year and wake up robust and ready to rumble. ... bears have a uniquely potent form of a substance called parathyroid hormone, which helps maintain bones. The ursine version of the substance spurs bone growth when it normally wouldn't occur, offsetting the deterioration that one would expect for a bear snoozing away in the woods. Dr. Donahue's group has sequenced the gene for the bear parathyroid hormone and has had a small amount of it made synthetically. He's applied for a government grant to fund the lab's efforts to insert the gene into bacteria and coax them to produce the substance." It's a fair way from basic research such as this to accurate, safe control over human biochemistry - but that is the end goal.
This paper indicates well why the biochemistry of naked mole-rats is attracting attention, now that more researchers are of the mindset that aging can be successfully - and greatly - manipulated through biotechnology and medical science. If you're intending to improve human biochemistry to enable greater healthy longevity, it makes sense to look at existing examples that are already better in that respect.
Aging refers to a gradual deterioration in function that, over time, leads to increased mortality risk, and declining fertility. This pervasive process occurs in almost all organisms, although some long-lived trees and cold water inhabitants reportedly show insignificant aging. Negligible senescence is characterized by attenuated age-related change in reproductive and physiological functions, as well as no observable age-related gradual increase in mortality rate. It was questioned whether the longest living rodent, the naked mole-rat, met these three strict criteria.
Naked mole-rats live in captivity for more than 28.3 years, approximately 9 times longer than similar-sized mice. They maintain body composition from 2 to 24 years, and show only slight age-related changes in all physiological and morphological characteristics studied to date. Surprisingly breeding females show no decline in fertility even when well into their third decade of life. Moreover, these animals have never been observed to develop any spontaneous neoplasm. As such they do not show the typical age-associated acceleration in mortality risk that characterizes every other known mammalian species and may therefore be the first reported mammal showing negligible senescence over the majority of their long lifespan.
Clearly physiological and biochemical processes in this species have evolved to dramatically extend healthy lifespan. The challenge that lies ahead is to understand what these mechanisms are.
Naked mole-rats are just one of the long-lived species that scientists would like to better understand:
The proposal focuses on three organisms (in order of priority): the naked mole-rat (Heterocephalus glaber) whose record longevity of 28.3 years makes it the longest-lived rodent, the white-faced capuchin monkey (Cebus capucinus) which can live over 50 years, and the bowhead whale (Balaena mysticetus), the longest-lived mammal with an estimated longevity of over 200 years. If approved, these organisms will be added to the queue of target organisms to be sequenced, the sequencing will be carried out in one of the NHGRI-funded sequencing centers, and the entire genome sequences will be deposited in free public databases.
The trend in resources devoted to more goal-oriented aging research will only continue as new science moves the conservative, consensus position towards the feasibility of engineered healthy life extension. Initiatives like SENS that are more promising than metabolic re-engineering - in terms of time to produce results, and the level of life extension that can be plausibly attained - also have the chance to benefit from this growing level of support in the scientific and funding communities.
ScienceDaily summarizes a recent demonstration of the dynamic role TNF-alpha plays in Alzheimer's disease. The full PDF paper is available for those who care to dig deeper. "Normally, TNF finely regulates the transmission of neural impulses in the brain. The authors hypothesized that elevated levels of TNF in Alzheimer's disease interfere with this regulation. To reduce elevated TNF, the authors gave patients an injection of an anti-TNF therapeutic called etanercept. Excess TNF-alpha has been documented in the cerebrospinal fluid of patients with Alzheimer's. The new study documents a dramatic and unprecedented therapeutic effect in an Alzheimer's patient: improvement within minutes." From the abstract: "In addition to its pro-inflammatory functions, TNF-alpha has recently been recognized to be a gliotransmitter that regulates synaptic function in neural networks. TNF-alpha has also recently been shown to mediate the disruption in synaptic memory mechanisms, which is caused by beta-amyloid and beta-amyloid oligomers." You might recall demonstrations in 2006 and 2007 showing mice full of beta-amyloid, but suffering no symptoms of neurodegeneration due to key changes in the mechanisms by which amyloid affects the brain.
Less regulation means greater progress. In medicine, that truism is demonstrated year after year in veterinary science. From ABC News: "You can see that the edges of the bone are very worn away. They're not nearly as smooth ... Facing the possibility of a shortened life for Hunter, the Rihas were considering a $10,000 hip replacement when the doctors offered something new, different and much less expensive. For only about $2,500, they could treat Hunter with his own stem cells, the healing and regenerative cells that live in both humans and animals. ... This is an excellent in-between that may mean he may never need a total hip ... In the race to perfect 'regenerative medicine,' stem cell therapy for animals is ahead of treatment for humans because it is not so strictly regulated. It's not experimental - it's here. ... There are no side effects and no problems with rejection, because the patient is also the cell donor. ... I don't see any reason why humans aren't doing it." There is no reason, beyond wasteful, damaging government restrictions and government employees more interested in pointless rules than progress, health and the lives of others.
You'll recall the klotho gene, and its effects on life span in mice:
The upper bound of life span extension in the study was 30% or so, in the same ballpark as the results of calorie restriction. The association with insulin suggests that both overexpression of Klotho and the gene expression changes caused by calorie restriction may work on an overlapping set of biochemical mechanisms - which certainly shouldn't prevent industrious researchers from trying both at once to see how that goes. I certainly would if I had the funds and a group of gene engineered Klotho mice.
A recent review paper summarizes the present state of knowledge, two years later. More of the field has been filled, but it still looks a lot like the state of calorie restriction biochemistry five years ago. Much more work to come, in other words.
The klotho gene functions as an aging-suppressor gene that extends life span when overexpressed and accelerates aging-like phenotypes when disrupted in mice. The klotho gene encodes a single-pass transmembrane protein
Klotho protein also protects cells and tissues from oxidative stress, yet the precise mechanism underlying these activities remains to be determined. Thus, understanding of Klotho protein function is expected to provide new insights into the molecular basis for aging, [cancer], and stem cell biology.
Regulation of metabolism involves a number of systems that interact in complex ways and that are far from completely understood. But based on the evidence to date, it does not seem unreasonable that many potential beneficial alterations to these systems exist, each capable of extending life span to the same degree as calorie restriction. The results of calorie restriction are, after all, exactly a beneficial alteration to the controlling mechanisms of metabolism.
But is this really the best path forward for aging science? Yes, all this knowledge will be useful, and help to speed many other areas of medical science. You can never know too much. But why try to reengineer metabolism to slow the damage of aging - a result of very limited use to those already old - when it is arguably no harder to work on repairing that damage of aging in the metabolism we have today?
This Telegraph piece is a good summary of the present direction at Sirtris Pharmaceuticals - producing more effective sirtuin activating drugs, and commercializing them as diabetes treatments. From the company: "A strong trend to lowering glucose and statistical significance in improving insulin sensitivity showed the benefits of activating the sirtuin anti-ageing genes to treat a disease of ageing. It is important to note that glucose and insulin are two of the key markers of ageing, and in this study, we seem to be having a positive effect on both. ... SRT501 may represent a promising treatment option for these [diabetic] patients. We look forward to obtaining the results from our other Phase 1b clinical trial and the results from our Phase 2a clinical trial later this year. ... If all goes well, SIRT1 activator drugs could be available on the market as early as 2012 or 2013." This is all a small step in a less productive direction, really, when viewed in the grand scheme of things. Regulators won't permit commercialization of therapies to tackle aging itself, hence the focus becomes patching up preventable, avoidable diseases - rather than doing something truly groundbreaking.
Progressive loss of muscle with age is a problem, and a number of lines of research show promise in engineering a way around that. Here, EureAlert! notes another possible path: "a transient and local rise in an inflammatory signal, the cytokine known as interleukin-6 (IL-6), is essential for the growth of muscle fibers. The findings offer the first clear mechanism for the stem cells' incorporation into muscle and the first evidence linking a cytokine to this process ... As we learn more about how muscles grow in adults, we may uncover new methods for restoring lost muscle mass in the elderly and ill ... IL-6 was produced both within myofibers and in their associated satellite cells, leading to muscle growth. In contrast, the muscles of mice lacking IL-6 did not show any significant increase in size after several weeks of overloading. The researchers also showed that IL-6 exerts its effects by inducing the proliferation of satellite cells. ... Treatments could be designed to compensate for or block the pathways leading to muscle loss. In muscles that have already lost mass, you might also be able to stimulate muscle growth."
The human condition, the biological part of it at least, might be described as a big list of "fix this, or else." For most of human history, fixing was out of the question and thus "or else" was the order of the day. Everyone aged, degenerated and died of critical failure in one or more vital biological systems. Every important component in your body is running down a timer determined by the rate of accumulation of various types of biochemical damage - and of course by the degree to which we step in and either slow or, far better, repair that damage.
Below is an interesting paper of a mindset I think should be encouraged. Given biological system A, what is its life expectancy? How long can we expect it to last, given its characteristics of damage and wear?
The selective decline of individual physiological functions - aging in spare-parts - indicates however the potential limitation of the life-span by the rapid decline of some of the vital parameters. We explored a possibility of such a limitation of maximal life-span by the age-related alteration of elastin, consisting in Ca-accumulation, lipid deposition and elastolytic degradation. The quantitative evaluation of these processes suggests an approximative upper limit for the elastic properties of the cardio-respiratory system of about 100-120 years, at least, as far as elastin is involved.
The technologies of slowing and repairing haven't progressed very far at all down the road of what is possible. Yet. But they will - and viewpoints like that in the paper above encourage more people to think in terms of damage and repair. This is important, because that mindset leads to initiatives and results.
Reversing bulk changes in chemical properties and structure in the body - like the changes that render elastin incapable of its function - is an area in which I would expect to see significant progress sooner rather than later. Once funding and a research community ramps up, that is. This is a situation ideally suited to the present generation of biotechnology: molecules and molecular complexes in state A that you'd rather have in state B - with the complication that your chemical tool for achieving that goal must be safe to put inside people. There are many, many different types of such biochemical changes that we'd like to undo, but each victory is incremental progress, and many research groups can work in parallel.
You might want to take a look at some of these references for more:
The Times Online is running an article on calorie restriction (CR) and its practitioners - suffering somewhat from the outsider looking in, per usual. "The problem with CR studies is that the majority have been done in short-lived animals like rats. Primates are more difficult to study as less is known about their nutrition and they live relatively long lives. A rhesus monkey can live 40 or 50 years in captivity, even without CR. ... Comparing the mice, monkey and human studies should give him a clearer picture of how, and if, CR works in humans. ... It's advantageous for mice to switch to a high reproductive gear in the season of plenty. Come winter it is better to switch that off because you don't want a lot of offspring when you have less food, body fat and energy ... In the wild, CR - a lack of food - helps animals get through winter so they can breed in spring. ... CR seems to switch down that sex drive (anecdotally more so in men) [and] diverts the body's energies elsewhere into a broad set of maintenance activities. The byproduct may be life extension."
EurekAlert! summarizes the results of a recent PLoS Medicine study: "People who adopt four healthy behaviours - not smoking; taking exercise; moderate alcohol intake; and eating five servings of fruit and vegetables a day - live on average an additional fourteen years of life compared with people who adopt none of these behaviours ... After factoring in age, the results showed that over an average period of eleven years people with a score of 0 - i.e. those who did not undertake any of these healthy forms of behaviour – were four times more likely to have died than those who had scored 4 in the questionnaire. Furthermore, the researchers calculate that a person who has a health score of 0 has the same risk of dying as someone 14 years older who had scored 4 in the questionnaire (i.e. someone engaging in all four healthy forms of behaviour)." The cost of harming yourself, or indeed even of just failing to take care of the health basics could be very large indeed, given the prospects for the repair of aging in the future. Ten years might be the difference between living to benefit from healthy life extension technologies, or missing that boat entirely.
A nice post from Chris Patil at Ouroboros; good explanations by an aging researcher are not so far removed from good advocacy for longevity research:
Over the weekend I had a novel experience: my first presentation about the biology of aging to an audience consisting entirely of non-scientists. ... Rather than drill down into technical details, I decided to use my five minutes to motivate the problem: Why should people care about biogerontology?
Surprisingly, comprehensive cures for all heart disease, stroke, diabetes and cancer are predicted to have rather modest effects on average lifespan (e.g., see Olshansky et al.). Such cures, in any event, are still far away even after years of study. Aging is the primary risk factor for these (and many other) diseases; as a relatively new science, biogerontology holds greater promise for near-term radical improvements in healthspan. The Olshansky projections really blew them away, especially when coupled with a few words about the longevity increases we’ve achieved with single-gene changes and dietary restriction in model organisms. Then I showed a pie chart comparing the NIH funds spent on diseases to those spent on basic aging research. Gasps.
There is very little research into aging versus diseases of aging. There's more; read the rest. Patil and I are somewhat distant on the eternal debate of government funding versus not, but no surprise there. I'd cheerfully see an end to the distortions placed upon medical research by government funding and regulation. For example, aging is not considered a disease, and therefore no treatment will ever be approved by regulators. Wonder why all the research investment goes to the diseases of aging instead? There's your reason. It is a great evil, a great net loss to our future:
At the moment, right this instant, the system is broken. The very fact that we have "a system" is a breakage; that entrepreneurs are held back from investment by rules and political whims that are now held to be of greater importance than any number of lives. That decisions about your health and ability to obtain medicine are made in a centralized manner, by people with neither the incentives nor the ability to do well.
As is always the case, the greatest cost of socialism in medicine lies in what we do not see. It lies in the many billions of dollars presently not invested in medical research and development, or invested wastefully, because regulations - and the people behind them, supporting and manipulating a political system for their own short term gain - make it unprofitable to invest well. Investment is the fuel of progress, and it is driven away by self-interested political cartels.
Waste, of time and resources, is inevitable and endemic in any venture undertaken by government - and time is something we have little of. We should all care greatly about biogerontology, because, if nurtured and supported, this science and research community holds the promise of many more years of healthy life for all. Equally, we should all care about the government rules, regulators and enforcers that are killing that promise dead, year after year after year.
ScienceDaily looks at the work of a German group in the tissue engineering field: "We pluck a few hairs off the back of the patient's head and extract adult stem cells from their roots, which we then proliferate in a cell culture for about two weeks. Then we reduce the nutrient solution until it no longer covers the upper sides of the cells, exposing them to the surrounding air. The increased pressure exerted by the oxygen on the surfaces of the cells causes them to differentiate into skin cells ... In this way, the researchers can grow numerous small pieces of skin, produced individually for each patient, which add up to a surface area of 10 to 100 square centimeters when pieced together. ... The researchers expect to grow skin grafts for 10 to 20 patients a month in 2008. ... At present, chronic wounds are treated by grafting on the patients' own skin, which is normally taken from the thigh. This leaves scars on both the thigh and the treated wound ... we can achieve the same chances of recovery without hurting the patient. Moreover, the artificial skin grows onto the wound without scarring."
Thoughts on the Methuselah Mouse Prize for longevity research from the Economist: "To encourage people to take his ideas seriously, Aubrey de Grey, the originator of the strategies for engineered negligible senescence, has organised a competition. He is offering a prize for the development of what he calls a Methuselah mouse. There are actually two prizes to be had. One is for longevity, the other for rejuvenation. The prize for longevity can be won by a new strain of mouse - one bred or genetically engineered to live a long time. That for rejuvenation requires treatment to begin when the mice are already in middle age. ... The winner establishes a record that others have to break. At the moment the records for longevity and rejuvenation are five years and almost four in an animal that normally lives for three. How translatable the lesson of a Methuselah mouse will be to people is a matter of debate. ... The reason mice age rapidly is that they have lots of predators and would get killed quickly anyway. Humans have few predators and tend not to get killed - at least not as easily as mice. It is therefore worthwhile for people to evolve better repair mechanisms than mice, and thus to age more slowly." Nonetheless, radical life extension in lesser mammals is an important step along the way - not just as a proving ground for the science, but as a way of educating the public as to the degree to which aging can potentially be reversed in humans.
Exercise is much like calorie restriction in its effects on biochemistry - overwhelmingly beneficial, when compared against those who don't keep up the effort. Everywhere that scientists look more closely at our biochemistry, it seems, they find some positive change for having maintained a modest regimen of exercise:
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.
Here's another example from recent research:
Reactive oxygen species production increases during aging, whereas protective mechanisms such as heat shock proteins (HSPs) or antioxidant capacity are depressed. Physical activity has been hypothesized to provide protection against oxidative damage during aging, but results remain controversial. This study aimed to investigate the effect of different levels of physical activity during aging on Hsp72 expression and systemic oxidative stress at rest and in response to maximal exercise.
The key finding of this study is that, in people aged 60 to 90 years, long-term high level of physical activity preserved antioxidant capacity and limited oxidative damage accumulation. It also downregulated Hsp72 expression, an adaptation potentially resulting from lower levels of oxidative damage.
These things add up. Every extra year of healthy life you engineer for youself the old-fashioned way is an extra year in which you can benefit from future advances in biotechnology and longevity medicine. Helping to make those years possible now is an investment that will pay an impressive return.
Many extremely long-lived animal species exist, and some may even be ageless. How can evolution, biased to early reproductive success at all reasonable cost, produce such a species? Some modelling in this paper: "Senescent aging is an irreversible deterioration in physiological condition with age, which many organisms express even when removed from harmful environmental influences. The inevitability of senescence for repeatedly reproducing organisms has well-developed theoretical foundations. Since reproduction carries physiological costs, natural selection in a hazardous environment favors reaping early benefits, and delaying the cost in physiological decline until later in life when there is a greater chance of being dead from exogenous factors. But some organisms show negligible senescence, and a few, such as Hydra and the Bristlecone Pine, appear to have indefinite lifespans. We ask how such species could have evolved from ancestors with senescent life histories. In large populations, juveniles attempting recruitment into the adult population can be 'crowded out' by already established adults. We show how this phenomenon can trigger a process of runaway selection on ever-reducing senescence, which can even result in the evolution of intrinsic immortality." There are good arguments for learning more about the biology of longevity in species near and far from humans.
The Economist looks at the Strategies for Engineered Negligible Senescence (SENS) and other longevity research: "To think about the question, it is important to understand why organisms - people included - age in the first place. People are like machines: they wear out. That much is obvious. However a machine can always be repaired. A good mechanic with a stock of spare parts can keep it going indefinitely. Eventually, no part of the original may remain, but it still carries on, like Lincoln's famous axe that had had three new handles and two new blades. ... All organisms are going to die of something eventually. That something may be an accident, a fight, a disease or an encounter with a hungry predator. There is thus a premium on reproducing early rather than conserving resources for a future that may never come. The reason why repairs are not perfect is that they are costly and resources invested in them might be used for reproduction instead. Often, therefore, the body's mechanics prefer lash-ups to complete rebuilds - or simply do not bother with the job at all. And if that is so, the place to start looking for longer life is in the repair shop."
We'd all like to see more funding for our favored longevity research. Yours may not be SENS, the Strategies for Engineered Negligible Senescence, but mine is. Engineers skip the unnecessaries and get right to the crux of the matter - getting the job done:
SENS is a detailed plan for curing human aging. SENS is an engineering project, recognising that aging is a medical condition and that medicine is a branch of engineering. Aging is a set of progressive changes in body composition, at the molecular and cellular level, which are side-effects of essential metabolic processes. Many of these changes are eventually bad for us -- they are an accumulation of damage, which becomes pathogenic above a certain threshold of abundance.
The traditional gerontological approach to life extension is to try to slow down this accumulation of damage. This is a misguided strategy, firstly because it requires us to improve biological processes that we do not adequately understand, and secondly because it can even in principle only retard aging rather than reverse it. An even more short-termist alternative is the geriatric approach, which is to try to stave off pathology in the face of accumulating damage; this is a losing battle because the continuing accumulation of damage makes pathology more and more inescapable.
Instead, the engineering (SENS) strategy is not to interfere with metabolism per se, but to repair or obviate the accumulating damage and thereby indefinitely postpone the age at which it reaches pathogenic levels. This is practical because it avoids both of the problems with the other approaches: it sidesteps our ignorance of metabolism (because it does not attempt to interfere with metabolic processes and their production of side-effects) but also it pre-empts the chaos of pathology (because it repairs the precursors of pathology, rather than addressing the pathology head-on).
Stop to think about that: we can defeat aging in the future, utterly and comprehensively. The door is open, the path is there. The science is laid out ahead of us, no obstacles from the laws of physics or chemistry in our way. It's all just a matter of work and will - a lot of work and will.
Research and development costs money, of course. Either we pay for a future that includes medical technology to repair aging or we moulder down the slow road of suffering to a painful death, just the same as every past generation. We have the option of doing better than that, and it'll be a damn shame if we let it slip away through the normal combination of cluelessness, unthought conservatism, laziness and general lack of nous.
Where do resources for research originate? From the wealth of those who step up to make a difference. Those who strive to improve the lot of longevity research are faced with a fairly simple economic choice whenever we would like to pour more wealth into the pot, to help more hands make progress arrive more rapidly. Do we work to create that needed wealth, or do we work to persuade those with wealth to invest in research that will benefit their future health and longevity? How long will each path take? What is the likelihood of success in either case? I can assure you that even if you don't think that you think about these things, you do. We are all creatures of rational economic action, at every level of choice from persuading a friend versus chipping in a dollar yourself up to making investments to grow capital versus raising funds from investors and philanthropists.
I believe it is hard to argue against the proposition that time spent on persuading wealth to fund research is better used than time spent on creating wealth to fund research. The amount of wealth in the world donated to research each year is massively greater than any individual can expect to create for themselves, and the level of wealth that lies unpersuaded and unallocated to any cause is far greater still. So many people focus on creating wealth that it is hard to see any shortage appearing in that camp due to the oomparative few who divert their efforts towards advocacy for philanthropy.
The only potent argument that springs to mind is the miserable past history of successful persuasion when it comes to meaningful levels of philanthropic funding for longevity research. Caution and conservatism increases with the number of digits on the check, and one might argue that creating and donating wealth is a form of persuasion itself in the early years. Certainly the Methuselah Foundation would not be where it is today, seeking more seven-figure sums from philanthropic sources, without thousands of modest donations from supporters over the years. Those folk put their seal of approval upon the Mprize for longevity research and the SENS research program, giving the Foundation's work valuable legitimacy in the marketplace of ideas.
Still, it is an open topic for discussion, with a right answer for each individual. Building wealth to help buy more years of life, or working to spread awareness of this era of potential in longevity science?
Globes Online gives good insight into one of the more active areas at the commercial end of tissue engineering research. Scaffold technology is maturing in a number of directions, including this one: Regentis' "replacement cartilage does not include live cells. In fact, it has expunged the tissue itself from the underlying concept behind its alternative tissue. Instead, it has formed a form of interim synthetic bridge which when applied to the injured limb, allows natural tissue to grow and regenerate. The company regulates the rate of the synthetic product's disintegration, in tandem with the growth of natural tissue. ... When body tissue has been damaged, a blood clot is usually formed which also acts a bridge for the building of new tissue and sends a signal that promotes tissue building. The problem occurs when the damage is too extensive and the blood clot can't create the bridge. Once that happens it disintegrates fairly quickly ... the implant can last for up to a year without breaking down. It is very much like the process of coating drugs with synthetic materials to enable a slow release."
Parkinson's disease researchers have been expanding their understanding of - and interfering in - processes that involve alpha-synuclein. EurekAlert! here looks at some of the important mechanisms of autophagy in this context: "Alpha-synuclein molecules modified by dopamine bound tightly to the lysosomal membrane, but they got stuck there and weren't effectively transported into the lysosome ... As a result, the alpha-synuclein molecules altered by dopamine were poorly degraded, and the presence of these molecules on the lysosomal membranes interfered with autophagic digestion of other compounds as well. ... We propose that inhibition of autophagy caused by dopamine's alteration of alpha-synuclein could explain the selective death of dopamine-producing nerve cells in Parkinson's disease ... interference with autophagy has also been implicated in other neurodegenerative diseases including Alzheimer's." One thread of the Strategies for Engineered Negligible Senescence (SENS) is devoted to repairing or preventing the failure of the lysosome under load - it is a broad problem that contributes to many age-related conditions.
Here's a little experimental work to remind us all that, whatever the apologists for an abundance of body fat might like to be the case, it's just not good for health and longevity over the long term:
Aging is associated with increases in fat mass (FM) and decreases in fat-free mass (FFM) that may affect physical capacity. However, it is not clear whether high FM or low FFM contribute more to a reduction in physical capacity.
our results showed that percentage of FM was significantly associated with physical capacity (p <.01), whereas no such association was observed with FFM. Other variables such as physical activity level, number of self-reported diseases, and age were associated with physical capacity (all p <.01).
FM was significantly and inversely correlated with physical capacity, whereas FFM was not associated when controlled for other potential confounding variables.
There's a more than reasonable weight of science behind the bad things that excess fat cells do to your metabolism - such as act as a source of chronic inflammation, continually generating damage at the cellular and biochemical level that your body cannot repair. That's not even to talk about what "reduction in physical capacity" and the resultant lack of exercise does for your prospects:
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.
Letting years of future health slide away through simple negligence of the basics is a choice; many people make it. It just doesn't seem the smartest way forward.
Here we are again, those of us who made it, a year older and a year more experienced; another swing round the sun completed. We are somewhat more damaged by the workings of our metabolisms and biochemical happenstance, that much closer to catastrophic failure of one of the many intricate biological systems we depend upon. I hope we've managed to use that time well - it passes us at great cost, when considering what it will take to create more of it.
You did know that we're early in the era of being able to buy time - years of health - with money, right? That's what investment in the most plausible longevity research is, in essence. Pay now for the therapies that will result in the decades ahead. No different in concept to investing for a comfortable retirement - but the payoff is enormously larger in scope.
But to the title of this post: what was the most important thing that happened in 2007? To be sure, the scientific community has turned out ten thousand new facts, theories, promising avenues of research, technology demonstrations - and more - that will prove relevant to a future in which aging is conquered by biotechnology. "Important" doesn't have to mean "beneficial," however. The most important thing that happened in 2007 is that somewhere in the vicinity of 40 million people lost their lives to aging. Looking back to comparable years - and all recent years are comparable years - we see:
Each one of us carries within us a complex universe of knowledge, life experience, and human relationships. Each individual is gifted with unique insights possessed by no one else. Almost all of this rich treasury of information is forever lost to mankind when we die. This lost treasury is truly enormous. If the vast content of each person's life can be summarized in just one book, then every year, natural death robs us of 52 million books, worldwide. But the U.S. Library of Congress, the world's largest collection of physical books, holds only 18 million volumes. So each year, we allow a destruction of knowledge equivalent to three Libraries of Congress.
It is as if in 2001, somebody burned the Library of Congress to the ground. Once in January. Then again in May. Then again in September. 52 million books go up in flames. And then in 2002, they burn it down again. Three more times. And then again in 2003.
If we conservatively assume that the population age structure and the age-specific mortality is the same worldwide as in the United States, then the worldwide natural death toll of 52 million people in the Year 2001 represents an economic loss of about $100 trillion dollars. Every year.
How big of an economic calamity is this? Taking Federal Reserve figures for the total tangible wealth of the United States, including all financial assets, all real estate, and all consumer durables, net of debt, and applying the ratio of U.S. to world GDP gives us an estimate of total global tangible net worth of $91 trillion dollars. So this means that every year, natural death robs us of human capital equivalent in value to the entire tangible wealth of the world.
Nothing else that takes place in our world even begins to compare in impact to the end result of aging, a process we can now envisage bringing to an end through medical science. The cost of aging will be the most important happening of 2008 - and so too in every future year until we can rescue people from suffering and the degeneration of their biology. All else that took place in 2007 and all that will take place in 2008 is a shuffling of the deckchairs on the Titanic. Never forget that.
From the Methuselah Foundation, news of more support for research aimed squarely at repairing the biological damage of aging: "I'm happy to report that December 2007 year-end donations to fund the Methuselah Foundation's Strategies for Engineered Negligible Senescence (SENS) research program succeeded in matching two consecutive $25,000 matching grants from Michael Cooper and Doug Arends. ... Looking to the year ahead, and plans for expansion into new branches of SENS research, Foundation supporter Ryan Scott has set up a $100,000 matching fund for all research donations made in 2008. The same rules apply as for this past December: donations are first matched 100% by Ryan's fund, and then that total is matched again at 50% by Peter Thiel's $3 million matching fund. That means that all your SENS research donations will be tripled - a $100 donation becomes $300 for new research into longevity medicine. Jump on in! These are the early years in a steep growth curve - and it's up to all of us to help make that statement true. Donations to help bring about a future of greater health and longevity can be made at the Methuselah Foundation website, where you can also learn more about how funds are spent and the results achieved to date."
To what degree does accumulated DNA damage contribute to the aging of stem cells? (Versus, say, changes in their niche or other potential causes). From this freely available review paper: "Adult stem cells are extremely important in the long-term maintenance of tissues throughout life. They regenerate and renew tissues in response to damage and replace senescent terminally differentiated cells that no longer function. Oxidative stress, toxic byproducts, reduced mitochondrial function and external exposures all damage DNA through base modification or mis-incorporation and result in DNA damage. As in most cells, this damage may limit the survival of the stem cell population affecting tissue regeneration and even longevity. ... a number of human genetic abnormalities associated with aging, and those replicated in the mouse, suggest that loss of DNA repair may contribute to the aging process. This review will provide support for the argument that maintenance of the adult stem cell genome through robust DNA repair is fundamental in the prevention of aging and disease; furthermore, that failure of genomic maintenance is a leading cause of cancer, as well as senescence."