An Update on Progeria Research

Hutchinson-Gilford Progeria Syndrome (HGPS, or just "progeria") is perhaps the best known of the accelerated aging conditions. Considerable progress has been made over the past decade in uncovering the biochemical mechanisms of this disease, and in the process it has come to seem plausible that a viable therapy for progeria may have some modest use in tackling normal aging as well. The same follows for other accelerated aging conditions, meaning that it's worth keeping an eye on this field of medical research.

With this in mind, here is an open access paper that outlines some of the latest advances in progeria research. Matters look a lot closer to a viable therapy than they did a few years back, and studies continue to show that the changing biology of normal aging shares - to a lesser degree - some of the unwanted biochemical signatures of progeria:

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare premature aging disorder caused by a [mutation within the] LMNA gene encoding A-type nuclear lamins. [Nuclear lamins are fibrous proteins providing structural function and transcriptional regulation in the cell nucleus.]


We analyzed global gene expression changes in fibroblasts from human subjects with HGPS and found that a lamin A-Rb signaling network is a major defective regulatory axis. Treatment of fibroblasts with a protein farnesyltransferase inhibitor reversed the gene expression defects. Our study identifies [tumor suppressor protein] Rb as a key factor in HGPS pathogenesis and suggests that its modulation could ameliorate premature aging and possibly complications of physiological aging.


Because the lamin A-Rb interaction is a new signaling axis in the pathogenesis of HGPS, we investigated its potential role in physiological aging. We found that LMNA and RB1 expression appeared to be inversely modulated in the elderly. These observations were similar to our findings in cells from subjects with HGPS. Although lamin A and lamin C levels were not altered, an abnormal prelamin A variant, progerin, is expressed and Rb expression is decreased. In addition to changes in the expression of A-type lamins, several studies suggest that abnormal prelamin A may accumulate in normal aging . Our results, therefore, suggest that therapeutic approaches to re-establish a proper lamin A-Rb signaling network may be beneficial in preventing complications of physiological aging.

At this stage it is unknown to what degree the observed changes in lamins in the elderly contribute to the degenerations of aging. It is certainly the case that an accumulation of damaged or malformed proteins of all sorts is noted in aging; the lamins may or may not be significant in comparison to others. But the right approach to aging is to work towards reversing all changes that cannot be positively identified as secondary effects: aim to repair and restore every fundamental change.

ResearchBlogging.orgMarji J, O'Donoghue SI, McClintock D, Satagopam VP, Schneider R, Ratner D, J Worman H, Gordon LB, & Djabali K (2010). Defective lamin A-Rb signaling in Hutchinson-Gilford Progeria Syndrome and reversal by farnesyltransferase inhibition. PloS one, 5 (6) PMID: 20559568

Are Old Stem Cells Less Useful?

Researchers are gathering evidence to suggest that stem cells from the old are less useful when transplanted - which means that some form of repair or other manipulations may need to be included in future stem cell therapies for the degenerative conditions of aging: "Clinical trials of cardiac cell therapy have indicated limited benefits in aging patients, even though preclinical studies using young animals consistently reported significant improvements. Animal studies have demonstrated reduced efficacy of donor cells isolated from older individuals. Here, we evaluated the effects of donor age on the function of human mesenchymal stem cells (hMSCs) in the context of cell therapy for ischemic cardiomyopathy. ... The regenerative capacity of hMSCs was significantly influenced by age. Transplanting young hMSCs improved functional outcomes after an MI by preventing matrix degradation and promoting angiogenesis. The clinical implication is that aged patients require an optimized source of stem cells for treatment."


Contemplating the Crayfish

Crayfish species, like lobsters, appear not to age in any easily measurable way. As for the study of other long-lived species, perhaps there is something to be learned here: "The marbled crayfish is an emerging laboratory model for development, epigenetics and toxicology that produces up to 400 genetically identical siblings per batch. It is easily cultured, has an adult size of 4-9 cm, a generation time of 6-7 months and a life span of 2-3 years. Experimental data and biological peculiarities like isogenicity, direct development, indeterminate growth, high regeneration capacity and negligible senescence suggest that the marbled crayfish is particularly suitable to investigate the dependency of ageing and longevity from non-genetic factors such as stochastic developmental variation, allocation of metabolic resources, damage and repair, caloric restriction and social stress. It is also well applicable to examine alterations of the epigenetic code with increasing age and to identify mechanisms that keep stem cells active until old age. As a representative of the sparsely investigated crustaceans and of animals with indeterminate growth and extended brood care the marbled crayfish may even contribute to evolutionary theories of ageing and longevity. Some relatives are recommended as substitutes for investigation of topics, for which the marbled crayfish is less suitable like genetics of ageing and achievement of life spans of decades under conditions of low food and low temperature. Research on ageing in the marbled crayfish and its relatives is of practical relevance for crustacean fisheries and aquaculture and may offer starting points for the development of novel anti-ageing interventions in humans."


The Mess of Modern Medicine

We live in an age in which personal accountability is a distant, unpracticed concept. It is taken for granted that every possible personal decision is open to socialization, and that any cost might be paid for by some distant other. People follow incentives, and when the incentives have been structured so as to eliminate the need for frugality, then waste and corruption inevitably follows. This is the rot that slays civilizations, and it will destroy the American empire just as surely as it did the British Empire and Rome.

We can see this corrosion underway most clearly in the centralized medical command and control infrastructures of the Western world. Unlike almost all other areas of technology, costs in medicine keep spiraling upward - and this should not be a surprise given the perverse incentives embedded in the system. Costs paid by other people. Services divorced from price considerations by the customer. Lack of competition. Use of regulators and the legalized bribery of lobbying to gain advantage in the marketplace, rather than research and development or price-cutting. And so forth.

But people know what they grew up with, and are exceedingly wary of change. Even when the long-established situation is terrible, as is the case for provision of medicine in most developed nations, the vast majority cannot see beyond its walls. So you'll find articles like this recent example, in which an presumably intelligent person argues that fixing the problems of socialized medicine requires the application of more socialism: more central command and control direction of economic behavior, more spending of other people's money, more separation between buyer, competition, and pricing.

There is a very simple solution to the problems of medicine. It's called freedom: freedom for providers to develop and compete as they see fit, and freedom for people to choose or reject their offerings with the money in their own pockets and savings accounts. For progress and efficiency to reign in an industry, people have to pay for goods with their own funds, and providers have to be free to innovate. Competition and the care with which people manage their own money keeps both sides as honest as any human culture is going to be.

Look at fashion. Shoes. Computers. DNA sequencing. Or any one of a thousand other important goods whose value has fallen over time and continues to do so. These are less regulated markets, not stifled and buried beneath chains like the provision of medicine. They are vibrant, constantly innovating and competing, and this is exactly because people pay for these products with the money they care about most.

If you want stagnation, terrible services, sanctioned cheating, and eventual collapse, then continue right on down the path forced on medical development and provision today: forcefully take people's money as taxes, throw it into a big pool, pay lip service to the proposed goals, and then watch the connected and the adept at bribery fight over claiming that loot for their own purposes. Every faction and individual is incentivized to take what they can grab, whilst trying to force other hands out of the purse. Pools of resources held in common are the death of charity: the sort of vicious infighting over a commons is anti-charity, the very polar opposite of charity in the spectrum of human behavior.

In short, government corrodes all it touches, and the rot has run deep in medical research, development, and commercialization. We all suffer for that, and will continue to do so until such time as revolution takes place to usher in a new age of honest competition and choice.

Progress Towards Understanding Memory

Understanding the physical basis of human memory will enable therapies to both enhance youthful memory and reverse its decline with age. From ScienceDaily, an example of present investigations into the biology of memory: "We found one of the key proteins involved in the process of memory and learning. This protein is present in the part of the brain in which memories are stored. We have found that in order for any memory to be laid down this protein, called the M3-muscarinic receptor, has to be activated. We have also determined that this protein undergoes a very specific change during the formation of a memory - and that this change is an essential part of memory formation. In this regard our study reveals at least one of the molecular mechanisms that are operating in the brain when we form a memory and as such this represents a major break through in our understanding of how we lay down memories. This finding is not only interesting in its own right but has important clinical implications. One of the major symptoms of Alzheimer's disease is memory loss. Our study identifies one of the key processes involved in memory and learning and we state in the paper that drugs designed to target the protein identified in our study would be of benefit in treating Alzheimer's disease."


More on Ovaries and Longevity in Mice

Another study to show that transplanting young ovaries into old mice extends life quite significantly: "successful ovarian transplants increased the lifespan of the mice by more than 40% ... All the mice in both experiments that had received transplants resumed the normal reproductive behaviour of young mice. They showed interest in male mice, mated and some had pups. Normally, old mice stay in the corner of the cage and don't move much, but the activity of mice that had had ovarian transplants was transformed into that of younger mice and they resumed quick movements. Furthermore, the lifespan of the mice who received young ovaries was much longer than that of the control mice: the mice that had received two ovaries lived for an average of 915 days, and the mice that had received one ovary, for an average of 877 days. The newest of our data show the life span of mice that received transplants of young ovaries was increased by more than 40%. ... The average normal lifespan for this particular breed of mice [is] 548 days. ... it was not known why the ovarian transplant increased the lifespan of the mice, but it might be because the transplants were prompting the continuation of normal hormonal functions."


Regeneration of Tooth Enamel: Cavities Healed in Mice

Dental researchers are forging ahead with their branch of tissue engineering and regenerative medicine. It hasn't been long since engineered growth in situ of replacement teeth was demonstrated in rats, and now a research group has shown they can regenerate tooth enamel in mice, thereby healing cavities:

A new peptide, embedded in a soft gel or a thin, flexible film and placed next to a cavity, encourages cells inside teeth to regenerate in about a month ... The gel or thin film contains a peptide known as MSH, or melanocyte-stimulating hormone. Previous experiments [showed] that MSH encourages bone regeneration. Bone and teeth are fairly similar, so the French scientists reasoned that if the MSH were applied to teeth, it should help healing as well. To test their theory, the French scientists applied either a film or gel, both of which contained MSH, to cavity-filled mice teeth. After about one month, the cavities had disappeared.

You can also take a look at the research paper if interested, though it's fairly dense. It is an excellent example of what can be achieved where materials science meets biotechnology and the life sciences, and overall a very encouraging proof of concept. It is reasonable to expect, based on the progress of the past few years, that by the time those of us in middle age now begin to experience serious issues of wear and breakage with our dentistry, the technology to regenerate and regrow teeth will be well developed and widely available.

ResearchBlogging.orgFioretti, F., Mendoza-Palomares, C., Helms, M., Al Alam, D., Richert, L., Arntz, Y., Rinckenbach, S., Garnier, F., Haïkel, Y., Gangloff, S., & Benkirane-Jessel, N. (2010). Nanostructured Assemblies for Dental Application ACS Nano, 4 (6), 3277-3287 DOI: 10.1021/nn100713m

More Decellularized Lungs Demonstrated

Following on from a demonstration of decellularized rat lungs, another team has produced similar work: "Researchers have been able to create tiny mouse lungs in the lab that are able to breathe. The lungs were created with stem cells and attached to a ventilator. ... They used a technique called decellularization, similar to the method used to create a beating mouse heart in a different lab at the University of Minnesota in 2008. In the cancer center, they took a mouse lung and stripped away all its cells. Then, injected the natural framework with stem cells. At first they used fetal mouse lung cells, but this year they had another breakthrough using adult stem cells called 'induced pluriopotent stem cells.' ... That's basically a cell that we can take from anybody and re-program to act like an embryonic stem cell ... The hope is one day human lungs could be re-created for transplant with a greater chance of success. Right now, there is no tissue matching for lung transplants. ... The beauty of that is that you can then create a tissue for an organ that's transplantable that is derived from the patient and therefore would not be recognized as foreign by the immune system and not rejected. By adding the ventilator to make the lungs breathe, the stem cells are further trained to act like lung cells. It's a huge success considering lungs are such complicated organs with some 60 different kinds of cells."


The State of Mitochondrial Medicine

A review paper: "Mitochondrial disorders can no longer be ignored in most medical disciplines. Such disorders include specific and widespread organ involvement, with tissue degeneration or tumor formation. Primary or secondary actors, mitochondrial dysfunctions also play a role in the aging process. Despite progresses made in identification of their molecular bases, nearly everything remains to be done as regards therapy. Research dealing with mitochondrial physiology and pathology has [greater than 20 years] of history around the world. We are involved, as are many other laboratories, in the challenge of finding ways to fight these diseases. However, our main limitation is the scarcety of animal models required for both understanding the molecular mechanisms underlying the diseases and evaluating therapeutic strategies. This is especially true for diseases due to mutations in mitochondrial DNA (mtDNA), since an authentic genetic model of mtDNA mutations is technically a very difficult task due to both the inability of manipulating the mitochondrial genome of living mammalian cells and to its multicopy nature. This has led researchers in the field to consider the prospect of gene therapy approaches that can roughly be divided into three groups: (1) import of wild-type copies or relevant sections of DNA or RNA into mitochondria, (2) manipulation of mitochondrial genetic content, and (3) rescue of a defect by expression of an engineered gene product from the nucleus (allotopic or xenotropic expression)."


Another Illustration as to Why There Will Be Many, Many Genetic Contributions to Longevity

As I mentioned not so long ago, there will most likely prove to be a great many subtle and overlapping genetic variants of human longevity. However, very few of them will be important in the sense that they will lead to ways to significantly increase human life span through new medicine. The effective way to greatly increase human longevity is to learn to repair the biochemical damage of aging, not to tinker with metabolism to slow down the rate at which damage occurs.

In any case, here is an excellent illustration as to why there will be thousands of genetic variations that contribute to human longevity: the effects on life expectancy of known single gene variants may be enhanced or diminished by other variations that do not themselves directly contribute to longevity. Combinations of genetic variants are probably just as important as single gene differences, in other words:

The search for longevity-determining genes in human has largely neglected the operation of genetic interactions. We have identified a novel combination of common variants of three genes that has a marked association with human lifespan and healthy aging.


Haplotype analysis was performed in three candidate genes, and the haplotype combinations were tested for association with exceptional longevity. An HRAS1 haplotype enhanced the effect of an APOE haplotype on exceptional survival, and a LASS1 haplotype further augmented its magnitude. ... this combination of gene variants is associated with healthy aging. The variation in LASS1 is functional, causing enhanced expression of the gene, and it contributes to healthy aging and greater survival in the tenth decade of life. Thus, rare gene variants need not be invoked to explain complex traits such as aging; instead rare congruence of common gene variants readily fulfills this role.

We humans have a lot of genes, which means there is a very, very large number of potential interactions between gene variants - even within a subset of genes associated with a specific biological system. Discovery and understanding in the face of this complexity represents an enormous amount of work, which is one of the reasons that researchers who favor the metabolic manipulation approach to aging believe that we are a long way from any significant slowing of aging or extension of the healthy human life span.

This is why those of us who want to see that progress happen in our lifetimes should favor approaches like Aubrey de Grey's SENS: don't try to find, test, and debug ways to alter human metabolism, but rather work on repair technologies that can remove the known forms of biochemical damage that build up in the metabolism we have now.

ResearchBlogging.orgMichal Jazwinski S, Kim S, Dai J, Li L, Bi X, Jiang JC, Arnold J, Batzer MA, Walker JA, Welsh DA, Lefante CM, Volaufova J, Myers L, Joseph Su L, Hausman DB, Miceli MV, Ravussin E, Poon LW, Cherry KE, Welsch MA, & for the Georgia Centenarian Study and the Louisiana Healthy Aging Study (2010). HRAS1 and LASS1 with APOE are associated with human longevity and healthy aging. Aging cell PMID: 20569235

The Youth Pill

A new popular science book on the manipulation of metabolism to slow aging, the author inspired by the Longevity Dividend initiative: "No scientific advances inspire more media hype than ones in gerontology, the study of aging. Even the crustiest editors have been known to turn giddy when new light is shed on the topic and take to blowing raspberries at the Reaper with headlines suggesting immortality elixirs are just around the corner. Biologists aren't so easily wowed, though, and before the mid-1990s they generally saw gerontology as a dismal bog where once-promising peers sank out of sight, or worse, re-emerged clutching beakers of snake oil. ... Studying the details of this inexorable, chaotic decay seemed a waste of time to most life scientists. ... Then in 1988 a miracle happened - the University of Colorado's Thomas Johnson reported that a gene mutation in nematodes could more than double their life spans. Five years later, Cynthia Kenyon at the University of California, San Francisco, nailed a similar worm 'gerontogene' dubbed daf-2. These flabbergasting discoveries revealed that not everything about aging is intractable chaos - worms, at least, apparently possessed gene-encoded modules poised to oppose the ravages of advancing age when activated by a single mutation. Optimists soon speculated that similar modules exist in mammals."


Cell Transplants for Macular Degeneration

From the MIT Technology Review: "Rats genetically engineered to lose their sight can be protected from blindness by injections of human neural stem cells ... a startup in Palo Alto, CA, plans to use the positive results to file for approval from the U.S. Food and Drug Administration to begin human trials. The company is already testing the cells in children with a rare, fatal brain disorder called Batten's disease. ... The company's cells are isolated from human fetal tissue and then grown in culture. To determine whether these cells can protect against retinal degeneration, scientists studied rats that were genetically engineered to progressively lose their photoreceptors - cells in the retina that convert light into neural signals. These animals are commonly used to model macular degeneration and retinitis pigmentosa, two major causes of blindness that result from cell loss in the retina. Researchers injected about 100,000 cells into the animals' eyes when the rats were 21 days old. ... the cells migrate over time, forming a layer between the photoreceptors and a layer of tissue called the retinal pigment epithelium, cells which nourish and support the photoreceptors. ... the cells protected vision in the part of the retina in which they were implanted."


Decellularization and Lung Tissue Engineering

Decellularization, or recellularization, is a fairly new technique in tissue engineering wherein a donor organ is chemically stripped of its cells, leaving behind the intricate structure of the extracellular matrix. That structure is then repopulated by stem cells drawn from a patient, which use the matrix as a guide to rebuild the fine structure of the organ. When transplanted, a recellularized organ has few of the issues of immune rejection associated with a normal donor organ transplant, as it is essentially built from a patient's own cells.

So far, researchers have used decellularization to build a new human trachea, a working rat heart, a number of human cardiac valves for children, and blood vessels, amongst other achievements.

Now I see that lungs in rats can be added to the list:

The team started with decellularized adult rat lungs, which retain the organs' branching airways and blood vessel network, and added a mixture of lung cells from newborn rats. Niklason says that the crucial step was nurturing the would-be lungs in a bioreactor that circulates fluid - simulating what would happen during fetal development - or air through them. The cells stuck to the scaffold in the right locations and multiplied. After up to 8 days in the bioreactor, they had coalesced into what the researchers' tests indicated was functional lung tissue.

To determine whether the new organs worked, the researchers removed rats' left lungs and stitched in lab-grown replacements. X-rays showed that the implanted lungs were inflating, though not fully. Tests of gas levels in blood flowing to and from the replacement organs showed that they were taking in oxygen and releasing carbon dioxide at 95% of normal efficiency.

This is an important step forward, as progress on tissue engineering and regenerative medicine for lungs has lagged behind comparable work on other organs in the past decade - lungs are both complex and inaccessible, which is not a helpful combination. Serious lung injuries are hard to treat and have a low survival rate, but these are facts that will change in a near future of engineered replacement lung tissue.

Progress in Viral Cancer Therapy

Scientific American looks at the state of viral cancer therapies: "The adapted virus that immunized hundreds of millions of people against smallpox has now been enlisted in the war on cancer. Vaccinia poxvirus joins a herpesvirus and a host of other pathogens on a growing list of engineered viruses entering late-stage human testing against cancer. ... After a decade of development of so-called oncolytic viruses, the newest strains hold the most promise yet ... In a two-pronged attack, these viruses specifically target tumor cells while delivering a cargo of immune-boosting genes. In contrast, viruses that cause cancer, such as the human papillomavirus that is responsible for most cases of cervical cancer, disrupt a cell's genome, thereby triggering out-of-control growth. When the engineered viruses recognize and infect cancer cells, they replicate and sometimes destroy their hosts. Several of the viruses also release the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) an immune system protein. The GM-CSF attracts a swarm of white blood cells and other immune system operatives that mount a further attack on the tumor. ... The vaccinia virus has been developed by the biotechnology company Jennerex ... Later this year, the company plans to launch a phase III clinical trial in advanced liver cancer patients, in which the virus will be added to standard antibody treatment."


Amniotic Membrane Used to Repair Cartilage

A novel methodology in regenerative medicine: "The objective was to evaluate the utility of cryo-preserved human amniotic membrane (HAM) as a support for repairing human articular cartilage injuries, which have a very limited capacity for self-healing ... The results [show] that cryo-preserved HAM is useful as a scaffold for growing human chondrocytes in cell therapy and for repairing human cartilage injuries. ... It provides a more regular surface and fills in the cavities and fissures ... The authors cultivated the chondrocytes (cells that form part of the cartilaginous tissue), isolated from human articular cartilage, on the amniotic membrane over a period of three and four weeks. The amniotic membranes were used to develop 44 repair models of arthritic human articular cartilage in vitro, which was assessed between four and 16 weeks later. The HAM also bonds well with the native cartilage. ... In some models, we could not differentiate between where the native tissue stopped and the neo-synthesised tissue began. ... This tissue had a fibrous appearance and high cellular density (cellularity), which in some cases was greater than that of the actual native cartilage."


Is Aging a Disease, Part II

Following on from a recent post on defining aging as a disease, I see that an article from Proto Magazine looks at the same question. This is really an examination of the slow boat mainstream of aging research: scientists who are careful to say in public that they are not in fact working towards greater maximum human longevity, but rather trying to achieve what is known as "compression of morbidity," wherein the period of illness at the end of life is shortened, but life span is not lengthened.

According to a Robert Wood Johnson Foundation estimate, some three-quarters of the $2.3 trillion the United States spends on health care each year goes to treat chronic diseases - most of which are diseases of aging. If scientists identify drugs that could push back the onset of several of those diseases, there could be an enormous economic benefit. But most people aren’t as frightened by aging’s economic burdens as they are by the prospect of lingering for years as mind and body fail. Avoiding that is the most tantalizing promise of longevity research, and in animals, at least, it seems possible. Describing an especially long-lived strain of mice, Washington University calorie restriction researcher Luigi Fontana says that as many as half die with no obvious cause of death. "There are no major pathological lesions," he says, comparing the manner of their passing with that of many human centenarians: They’re healthy until almost the very end.

Death itself is still inevitable and - in these seemingly symptom-free cases - a fascinating scientific puzzle. "Maybe it’s a systemic failure, where you can’t maintain homeostasis," Sierra says. But the puzzle of those deaths is perhaps less important than their nature. "The fact that we can’t ascertain the cause of death might be a good thing," he says. "We all want to die in our sleep, in perfect health. That’s the ideal."

No, no, no. Not an ideal at all - unless you have very little imagination and drive. The reason we strive for engineered longevity is so that we never find ourselves in the position where dying in our sleep looks like a worthy goal to aim for. To be at that point implies you have already given up, a long time ago.

Firstly, the mystery of centenarian deaths is no longer a complete mystery, thanks to the work of the Supercentenarian Research Foundation: the oldest old, who survive or evade all other forms of age-related disease, die from a form of creeping amyloidosis:

What kills most of them, he says, is a condition, extremely rare among younger people, called senile cardiac TTR Amyloidosis. TTR is a protein that cradles the thyroid hormone thyroxine and whisks it around the body. In TTR Amyloidosis, the protein amasses in and clogs blood vessels, forcing the heart to work harder and eventually fail. "The same thing that happens in the pipes of an old house happens in your blood vessels," says Coles.

Secondly, there is every reason to believe that compression of morbidity is actually impossible. If you look at considerations of the mechanics of aging such as reliability theory, and the demographic data accumulated over the past decades, it becomes very clear that (a) aging is simply an accumulation of biochemical damage, and (b) less damage means both a longer period of health and longer overall life expectancy - you can't separate the two.

Compression of morbidity is something of the declared goal of those in the mainstream of aging research who don't want to talk about extending life span, however, which makes it a little more than a matter of statistical interpretation. When a researcher talks about compression of morbity, that is something of a cipher, an identifying mark as to where he stands on the topic of engineered longevity: possibly in favor, but not willing to risk offending conservative funding organizations, possibly against. Either case has much the same result - a researcher who isn't working as freely as he might to extend human longevity.

Like compression of morbidity, the designation of aging as disease is also a marker for where a scientist stands in the politics of aging and longevity research. Scientists are people too, and their organizations are rife with the normal human failings, infighting, and pressure to conform to old, broken worldviews - just like the rest of us. Be aware of this, and you'll be able to more easily read the tides of the scientific process, and the output of research programs.

The Risks that Come With Excess Body Fat

Another reason why you really don't want to live a lifestyle that makes you overweight: "For individuals 65 years of age and older, obesity, excess body fat around the waist and gaining weight after the age of 50 are associated with an increased risk of diabetes. ... Adiposity [body fat] is a well-recognized risk factor for type 2 diabetes among young and middle-aged adults, however, the relationships between different measures of body composition and diabetes in older adults [65 years of age or older] are not well described ... [researchers] examined the relationship between measures of overall body fat, fat distribution, changes in these measures, and diabetes risk among 4,193 men and women 65 years of age and older. ... The researchers found that BMI at baseline, BMI at 50 years of age, weight, fat mass, waist circumference, waist-hip ratio, and waist-height ratio were all strongly related to the risk of diabetes. ... For each measure, there was a graded increase in the risk of diabetes with increasing quintiles of adiposity. Participants in the highest category of adiposity had an approximately 2- to 6-fold increased risk of developing diabetes compared with those in the lowest category."


Inflammation, Genetics, and Longevity

A review paper from Italian researchers who have been working on understanding inflammaging for a number of years: "Ageing is an inexorable intrinsic process that affects all cells, tissues, organs and individuals. Due to a diminished homeostasis and increased organism frailty, ageing causes a reduction of the response to environmental stimuli and, in general, is associated to an increased predisposition to illness and death. Actually, it is characterized by a state of reduced ability to maintain health and general homeodynamics of the organism. A large part of the ageing phenotype is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status of ageing, 'inflamm-ageing'. It is strictly linked to immunosenescence, and on the whole they are the major contributory factors to the increased frequency of morbidity and mortality among elderly. Inflamm-ageing is compatible with longevity; even if centenarians have an increased level of inflammatory mediators in comparison to old subjects and they are very frail, they also have high level of anti-inflammatory cytokines together with protective genotypes. Actually, data on case control studies performed in Italian centenarians suggest that a pro-inflammatory genotype is unfavourable to reach extreme longevity in good health and likely favours the onset of age-related diseases such as cardiovascular diseases and Alzheimer's disease."


Debating the Merits of Various Slow Boats to China

One boat is red, one is green. The sails are a different shape. One has a cook, the other a raconteur. But they're both going to China, and both are going to take a long time in doing so. This little scene is what springs to mind when I see people debating the merits of different attempts to develop drugs that can slow aging. Slowing aging is the slow and expensive path to a poor end result:

It is likely to be easier and less costly to produce rejuvenation therapies than to produce a reliable and significant slowing of aging. A rejuvenation therapy doesn't require a whole new metabolism to be engineered, tested, and understood - it requires that we revert clearly identified changes to return to a metabolic model that we know works, as it's used by a few billion young people already. Those rejuvenation therapies will be far more effective than slowing aging in terms of additional years gained, since you can keep coming back to use them again and again. They will also help the aged, who are not helped at all by a therapy that merely slows aging.

We who are middle aged have a few decades of leeway - in which one development path or another will be pursued. If at the end of the day, when we are old and damaged, the result is a therapy that only slows aging, then we are out of luck. Thanks for playing.

But today, the vast majority of longevity research is focused on the slow boats to China - on producing ways to change human metabolism to modestly slow down age-related degeneration. This state of affairs will be the death of us all, unless the focus shifts to the Strategies for Engineered Negligible Senescence and other repair-based approaches to reversing the damage of aging.

In any case, here is a Technology Review article that looks at the slow boats: lines of research that won't make much of a meaningful and direct difference to the longevity of the presently middle aged, but which are illustrative of the mainstream of present aging and longevity research:

Elixir Pharmaceuticals, which was cofounded by Kenyon and Guarente in 1999 to translate their findings on the genetics of aging into a pill, was once "the leading commercial effort to turn research on aging into antiaging drugs," says Stipp. But the company has been far less successful than Sirtris in generating funding and excitement; today it employs just a handful of people, who are still pursuing sirtuins but have also moved on to developing other types of drugs. (Both Kenyon and Guarente have since left Elixir. Guarente joined Sirtris's scientific advisory board in 2007.) Peter S. DiStefano, chief scientific officer of Elixir, is no fan of the rival company, accusing it of weak science and overzealous claims. "While Sirtris was way more successful than Elixir from a business perspective, at least I have my scientific integrity and can look at myself and say I did the right thing the right way," he says.


But some scientists doubt that sirtuins hold the key to life extension; for one thing, sirtuin activation hasn't been shown to extend life in healthy animals. A number of other molecular mechanisms are also under close scrutiny for their effects on aging. Kenyon, director of the Hillblom Center for the Biology of Aging at UCSF, points to a different drug, called rapamycin; as Stipp explains, one way it appears to lengthen life is by slowing the production of the proteins needed for cell division. As more proteins are produced, so are more defective proteins, which can accumulate in cells and contribute to the symptoms we see as aging.

And so forth. Elixir, Sirtris, and others in the wings are just the early examples of a great wave of similar ventures that will arrive over the next decade, each based on some newly discovered and distinct aspect of metabolism that might be manipulated with drugs in order to modestly slow aging.

My prediction, as above, is that none of these efforts will ultimately affect your life expectancy in any meaningful way. We will either develop working repair strategies for age-related biological damage, such as by realizing SENS, and live for additional centuries in good health, or we will get to live a few years longer by using age-slowing drugs. The technology for either result is achievable within a few decades of now, assuming adequate funding. I know which path I prefer.

A Potential Mechanism of Brain Aging

Here, researchers investigate one of a number of mechanisms that may explain degeneration in the aging brain: "A common way of describing the behavior of older adults is that they are more rigid and set in their ways. The wide range in sensory and cognitive functional changes that accompany normal, healthy aging are suggestive of widespread cortical dysfunction. Neurobiological studies are beginning to link these functional changes and common descriptions with a loss of experience-dependent plasticity that reflects age-related changes in synaptic plasticity mechanisms. ... many changes occur at the aging synapse and it is likely that more than just one synaptic mechanism contributes to visual deficits in aging. Recent studies have highlighted the important role of ubiquitin-mediated degradation of proteins at the synapse as a potent mechanism for changing synaptic structure and function. ... Ube3A, an E3 ubiquitin ligase that is absent in Angelman's syndrome, is required for experience-dependent plasticity during development of the visual cortex. We found that Ube3A expression declines across the lifespan in human, monkey, and cat cortex. The losses were substantial (50–80%) in all areas studied."


Lifestyle and Aging-Related Biomarkers

This should be an expected result: "Cellular aging is characterised by telomere shortening, which can lead to uncapping of chromosome ends (telomere dysfunction) and that activation of DNA damage responses. There is some evidence the DNA damage accumulates during human aging and that lifestyle factors contribute to the accumulation of DNA damage. Recent studies have identified a set of serum markers that are induced by telomere dysfunction and DNA damage and these markers showed an increased expression in blood during human aging. Here, we investigated the influence of lifestyle factors (such as exercise, smoking, body mass) on the aging associated expression of serum markers of DNA damage [in] comparison to other described markers of cellular aging (p16(INK4a) upregulation and telomere shortening) in human peripheral blood. The study shows that lifestyle factors have an age-independent impact on the expression level of biomarkers of DNA damage. Smoking and increased body mass indices were associated with elevated levels of biomarkers of DNA damage independent of the age of the individuals. In contrast, exercise was associated with an age-independent reduction in the expression of biomarkers of DNA damage in human blood. The expression of biomarkers of DNA damage correlated positively with p16(INK4a) expression and negatively with telomere length in peripheral blood T-lymphocytes. Together, these data provide experimental evidence that both aging and lifestyle impact on the accumulation of DNA damage during human aging."


Gender Longevity Differences: Another Few Theories for the Pile

There are a great many theories and associated studies relating to the well known difference in life expectancy between genders in our species:

Differing smoking rates, stem cell effectiveness, mitochondrial effectiveness, and the possible effects of hormones on the immune system are all on the list. [As well as the theory] that hormones influence the expression and activity of known longevity genes.

At the Longevity Meme, I recently pointed out a paper suggesting that men age faster for evolutionary reasons. Today I'll direct your attention to another evolutionary examination, via In Search of Enlightenment, where links are provided to the PDF format paper and related press release:

Researchers have long known that women outlive men on average, and more recently have discovered that men have higher mortality risks across the entire lifespan. University of Michigan researcher Daniel Kruger offers this explanation: It is all about sex. Women invest more physiologically in reproduction than men, thus men compete with other men for mating partners and try to make themselves attractive to women. This competition leads to strategies that are riskier for men both behaviorally and physiologically, and these result in higher levels of mortality.


This study examines three socio-demographic factors related to variation in human male reproductive success; polygyny, economic inequality, and the population ratio of reproductively viable men to women across nations with available data. The degrees of economic inequality and polygyny explained unique portions in the sex difference in mortality rates, these predictors accounted for 53% of the variance.

This is interesting, but is it at all important? Probably not, as is the case for much of the study of the area in which metabolism, aging, and longevity overlap. There is no such thing as useless information in the life sciences, but this sort of research will have most likely have limited utility when it comes to greatly extending the healthy human life span. Fully understanding and reengineering metabolism isn't as important to progress as learning to repair the metabolism we have.

The Open Letter on Brain Preservation

Every year something on the order of 50 million people die, and the fine structure of the brain that houses their minds is allowed to decay, destroying them forever. It does not have to be this way: the technology exists to plastinate and store the newly deceased, preserving the data of the mind until such time as medical technology can work a restoration. "The Open Letter on Brain Preservation seeks to raise awareness regarding the science, ethics and legality surrounding the emerging scientific process of chemical, whole-brain preservation. ... We, the undersigned, hereby publicly profess our human right to undergo a high-quality elective chemical brain preservation procedure immediately upon our physical death, and demand that such a procedure be made legal and accessible within the existing medical system in our countries of residence. We further demand that if medical evidence exists that an individual's brain is being substantially damaged by Alzheimer's, tumors, or other disease processes that elective brain preservation be available prior to that individual's natural death."


There Will Always Be Foolish Objections

A Newsweek article runs through some of the standard foolish objections to greater human longevity. There is no change so beneficial that people will refrain from protesting it - it is human nature to be vehemently against a new idea before being grudgingly for it: "When we consider the problem of aging, and imagine that we might be able to cure it, that alternating current we feel consists of longings and dread. We are afraid of what we wish for; and most of our fears, like our hopes, have always cycled in us. Dreams of immortality have led to terrible nightmares of boredom ever since people began writing down their thoughts. ... What happens when we have real antiaging pills that pass the tests of clinical trials? As bioethicists have begun to note, this is a problem that would make all our bioethical debates to date look small. What are the bioethical problems that have exercised us in the last 10 or 20 years? Stem cells. Cloning. Gene therapy. The privacy of genetic information. Steroids. All these problems matter in themselves, but all of them would be subsumed in the transformations of society and human nature that would be wreaked by a significant success with the human life span. And then will come the option of changing the genome itself. We will add or subtract genes to lengthen our lives, until there is no going back, because no human beings alive (however long they may live) will ever be human in the same way again. If we are going to survive to enjoy a good portion of the future, our health and happiness depend on a great deal of luck. The trouble with immortality is endless." There is no objection to longevity that comes close to touching the present horror of aging - the more than 100,000 people who die each and every day.


Naked Mole Rats Do Not Suffer From Cancer

When it comes to wandering Methuselah's zoo in search of comparisons between species that might lead to greater understanding of human longevity - and how to increase it - the naked mole rat stands out as a prominent point of interest. It lives for something like nine times longer than some similar rodent species, and appears to have unusually resilient biochemistry for a mammal.

You might recall that different fatty acid or lipid composition in cell membranes was floated as a reason for the ninefold longevity of naked mole-rats over related rodent species. Plenty of oxidative stress in the older mole-rats, but little sign of biochemical damage resulting from it - in comparison to those other rodents long since aged to death, that is. Better, more damage-resistant building blocks down at the molecular level might be the cause.

The concept of "better membranes" has a theory of aging to go along with it: the membrane pacemaker hypothesis. Follow that link if you care to find out more.

Naked mole rats are not just very long-lived, however. They also appear to be immune to cancer. No naked mole rat has been observed to suffer from cancer, a fact that is attracting interest from the cancer research community as this species becomes more widely studied. If the biochemistry that leads to this feat can be understood, it is possible there exists an economical way to port that cancer immunity to humans.

One of a number of further lines of investigation into naked mole rats and cancer caught my eye today. It's the essence of genetic research on the frontier of the unknown: change some genes and see what happens next. In this case the researchers demonstrate that naked mole rat cells essentially fall to pieces and become non-viable when cancer-causing genes are introduced:

The naked mole-rat (NMR, Heterocephalus glaber) is a long-lived mammal in which spontaneous cancer has not been observed. In order to investigate possible mechanisms for cancer resistance in this species, we studied the properties of skin fibroblasts from the NMR following transduction with oncogenes that cause cells of other mammalian species to form malignant tumors.

NMR fibroblasts were transduced with a retrovirus encoding [the cancer-causing oncogenes]. Following transplantation of transduced cells into immunodeficient mice, cells rapidly entered crisis, as evidenced by the presence of anaphase bridges, giant cells with enlarged nuclei, multinucleated cells, and cells with large number of chromosomes or abnormal chromatin material. In contrast, similarly transduced mouse and rat fibroblasts formed tumors that grew rapidly without crisis.


Thus, rapid crisis is a response of oncogene-expressing NMR cells to growth in an in vivo environment ... The unique reaction of NMR cells to oncogene expression may form part of the cancer resistance of this species.

Give it another five years or so and we might expect to see good answers as to whether exploitable knowledge lurks behind the absence of cancer in naked mole rats.

ResearchBlogging.orgLiang S, Mele J, Wu Y, Buffenstein R, & Hornsby PJ (2010). Resistance to experimental tumorigenesis in cells of a long-lived mammal, the naked mole-rat (Heterocephalus glaber). Aging cell PMID: 20550519

Cold Water Cast on Longevity Mutations

An opinion paper by researchers who feel that too much emphasis is placed on the discovery of longevity mutations: "The biological reasons for ageing are now well known, so it is no longer an unsolved problem in biology. Furthermore, there is only one science of ageing, which is continually advancing. The significance and importance of the mutations that lengthen the lifespan of invertebrates can be assessed only in relationship to previous well-established studies of ageing. The mutant strains of model organisms that increase longevity have altered nutrient signalling pathways similar to the effects of dietary restriction, and so it is likely that there is a shift in the trade-off between reproduction and maintenance ... To believe that the isolation and characterisation of a few invertebrate mutations (as well as those in yeast) will 'galvanise' the field and provide new insights into human ageing is an extreme point of view which does not recognize the huge progress in ageing research that has been made in the last 50 years or so." I believe that the focus on longevity mutations is not the most effective use of resources, but for different reasons: it's a part of the metabolic manipulation school of slowing aging, which is a slow path to a poor end result in comparison to repair strategies.


Autologous Stem Cell Repair for Damaged Corneas

From BusinessWeek: "Patients blinded in one or both eyes by chemical burns regained their vision after healthy stem cells were extracted from their eyes and reimplanted ... The tissue was drawn from the limbus, an area at the junction of the cornea and white part of the eye. It was grown on a fibrous tissue, then layered onto the damaged eyes. The cells grew into healthy corneal tissue, transforming disfigured, opaque eyes into functioning ones with normal appearance and color ... The stem-cell treatment restored sight to more than three-quarters of the 112 patients treated. ... The key to success is to be certain that when the stem cells extracted from the limbus are grown in culture they have the right mix of stem cells and the differentiated cells that form the corneal tissue ... If there are too few stem cells in the transplant, the improvement won't last because there will be no reservoir to form the new corneal cells needed with the normal recycling of cells over time. ... Depending on the depth of the injury, some patients regained sight in as little as two months. ... Others with deeper injuries needed a second procedure and waited a year before sight was restored."


Aubrey de Grey Presenting at the MIT Enterprise Forum

Biomedical gerontologist and engineered longevity advocate Aubrey de Grey presented at the MIT Enterprise Forum in March of this year. I somehow failed to notice the resulting video, despite a link to it sitting quite prominently on the SENS Foundation home page.

Aubrey de Grey, author and researcher on aging, claims he has drawn a roadmap to defeat biological aging. He provocatively proposes that the first human beings who will live to 1,000 years old have already been born.


Dr. de Grey holds a bachelors degree in Computer Science and a PhD, both from Cambridge University. Until 2006 he was in charge of software development at the university's Genetics Department for the FlyBase genetic database. In 1999, his book The Mitochondrial Free Radical Theory of Aging was published. Then in 2007, de Grey wrote, with Michael Rae, the book Ending Aging that provides a detailed account of the science, politics and social challenges of the entire SENS agenda.

You can watch the video in a player that combines the presentation with a slideshow.

Investing in Cryonics for the Long, Long Term

An open access anthropology paper on cryonics, illustrating in a number of subtle and less subtle ways the eternal divide between students of soft sciences and students of hard sciences: "Cryonics is a particularly American social practice, created and taken up by a particular type of American: primarily a small faction of white, male, atheist, Libertarian, middle- and upper-middle-income, computer/engineering 'geeks' who believe passionately in the free market and its ability to support technological progress. In this article, I investigate the relations between the discourses and practices of cryonics and its underpinnings in the values associated with neoliberal capitalism. I take seriously the premise that cryonics is an investment in the possibility of an extended future and a potential insurance policy against death. I show how cryonics is conceived of as an attempt to gain sovereignty over the limits of biological time, achieved through both monetary investment and the banking of biological objects understood to be actual selves. Cryonics demonstrates a unique way in which time, capital, and biotechnoscience can come together in the name of future life. An examination of the extreme example of cryonics reveals how speculative economic reasoning is applied to lives and bodies in the United States. I argue that cryonics is one response to American anxieties about time, the impending decline of the human body, and its culmination in death that draws on logics of biomedicine, technological progress, and investment forms. I describe some of the many unique aspects of cryonics and some of its similarities to venture capitalism, mainstream biomedical practice, and other sites where investment in the self and biotechnoscience come together, chiefly in other forms of tissue banking."


Evolution and Gender Longevity Differences

This particular researcher is somewhat fixated on TOR (when all you have is a hammer...) but this open access paper provides an interesting set of ideas on why men and women have differing life expectancies: "Women have lived longer than men in different countries and in every era ... Yet, it is believed that men do not age faster than women but simply are weaker at every age. In contrast, I discuss that men [do] age faster. From [an] evolutionary perspective, high accidental death rate in young males is compatible with fast aging. Mechanistically, hyper-activated mTOR (Target of Rapamycin) may render young males robust at the cost of accelerated aging. But if women age slower, why then is it women who have menopause? Some believe that menopause is programmed and purposeful (grandmother theory). In contrast, I discuss how menopause is not programmed but rather is an aimless continuation of the same program that initially starts reproduction at puberty. This quasi-program causes over-activation of female reproductive system, which is very vulnerable to over-activation."


Ash-2, Another Longevity Gene in Worms

Researchers have been turning up quite the trove of longevity-influencing genes and processes in nematode worms of late. Here is the latest:

Study identifies proteins that modulate life span in worms

The gene with the most pronounced effect, Ash-2, makes a protein that functions as a methyltransferase - meaning it works together with other proteins to add a chemical tag called a methyl group to a component of a cell's DNA packaging machinery, which is known as a histone. The presence or absence of this tag affects whether the DNA remains wound up tightly like thread on a spool, or unfurls to allow its genes to be expressed. Inhibiting Ash-2 activity reduces the number of methyl tags on the histone, which keeps the DNA inaccessible and somehow extends the animal's life by as much as 30 percent.


The researchers found that Ash-2 is highly expressed in the germline, or reproductive cells, as well as in newly formed eggs. These cells also had high levels of the methyl tag. When Greer blocked the expression of Ash-2 in worms that lacked normal reproductive cells, he found that this no longer extended worm life span, suggesting that an intact germline is necessary for Ash-2 to regulate longevity.

A little more context can be found in the paper itself; this is a discovery found by exploring mechanisms similar to those in which sirtuins play a role:

The plasticity of ageing suggests that longevity may be controlled epigenetically by specific alterations in chromatin state. The link between chromatin and ageing has mostly focused on histone deacetylation by the Sir2 family, but less is known about the role of other histone modifications in longevity. Histone methylation has a crucial role in development and in maintaining stem cell pluripotency in mammals

Given the pace at which new significant metabolic contributions to longevity are emerging, I'd expect this to be far from the last.

ResearchBlogging.orgGreer, E., Maures, T., Hauswirth, A., Green, E., Leeman, D., Maro, G., Han, S., Banko, M., Gozani, O., & Brunet, A. (2010). Members of the H3K4 trimethylation complex regulate lifespan in a germline-dependent manner in C. elegans Nature DOI: 10.1038/nature09195

Bone Scaffolds to Order

Researchers continue to make progress in scaffolding materials that enable the body to regrow missing bone: "In contrast to long-term solutions based on titanium, degradable implants are intended to replace the missing pieces of bone only until the fissure closes itself up. That may last months or even years, depending on the size of the defect, the age and health status of the patient. A new implant improves the conditions for the healing process. It emerged from the "Resobone" project of the federal ministry for education and research, and is sized-to-fit for each patient. Unlike the conventional bony substitutes to date, it is not made up as a solid mass, but is porous instead. Precise little channels permeate the implant at intervals of just a few hundred micrometers. ... The porous canals create a lattice structure which the adjacent bones can grow into. ... the Resobone implants will primarily replace missing facial, maxillary and cranial bones. Currently, they are able to close fissures of up to 25 square centimeters in size. ... The patient's computer tomography serves as the template for the precision-fit production of the implants. The work processes - from CT imaging, to construction of the implant, through to its completion - are coordinated in such precise sequences that the replacement for a defective zygomatic bone can be produced in just a few hours, while a five-centimeter large section of cranium can be done overnight."


More Tissue Engineered Skin

From the Sydney Morning Herald: "A full thickness artificial skin which should dramatically reduce the pain and scarring associated with skin grafts is being developed by Sydney researchers. Burns experts from the University of Sydney and Concord Hospital have started animal trials of a living skin that is grown outside the body and is completely functional when grafted on to the body. Unlike traditional skin grafts, which involve only the thin outer layer of the skin known as the epidermis, the new skin will be able to replace the crucial second layer of skin called the dermis. ... It takes the body weeks to grow into a skin graft and in that time a lot of excess elastic fibres and collagen will be produced that will then turn into a scar. The scar contracts and it can get so tight that patients lose the movement of their mouth and can't talk, or they can't bend their fingers. ... Initial testing of the artificial dermis in mice has found it does not scar and contract when it is transplanted. ... The research has been so successful that a new foundation has been created to centralise the burns research being done at three Sydney hospitals. ... They hope to create scaffolds that can individualise the skin, allowing it to be different colours."


Russian Language Longevity Advocacy

The world is getting smaller, year by year, and the steady improvement in freely available automated translation engines has a lot to do with that. Unlike even just a few years ago, it's now possible to dive right into a foreign language community online and follow the conversation using tools such as Google Translate. The one area where this is a still a challenge is scientific literature, science being one of the last fields of human endeavor in which it is still legitimate to (a) make up entirely new words and new meanings for existing words, and (b) refuse to explain yourself in anything other than a highly formalized, esoteric dialect of your language.

But the language barrier for reading the results of scientific research will fall, just as the barriers for common subjects are now almost gone.

On this topic, I should point out that an energetic Russian language healthy life extension community exists online these days. We monolingual English speakers could only see a fraction of their writings until fairly recently, and that fraction thanks to the efforts of people such as Maria Konolavenko, Leonid Gavrilov and Natalia Gavrilova, and a brace of other volunteer translators over the years.

But now with Google Translate, it's quite possible to browse the Russian language blogs and other websites where people debate and advocate for engineered human longevity. "Translator" will soon be, like "computer," one of those words that used to mean a profession, and now means a machine. A couple of starting points are below:

We are fortunate indeed to live in an age in which any one of us can wave a magic wand over incomprehensible runes and have them transform into plain, readable text. Even as recently as my youth, such a thing was a pipe dream. Why aren't you taking advantage of this wonder? All the world's communities await, just a single automated translation away.

A Five Year Timeline for Tissue Engineered Livers

From the Telegraph: a new methodology "could be used to recycle thousands of donated organs which are at present considered too old or damaged for transplantation. ... Many livers have to be discarded because they are too old or too damaged to be of any use.
The new technique works by effectively chemically stripping the old liver down too its basic 'scaffold' or exoskeleton in a process of called 'decellularisation'. Onto this frame of connective tissue and blood vessels, they then regrow the new liver using stem cells from the patient. Stem cells from embryos could also be used. The effectively brand new liver is then transplanted back into the patient. At the moment the technique will require donor organs but it is hoped that eventually pig's livers or artificial scaffolds can be used instead - effectively avoiding donors altogether. ... This scaffold retains for the most part the detailed microarchitecture of the liver, including essential structures such as the blood vessels. We take advantage of this remaining structure to repopulate the scaffold with liver cells to recreate a functional liver. As we have shown this re-engineered liver performs the most essential liver functions in the lab and can be transplanted into rats and stays intact, with the cells able to survive."


Thoughts on Calorie Restriction

A recent review paper: "Calorie Restriction (CR) research has expanded rapidly over the past few decades and CR remains the most highly reproducible, environmental intervention to improve health and extend lifespan in animal studies. Although many model organisms have consistently demonstrated positive responses to CR, it remains to be shown whether CR will extend lifespan in humans. Additionally, the current environment of excess caloric consumption and high incidence of overweight/obesity illustrate the improbable nature of the long-term adoption of a CR lifestyle by a significant proportion of the human population. Thus, the search for substances that can reproduce the beneficial physiologic responses of CR without a requisite calorie intake reduction, termed CR mimetics (CRMs), has gained momentum. ... The first results from a long-term, randomized, controlled CR study in nonhuman primates showing statistically significant benefits on longevity have now been reported. Additionally, positive results from short-term, randomized, controlled CR studies in humans are suggestive of potential health and longevity gains, while test of proposed [CR mimetics] have shown both positive and mixed results in rodents. ... Whether current positive results will translate into longevity gains for humans remains an open question. However, the apparent health benefits that have been observed with CR suggest that regardless of longevity gains, the promotion of healthy ageing and disease prevention may be attainable."


Humanity+ Summit 2010 Coverage and Video

The 2010 Humanity+ Summit was held this past weekend. Video from the event is archived at Livestream and you can find a brace of posts covering the event at the Speculist:

If you want to browse through the video streams, the links above are a useful guide to finding the presenters and topics of interest. A few items of interest related to engineered longevity:

There is a very ambitious schedule with an A-list group of speakers, full streaming worldwide over the internet


John Smart announced his new venture to provide a push prize for brain preservation (25% for a mouse brain and 75% for a pig brain) at a nano-scale resolution. They have $100,000 but are hoping to grow that prize with additional donations. He discussed the plastination process in more detail, and his colleague demonstrated via video the extremely high resolution that they get with that now for small brain tissue samples.


Aubrey de Grey described a role for citizen scientists to aid the work on anti-aging: improve the accuracy of media coverage by evaluating carefully and publicly reacting to press accounts of "breakthroughs" (many of which are not really). This keeps things realistic and reduces the fuel for the anti-hype side which can slow public acceptance.

From the other side of the aisle, the deathists-slash-anti-transhumanists at Futurisms have put together a large set of posts covering the Summit. Just read between the snark:

There's always a strange split at these sorts of conferences between big-picture visionary, scientific, and philosophical talks, and presentations on specific but low-level scientific findings that you'd expect to find at a more focused technical conference. The latter seem designed both to fill space and to give the attendees a sense that they are involved in an organized scientific project, and that they're in touch with what's going on. Given the dizzying pace, I'll probably be focusing on the more big-picture talks.

Calorie Restriction Slows Aspects of Brain Aging

More data from primate studies: "Caloric restriction (CR) reduces the pathological effects of aging and extends the lifespan in many species, including nonhuman primates, although the effect on the brain is less well characterized. We used two common indicators of aging, motor performance speed and brain iron deposition measured in vivo using MRI, to determine the potential effect of CR on elderly rhesus macaques eating restricted and standard diets. Both the CR and control monkeys showed age-related increases in iron concentrations in globus pallidus (GP) and substantia nigra (SN), although the CR group had significantly less iron deposition in the GP, SN, red nucleus, and temporal cortex. A diet x age interaction revealed that CR modified age-related brain changes, evidenced as attenuation in the rate of iron accumulation in basal ganglia and parietal, temporal, and perirhinal cortex. Additionally, control monkeys had significantly slower fine motor performance on the Movement Assessment Panel, which was negatively correlated with iron accumulation in left SN and parietal lobe, although CR animals did not show this relationship. Our observations suggest that the CR-induced benefit of reduced iron deposition and preserved motor function may indicate neural protection similar to effects described previously in aging rodent and primate species." You might recall that iron buildup is associated with lipofuscin accumulation in our cells, which damages the process of autophagy, which in turn leads to degeneration.


Stem Cell Tourism

PopSci examines medical tourism for stem cell therapies, an entirely rational response to the unnecessary costs and delays imposed on medical development by the FDA: "The FDA thinks all stem-cell procedures should undergo clinical trials for safety and efficacy before companies begin selling them as therapies. Its formal review process, the agency maintains, is the only way to protect patients from treatments that are ineffective or downright dangerous. But with multistage clinical trials lasting up to five years and costing as much as $100 million, a growing number of doctors and patients have started pursuing other options. ... In a controversial move in 2005, the FDA reclassified autologous stem cells that are manipulated by growth factors or other compounds as drugs. This criterion holds whether the cells are derived from a patient's own body or from someone else's. Many believe that the policy change gives the agency more authority than Congress ever intended it to have. Grekos's theory is that pharmaceutical companies are pressuring the FDA to treat autologous stem cells as a drug in order to secure their own future profits." Clinical trials are taking place overseas, as the article notes. The quality of therapies offered varies widely, as is true whether or not a market is regulated: this means you have to do some legwork to find out who is well regarded. But at least the option is available - there has to be freedom to experiment and to choose if there is to be rapid progress.


Structural Causes of Increasing Life Expectancy

As I'm sure you're all aware by now, human life expectancy for both young and old in the most developed regions of the world is slowly increasing, and this has been the case for some time. As medical technology advances and our wealth grows, we benefit in ways that lead to less biochemical damage to the complex machinery of our body accumulated over the course of a lifetime - and thus a greater likelihood of living longer.

That the medical and research establishments have achieved this ongoing benefit even in advance of any structured, deliberate, large-scale efforts to slow or (more preferably) repair the consequences of aging bodes well for the future. The scientific community should be able to achieve far more impressive results when they are actually trying to directly tackle aging.

I noticed an open access paper today (PDF version included) that applies some mathematical wizardry so as to break out the most important structural contributions to increasing longevity. I think you'll find it interesting:

The ongoing increase in life expectancy in developed countries is associated with changes in the shape of the survival curve. These changes can be characterized by two main, distinct components: (i) the decline in premature mortality, i.e., the concentration of deaths around some high value of the mean age at death, also termed rectangularization of the survival curve; and (ii) the increase of this mean age at death, i.e., longevity, which directly reflects the reduction of mortality at advanced ages. Several recent observations suggest that both mechanisms are simultaneously taking place.


We illustrate the method with the evolution of the Swiss mortality data between 1876 and 2006. Using our approach, we are able to say that the increase in longevity and rectangularization explain each about 50% of the secular increase of life expectancy.

There's more of the same in a past PDF format paper by one of the same authors. A further good resource is chapter 3 of Between Zeus and the Salmon: The Biodemography of Longevity - a good read if you have the time. The book is available for free online and that chapter contains some visual examples of what is meant by rectangularization of the survival curve.

ResearchBlogging.orgRousson, V., & Paccaud, F. (2010). A set of indicators for decomposing the secular increase of life expectancy Population Health Metrics, 8 (1) DOI: 10.1186/1478-7954-8-18

Towards a Universal Amyloid Strategy

Here is a dense scientific post from the SENS Foundation that might be better read back to front, starting with the research partnership announcement at the end. Some fraction of degenerative aging is caused by an accumulation of various forms of amyloids between cells, probably the best known of which is that involved in Alzheimer's disease. One goal for the Strategies for Engineered Negligible Senescence (SENS) approach to aging is to establish a general technology platform that can be used to remove any form of amyloid: "In late 2008, we reviewed then-unpublished work by Dr. Mark Pepys, who was working on an ambitious project anticipated to allow for the disaggregation of nearly all disease-associated amyloids. ... I am therefore delighted to have the privilege to be given permission [to] make the first public announcement that the Supercentenarian Research Foundation has recently helped to facilitate a collaboration between researchers already working in amyloid diseases, to develop antibodies to cleave aggregated wild-type and mutant transthyretin - the form responsible for senile cardiac amyloidosis (a prevalent, but not exclusive, cardiac amyloidosis in supercentenarians)."


Novel Immune Cells Kill Cancer

Via EurekAlert!: "A team of researchers has developed a method to produce cells that kill tumour cells in the lab and prevent tumours forming in mouse models of cancer. ... In this research, T cells were transformed into cells similar to another type, Natural Killer (NK) cells, which commonly act against viruses and cancer cells. ... We had shown that a gene called Bcl11b was essential for normal development of immune system cells - and of particular interest in the development of T cells. Here we can see the fruits of that work: we show, for the first time, that we can modify the developmental fate of immune system cells to produce a novel type that - if we can see the same effect in humans - could be of enormous value in cancer treatment. ... the Bcl11b gene was active only in T cells in the immune system and that its activity was needed at the earliest stages of production of T cells. When the team knocked out the Bcl11b gene, the mice produced no T cells. ... Remarkably, the mice lacking the Bcl11b gene produced a new type of immune system cell - the Induced T to Natural Killer cells. This is the first time we have seen these cells ... Even more important, we can see that these reprogrammed killer cells can attack cancer cells, whether in test tubes or in mouse models. ... The ITNK cells killed melanoma and lymphoma cells in experiment in test tubes and were much more efficient than unmodified Natural Killer cells in the mouse and in human."


Building the Foundation of Tomorrow's Immune System

The human immune system of tomorrow will look, conceptually, a lot like today's software defenses:

Scientists are making real inroads into replicating and controlling the cells and mechanisms of our immune system. Producing immune cells, directing their actions, deciphering the biochemistry of pathogens - all these pieces are waiting to be put together as a bioartificial immune system, many times more selective, efficient and resistant to damage than the basic version we're all equipped with. ... One might imagine the future providers of immune system technology looking a lot like today's providers of anti-virus software for your computers, harvesting information on potential infections and streaming update information to bioartificial antibody manufactories in your bloodstream.

Wireless anti-virus nanotechnology in the blood may seem like a far future vision, but the first building blocks of that technology are already emerging from present day research. For example, it won't be long before clinics can assemble massive doses of artificial antibodies to order and then infuse them into your body. Antibodies are the immune system's weapons, molecules tailored to a specific threat that either directly kill attackers or flag them for ingestion and destruction by white blood cells. An infusion of antibodies produced in the clinic could be vastly larger than what the body is capable of producing on its own, overwhelming an assault. Here is the latest advance towards this near-term goal:

Using plastic nanoparticles just 1/50,000th the width of a human hair, the team has created plastic antibodies that successfully function in the bloodstream of living animals to identify and fight a variety of antigens.

Antibodies are the proteins in our bodies produced by the immune system to recognize and neutralize foreign threats like infections, allergens, viruses and bacteria. These can include things as annoying but benign as plant pollen and dust to food allergens, bee venom, and other toxins. Our body produces antibodies in decent quantities, but in the case of allergies our immune systems can be unequipped to deal with certain antigens, and in other cases - such as a bad infection - our own natural antigens can simply become overwhelmed.


researchers could tailor a variety of these nanoparticles for use in just about any case where the body relies on antibodies for to fight off threats. That’s a lot of cases, opening the door to a synthetic immune booster that could potentially be used to treat myriad allergies, illnesses and infections.

For those interested, you can find the original scientific paper at the Journal of the American Chemical Society. We certainly live in interesting times.

Where does this fit into the near future of aging and engineered longevity? Well, a significant component of age-related frailty and suffering stems from the decline of the immune system. The ability to manufacture antibodies for common threats might be used to sidestep some of that decline, and that's almost as big a deal as finding ways to rejuvenate the age-damaged immune system.

ResearchBlogging.orgHoshino, Y., Koide, H., Urakami, T., Kanazawa, H., Kodama, T., Oku, N., & Shea, K. (2010). Recognition, Neutralization, and Clearance of Target Peptides in the Bloodstream of Living Mice by Molecularly Imprinted Polymer Nanoparticles: A Plastic Antibody Journal of the American Chemical Society, 132 (19), 6644-6645 DOI: 10.1021/ja102148f

Why Aging Research?

From In Search of Enlightenment: "A person’s interest in remaining healthy and alive does not evaporate as the number of birthday candles they accumulate increases. The aged, like the young, have an interest in remaining healthy and vigorous for as long as possible. When a person over age 65 is murdered or killed in a car accident we conceive of these events as constituting a serious harm. We believe that there is a moral duty to prevent these harms from being realized, if it is possible to do so. Whether these harms come from an external source that we can easily perceive (such as a criminal wielding a gun or a speeding car) or from complex biological processes that are internal to our biology is irrelevant to the stringency of the moral duty to prevent harm. ... the general affluence of a country, as well as its natural resources, profoundly influences the quality of sanitation it can offer its citizens. But in the case of developing an antiaging pill to protect against chronic disease, there is good reason to believe that many of these obstacles will be less of a challenge. Unlike sanitation, the main costs associated with the development of an antiaging pill will most likely be with research and development, rather than the manufacture and dispersion of such a pill. So I believe there is good reason to be optimistic that such an antiaging intervention could be enjoyed by most of the world’s population in a relatively short time from when it is first developed."


The Other Use for Stem Cells

A low-cost source of stem cells can generate diseased tissue for study in the laboratory, a use that is probably just as important at the present time as regenerative medicine: researchers "have for the first time differentiated human stem cells to become heart cells with cardiomyopathy, a condition in which the heart muscle cells are abnormal. The discovery will allow scientists to learn how those heart cells become diseased and from there, they can begin developing drug therapies to stop the disease from occurring or progressing. ... [Researchers] took patient skin cells and reprogrammed them to become pluripotent stem cells. Such cells can then develop into almost any type of cell in the human body. The researchers then created heart cells that had characteristics of hypertrophic cardiomyopathy. ... We knew there was potential in using pluripotent stem cells from people with genetic disorders to develop diseases in vitro, but our study is the first to successfully create abnormal heart cells. Now that we have developed these cells, we can study why they become enlarged and develop treatments to prevent them from overgrowing."


There Will Be Ten Thousand Subtle Gene Variants of Human Longevity

There will be ten thousand subtle gene variants of human longevity. Or rather, these differences between individuals most likely exist now and will be steadily uncovered in the years ahead as the cost of DNA sequencing continues to fall. Most of these longevity-associated genetic variants will look much like this one: an association discovered by comparing long-lived people to average members of the population, and neither terribly exciting nor particularly exploitable:

Cytokines are crucial for the regulation of inflammation development in humans. Many studies have shown that variations in cytokine genes might play a role in determining human longevity.

This study examined the changes in the gene pool relevant to the -308 G/A polymorphism in the promoter region of the proinflammatory cytokine tumour necrosis factor (TNF)-alpha gene and the -1082 G/A polymorphism in the promoter region of anti-inflammatory cytokine interleukin (IL)-10 gene with aging and survival selection occurs in the Jordanian population. .. the IL-10 genotype and allele frequencies were significantly associated with longevity in men but not in women.

We should expect to see subtle associations with human longevity in genes associated with processes known to be important in long-term health - such as the inflammatory response, or indeed anything else associated with the operation of the immune system. But what can be done with this information? As things stand, probably little of consequence. All new knowledge in the biology of human aging will prove useful eventually, but in the near term it seems very unlikely that as much benefit can be derived from such exploration and analysis as from, say, effort put into developing repair technologies for the known forms of age-related damage.

ResearchBlogging.orgKhabour OF, & Barnawi JM (2010). Association of longevity with IL-10 -1082 G/A and TNF-alpha-308 G/A polymorphisms. International journal of immunogenetics PMID: 20518833

On Comparative Studies of Aging

Maria Konovalenko on the study of the often large life span differences between similar species - or rather the lack of such research work in comparison to other fields of life science: "Here's this quite simple idea: to take two species similar in size and basic biology, but having a substantial difference in longevity, and figure out what's the reason for this difference. What are the distinctions in the mechanisms of aging and stress resistance? It's desirable to carry out this work in various species. However, not a lot of people are excited about this simple idea. Even the genome of the famous naked mole rat has not been sequenced yet, although many people believe it's got 'negligible' senescence. For now all that we have is negligible funding of evolutionary-comparative biology of aging. Moreover, previously obtained results are put into cold storage. ... And here comes the main question in biogerontology. Why is the research into the fundamental mechanisms of aging so scarcely funded?" Aging and longevity research in general receives very little funding and attention in comparison to its importance to the future of human health. This state of affairs is slowly changing, but not fast enough for my liking.


TOR and Calorie Restriction

Via Newswise: "Why all the attention on TOR? TOR (target of rapamycin) is a key nutrient-sensing catalytic enzyme that evolution has conserved among every plant and animal species that has cells containing a nucleus. TOR mediates the connection between nutrients in the environment to the growth and metabolism of the organism. Studies in flies, worms, yeast and mice support the notion that the TOR signaling network also plays a pivotal role in regulating the aging process. When TOR signaling is reduced, either through genetic manipulation or via the use of drugs, the organism presumes there are reduced nutrients in its environment and goes into a 'survival' mode similar to that seen in dietary restriction, which has been shown to extend lifespan and slow the onset of certain age-related diseases. ... it remains to be seen which downstream effectors of TOR are key drivers of longevity and which ones elicit only minor effects. In addition to simply extending lifespan, research on the protective effects of TOR is likely to identify which age-related diseases can be slowed by inhibition of the TOR pathway."


The Immortality of Supercentenarians

For the purposes of his work into aging and longevity, researcher Michael Rose defines the condition of mortality as being a rising risk of death as time goes on. This is what we see in the world we know: the older a person, a pet, a plant becomes, the more likely it is to die in any given period of time. Immortality, it then follows, is the state of being in which the risk of death does not rise with advancing time.

As it turns out, our intuitions about the way in which aging and risk of death progress do not accurately reflect what happens in very late life - for those who live much longer than the average. Rose demonstrated that very old flies no longer suffer an increasing risk of death; even though the actual mortality rate is high, it stops growing. These are immortal flies by his definition.

This plateau of late-life immortality is expected to exist in all higher animals, and hints have been seen in human data in recent years:

Increased age is regularly linked with heightened cancer risk, but recent research suggests a flattening around age 80. We report that, independent of cancer site or time period, most incidence rates decrease in the more elderly and drop to or toward zero near the ceiling of human life span

Via Next Big Future I see that recently published demographic work (for which the full PDF version is available) claims to find the immortality plateau in supercentenarians:

The International Database of Longevity (IDL) offers detailed information on thoroughly validated cases of supercentenarians. These data are used to estimate human mortality after age 110. The procedure properly accounts for the country-specific sampling frames in the IDL. The analysis confirms that human mortality after age 110 is at at a level corresponding to an annual probability of death of 50%. No sex-specific differences in mortality could be found, and no time trend in supercentenarian mortality between earlier and later cohorts could be detected.

This should not be too surprising, and is a result expected by many researchers. The immortality plateau behavior might be thought to be a fundamental property of the aging and failure of complex redundant systems - such as us. As immortality goes, it's a pretty raw deal, of course. Our job in the here and now is to work hard at developing the near-term biotechnology of rejuvenation, so that we never have to experience late life immortality the natural way.

A Report on the Fourth Asset Preservation Group Meeting

From Depressed Metabolism, a look at the folk who are trying to ensure that cryonics patients can preserve their resources as well as the fine structure of their brains: "On the weekend of April 23-25 I attended a meeting of the cryonics Asset Preservation Group held [near] Gloucester, Massachusetts. I will try to give a few brief summaries without going into detail about every presentation. ... A central problem for cryonicists wanting revival trusts is that Cryopreserved Persons (CPs) are legally dead and are not ascertainable beneficiaries under trust law. My solution to this problem has been to have cryonics organizations (rather than the legal system) recognize the reanimated CP as the beneficiary. But finding the right cryonics organization to do this is not always easy. ... the best presentation at this meeting of the Asset Preservation Group was the one on 'Personal Revival Trusts' by Igor Levenberg. I have been working with the thorny problems associated with cryonics reanimation trusts for years and I have never seen such careful and persuasive legal analyses."


Artificial Corneas

From Singularity Hub: "In order to work in the human body, an artificial cornea has to meet some rather stringent requirements. First, it has to bond to the human eye around its edge, but stay unclouded by cells in its center. To that end, [researchers] took a widely used opthalmological polymer (found often in intraocular lenses) and adapted it with other special polymers around the edges. Combined with the application of a growth factor protein, the modified edge promoted cell growth around the periphery of the implant and secured it in place using the body's own cells. The center of the artificial cornea, however, does not promote cell growth and remains clear so that it can be seen through. The artificial cornea also has to move freely with the eyelid and balance moisture on its faces. The polymer [researchers] chose is hydrophobic, allowing tears to lubricate the surface and provide the correct moisture on both of its sides. ... The artificial cornea has passed clinical trials and is ready to see expanded use in patients this year."


The Tumbling Walls of Formal Science

Science is not really an institution per se. It is a state of mind - a willingness to follow the scientific method and the willingness to put in time on a particular job that needs doing. That science is currently and has been an institution for most of the later 20th century is something of an aberration when considered against the broader scope of history. Science has far more often been a matter of folk with the right mindset stepping in to learn what they needed and make progress as they could. Most blurred the line between engineer and scientist - cheerfully mixing discovery through the scientific method with implementation that worked around gaps in knowledge within their field.

As the h+ summit this next weekend puts it, these people were citizen scientists. Their time is coming again, arriving alongside the age of garage biotechnology:

For my money, the most interesting part of this process is the enabling effects of cheap computing power - and the tools to take advantage of it - on people who are not professional researchers. To put it another way, the line between researcher and nonresearcher will become very blurred, just as the line between programmer and nonprogrammer is today. The present open source software development community contains diverse individuals, small teams, academic, non-academic, corporate and non-corporate groups producing solutions for specific problems that bother them or inspire them. In the future, equally diverse organizations will form and collaborate to produce solutions for health and longevity using open biotechnology yet to come.

At the end of July, the Open Science Summit will be held in Berkeley, California:

Ready for a rapid, radical reboot of the global innovation system for a truly free and open 21st century knowledge economy? Join us at the first Open Science Summit, an attempt to gather all stakeholders who want to liberate our scientific and technological commons and enable an new era of decentralized, distributed innovation to solve humanity’s greatest challenges.

The host is an energetic fellow in the growing open biotechnology community, as illustrated by this recent article from h+ magazine:

A Citizen-Scientist is anyone who uses the scientific method to investigate themselves or their environment to answer a particular question or satisfy their curiosity. Several exemplary historical citizen scientists come to mind. Thomas Jefferson is the archetype of the gentleman scholar. Benjamin Franklin invented bifocals when he got tired of switching between two pairs of glasses and of course, famously flew a kite in a lightning storm to discover the principles of electricity. Edward Jenner discovered inoculation and performed the first vaccination against smallpox.


I am CEO of Lava-Amp, a company I co-founded with Venezuelan computational biologist Guido Nunez to develop extremely low-cost DNA amplification technology. PCR, which Lava-Amp performs, is the fundamental technique of molecular biology. Our device brings the cost of the hardware down from thousands of dollars, to hundreds, enabling portable DNA testing in the field, and also providing an affordable system for garage bio-hackers and amateur biologists learning the basics. ... am also convening the first Open Science Summit, July 29-31st at Berkeley. Finally, I am co-founder of BioCurious the first Bay Area community lab for citizen science and "biohacking." The DIY biology movement has been gaining ground for the last two years with many groups meeting informally. However, we still lack infrastructure and access to equipment that is beyond the budget of a garage hobbyist. To remedy this, and also assuage some of the concerns with garage biohacking, we’ve pooled resources and gathered a group of Bay Area activists to found a lab for non-institutional science.

If you're in that part of the world and have an interest, note that cancer immunotherapy nonprofit Livly also rents out lab space.

But why should we folk interested in engineered longevity spend much - or any - time following or helping support the open biotechnology movement? I think that the most obvious reason stems from the analogy to the open source software development movement I made at the head of this post. If you look at the software infrastructure of the present day internet, vast swathes of it are open source, the quality of its software only made possible by the gift economy that takes shape in unfettered collaborative marketplaces of this nature. A very large fraction of all new innovation on the web now builds on top of open source infrastructure, for example.

Similarly, we can envisage the future of biotechnology bolstered greatly by open development and sharing of information: in an environment where hundreds or thousands of people can put in time on one problem, progress happens rapidly, and blocking problems quickly evaporate. The tools used to build solutions will be open source, and thus of excellent quality and low cost, just like the infrastructure for software development today.

Low cost, high quality tools are the necessary precursors for a large community of skilled amateurs to arise in any field. It happened for software development, and we all benefit greatly from the results of that process. I would like to see it happen in the life sciences as well, because the only thing better than thousands of people advocating for engineered longevity is thousands of advocates who can also step in, do the work, and help to get the job done. Not all biotechnology is rocket science: a great many useful and necessary tasks in any project can be accomplished by undergraduate students - or anyone who has put in a few months of evening reading and practice.

In short, open science and garage biotechnology will lead to faster progress - and we all want to see that happen.

The Longevity Gene 'Takeout' in Flies

Researchers are turning up new longevity genes at a fair rate these days, and this latest discovery is illustrative of the methods used - start with what you know, and compare and contrast: "A major challenge in translating the positive effects of dietary restriction (DR) for the improvement of human health is the development of therapeutic mimics. One approach to finding DR mimics is based upon identification of the proximal effectors of DR life span extension. Whole genome profiling of DR in Drosophila shows a large number of changes in gene expression, making it difficult to establish which changes are involved in life span determination as opposed to other unrelated physiological changes. We used comparative whole genome expression profiling to discover genes whose change in expression is shared between DR and two molecular genetic life span extending interventions related to DR, increased dSir2 and decreased Dmp53 activity. We find twenty-one genes shared among the three related life span extending interventions. One of these genes, takeout, thought to be involved in circadian rhythms, feeding behavior and juvenile hormone binding is also increased in four other life span extending conditions: Rpd3, Indy, chico and methuselah. We demonstrate takeout is involved in longevity determination by specifically increasing adult takeout expression and extending life span. These studies demonstrate the power of comparative whole genome transcriptional profiling for identifying specific downstream elements of the DR life span extending pathway."


Learning from Werner Syndrome

Accelerated aging conditions may result from individual aspects of "normal" aging run wild and out of control. This means we can potentially learn more about those mechanisms. For example: "a gene shown to play a role in the aging process appears to play a role in the regulation of the differentiation of embryonic stem cells. ... researchers identified a protein interaction that controls the silencing of Oct4, a key transcription factor that is critical to ensuring that embryonic stem cells remain pluripotent. The protein, WRNp, is the product of a gene associated with Werner syndrome, an autosomal recessive disorder hallmarked by premature aging. ... We showed that the depletion of WRNp blocked the recruitment of Dnmt3b to the Oct4 promoter, and resulted in reduced methylation. The reduced DNA methylation was associated with continued Oct4 expression, which resulted in attenuated differentiation. ... These results reveal a novel function of WRNp, and demonstrate that WRNp controls a key step in pluripotent stem cell differentiation. Our data support the emerging hypothesis that attenuated stem cell differentiation is involved in aging. This lack of differentiated cells may contribute to failure to maintain organ or tissue function in the later stages of life."


Allen Human Brain Atlas Launched

While we're on the subject of the importance of the brain to engineered longevity, here is news of an infrastructural advance from EurekAlert!: "The Allen Institute for Brain Science announced today that it has launched the Allen Human Brain Atlas, a publicly available online atlas charting genes at work throughout the human brain. The data provided in this initial data release represent the most extensive and detailed body of information about gene activity in the human brain to date, documenting which genes are expressed, or 'turned on' where. In the coming years, the Atlas will be expanded with more data and more sophisticated search, analysis and visualization tools to create a comprehensive resource useful to an increasingly wide range of scientists and research programs worldwide. The Allen Human Brain Atlas, available at, is a unique multi-modal atlas of the human brain that integrates anatomic and genomic information to create a searchable, three-dimensional map of gene activity in the brain. Data modalities in this resource include magnetic resonance imaging (MRI), diffusion tensor imaging (DTI) and histology - providing information about gross neuroanatomy, pathways of neural connections, and microscopic anatomy, respectively - as well as gene expression data derived from multiple approaches."


A Regenerative Medicine Roadmap from the Science for Life Extension Foundation

Via Maria Konovalenko we are pointed to an updated English-language version of the PDF roadmap for regenerative medicine, a document assembled by the PhD-laden Russian volunteers at the Science for Life Extension Foundation. This is a work in progress, but it's pretty comprehensive on the scientific side - just the sort of thing to pass around to people not yet convinced that the future of tissue engineering is golden.

Regenerative medicine roadmap

Here is the updated edition of the Roadmap in Regenerative Medicine ... Cell therapy and tissue engineering are described in more detail, than the rest of the scientific issues. I welcome everybody to take a look and add what's missing and/or what's wrong. I'd also like to notice that the organizational issues aren't described at all, but this is probably the most important part of the roadmap. There should be an implementational plan of how exactly the Roadmap should work included in the organizational part. To do that we need to address the specialists in the given fields.

But at least for now the question is - what's missing in the scientific part?

This covers the large areas of interest for cell therapies: (a) removing unwanted cells, such as the growing senescent cell population in every older body, (b) adding cells where they have been lost, so as to reverse sarcopenia, for example, or replace the dying motor neurons that cause the symptoms in a number of unpleasant degenerative conditions, (c) reprogramming cells to create unlimited sources of stem cells or specialized cells to order, (d) restoring the ability for cells to regenerate damage in the body, an ability gradually lost with age, and (e) the use of larger scale tissue engineering to create new replacement organs when needed.

There is a lot of detail hidden within all of these areas - even small sub-fields within regenerative medicine are sufficiently complex and fruitful to occupy many research groups for years on end. The end goal, however, is well worth the expense. Nothing on earth causes more economic harm than aging and degeneration. No feasible level of resources devoted to rejuvenation research could be thought too great when compared with the magnitude of the ongoing disaster that is aging.

The Logical Endpoint of Neuroinformatics

Here is a presentation given by researcher Anders Sandberg for Google's Tech Talk series: "The idea of creating a faithful, one-to-one computer copy of a human brain has been a popular philosophical thought experiment and science fiction plot for decades. While computational neuroscience and systems biology are currently very far away from this goal, the trends towards large-scale simulation, industrialized neuroinformatics, new forms of microscopy and powerful computing clusters point in this direction and are enabling new forms of simulations of unprecendented scope. In this talk I will discuss current estimates of how close we are to achieving emulated brains, technological requirements, research challenges and some of the possible consequences." A little while back the Future of Humanity Institute published a roadmap to whole brain emulation. This topic is of interest to supporters of engineered longevity as a part of the very long term goal of incrementally replacing the vulnerable biology of the brain with something more robust and damage-resistant. Such as, for example, clusters of diamondoid nanomachines designed to emulate the functions of neurons.


Examples From the Dawn of the Age of Tissue Engineering

These are the opening years of the biotech century, in which scientists first develop the means to rebuild every part of the human body, and then go on to design better, more durable, and more functional versions of our bodily systems. First we'll learn how to actually maintain the human body, and then we'll learn how to improve it.

A gilded age of ever-increasing health lies ahead, but these are the early, experimental years. Here are two examples of the work undertaken by research groups at the present time, both of which are, I think, illustrative of the state of the field.

Doctors seek heart valve that grows with kids

Hanley is one of a handful of researchers around the country trying to build a heart valve made of living human tissue that would grow with a child and repair itself over time. It's a remarkably complicated task that incorporates stem cell science and biomechanical engineering, and an understanding of exactly how tissues grow and function amid the constant rush of blood in a beating heart - and scientists have been stuck on it for more than a decade.

New Surgical Technique Attempts to Re-grow Breasts After a Mastectomy

Researchers at the Bernard O'Brien Institute of Microsurgery in Melbourne, Australia are pioneering a radical new surgical procedure that would allow women to re-grow breasts after undergoing a mastectomy, a cancer treatment that removes part or all of a cancerous breast. After a decade of experiments in the laboratory as well as numerous tests on animal models, the researchers are ready to begin clinical trials to test the procedure in humans in the next few months. If all goes as planned, this treatment might become available within 3 years, providing an alternative to breast implants and reconstructive surgery for breast cancer patients.


Doctors would first implant a biodegradable scaffold that is in the shape of a breast. Next, they would introduce fat stem cells into the area and nearby blood vessels would be redirected towards the implanted stem cells in order to supply necessary nutrients. Within 6 - 8 months, the cells are expected to grow and fill the area enclosed by the scaffold, which is then broken down by the body.

Revolutions in science always seem grindingly slow while you're living through them in anticipation. But progress is taking place, faster with each passing year, as improvement builds upon improvement.

Eat Less, Live Longer

The New Scientist on calorie restriction: "Dreams of eternal youth feature in many cultures throughout history, but it was only in the 20th century that research into longevity really began. Much about ageing is still mysterious - we don't even know the underlying reasons why we journey into old age. There are many lines of enquiry into how to live longer, though, with one of the most intriguing being calorie restriction: in effect, going on a lifelong diet. Calorie restriction dramatically extends not only the lifespan of laboratory animals, but also their 'healthspan' - how long they live free of disease. On the assumption that it has the same effect in people, some individuals have already adopted a restricted diet. The latest evidence suggests that while calorie restriction is indeed beneficial for humans, when it comes to lifespan extension, it may not be the whole story. The good news is that we might be able to delay ageing without cutting our food intake. ... There's a definite possibility that if you balance the diet correctly, a longer lifespan can be achieved without full food restriction. ... It is unclear why eating less should make animals live longer. While a restricted diet triggers numerous changes at the molecular and genetic levels, only some of these are common across all the species tested. However, there does seem to be a general principle that a dearth of nutrients causes organisms to divert resources away from growth and reproduction and towards basic survival functions. From an evolutionary perspective, these adaptations could help an organism survive famine."


Secular Humanists and Apologism for Death

From Depressed Metabolism: "Some contemporary atheists and secular humanists do not stop at debunking the idea of God but seem to think that making a persuasive case against religion requires them to refute all of its associated ideas as well; including the desire for immortality. Paula Kirby is not the first secular person praising our limited lifespan and glorifying death: 'For atheists it is the very transience of life that helps to give it its meaning: for it prompts us to live it to the full' ... Kirby does not just repeat the hollow non-empirical cliche that life can only have meaning in the face of death but she also pretends to speak on behalf of all atheists. As can be expected, she cannot imagine an extremely long lifespan to be anything else than unspeakable boredom. When she writes that 'Susan Ertz got it spot on with her witty remark that millions yearn for immortality who don't know what to do with themselves on a rainy Sunday afternoon' one cannot help thinking that she is conveying more information about herself and Susan Ertz than about humans in general. ... It is remarkable to what extent the notion of death as not only biological but ontological necessity has permeated Western philosophy - remarkable because the overcoming and mastery of mere natural necessity has otherwise been regarded as the distinction of human existence and endeavor."


Two Films on the Topic of the Singularity that Lies Ahead

The technological singularity, when considered rigorously, is something of a framework for thinking about the future of human engineering and the capabilities of the tools we build. It is of interest to supporters of healthy life extension for the same reasons as any consideration of the future of biotechnology: we want to gain a better idea of (a) what it will take to create foreseeable medical technologies of rejuvenation, and (b) whether it is possible or plausible for these advances to arrive within our remaining lifetimes. It is self-evident that agelessness is possible in the long run, given what we know about our biology and the laws of physics:

Imagine living in a body fashioned from "designer cells" that can never age or get sick; and sporting a mind that thinks millions of times faster than today’s brain. ... experts believe that nanotech, biotech, infotech, and cognitive science advances [could] create this future.

But will the first effective rejuvenation technologies arrive in time for us to benefit? Therein lies the all-important question. Thus you will find some considerations of the singularity back in the Fight Aging! archives, such as:

On this topic, two forthcoming films examine the singularity concept:

'Turning Into Gods' - Jason Silva's Documentary on the Singularity (Trailer)

[Jason Silva's] upcoming documentary, Turning Into Gods aims to get its audience believing in the promise of technology, to spread a sense of techno-optimism. The documentary will follow Silva as he interviews the leading minds of our day, and seeks to understand (and revel) in the vast potential of the near future.

The Singularity is Near Premieres at Breckenridge Festival of Film

The feature-length documentary film presents the daring arguments from Kurzweil's New York Times bestselling book, "The Singularity is Near." He predicts that with the ever-accelerating rate of technological change, humanity is fast approaching an era in which our intelligence will become trillions of times more powerful and increasingly merged with computers. This will be the dawning of a new civilization, enabling us to transcend our biological limitations. In Kurzweil’s post-biological world, boundaries blur between human and machine, real and virtual. Human aging and illness are reversed, world hunger and poverty are solved, and we cure death.

You might also take a look at Jason Silva's short film The Immortalists, and an interview with Silva at h+ magazine.

KrioRus Cryopreserves 12th Patient

Depressed Metabolism notes that Russian cryonics provider KrioRus is forging ahead with its work: "On May 16, 2010 the only non-US cryonics provider KrioRus announced the cryopreservation of its 12th patient. The patient was pronounced legally dead on May 5 in Kiev and cryoprotectant perfusion was completed on May 7 after initial cooldown and ground transport to Moscow. A more extensive report is available here. It is encouraging to see more cryonics activity outside of the United States. The statistics of Alcor, Cryonics Institute and KrioRus indicate that there are currently more than 200 cryonics patients in the world and that more than 1,300 people have made cryonics arrangements. The 2009-1 issue of Cryonics has a two page feature on KrioRus." Every new group starts small. Cryonics is the only present way to gain a chance of evading the destruction of the self: preserving the fine structure of your brain (and thus your mind) at low temperatures in order to reach a future in which advanced medical technology can restore you. Sadly this is still a niche industry - and tens of millions die every year who might have been saved in a kinder world.


A Review of To Age or Not to Age

From Geeks of Doom, a review of To Age or Not to Age: "Immortality. We as human beings have desired it for as long as mankind has feared death. Because of the impossibility of everlasting life, we’ve lived vicariously through the fantasy of it in our books and movies and comics and TV shows and anything else that allows us to dream of possessing this amazing fictional power. But what if this once-impossibility was starting to look not only like a possibility, but more like a probability? Do I have your attention? OK, so maybe we're not looking at 'immortality' here, but To Age or Not To Age offers up the idea that we as human beings could live 20% to 40% longer, and that 120-year-old people could be able to look, feel, and move around like a 60-year-old does today. If true, it could be one of the most amazing scientific discoveries ever made. ... To Age or Not To Age is an incredible documentary to watch, and everyone should really see it themselves, because gods know I surely can't do it justice with a few words here. That, and no matter what you think after seeing the film, many great discussions and debates will come from it. Whether this revolution actually takes place in the next five to ten years or not is yet to be seen, but if you're interested in how we or our future bloodlines may just be living for hundreds of years in the future, this is the very first step."


The Carrot of Happiness

The twin incentives for engineering greater human longevity: on the one hand, we have the stick of disease, degeneration, and suffering. On the other hand we have the carrot of a life that in all other aspects generally keeps getting better. Being older brings with it wisdom, knowledge, experience, and perhaps most importantly independence - the ability to be your own person and forge your own path.

Happiness May Come With Age, Study Says:

It is inevitable. The muscles weaken. Hearing and vision fade. We get wrinkled and stooped. We can’t run, or even walk, as fast as we used to. We have aches and pains in parts of our bodies we never even noticed before. We get old. It sounds miserable, but apparently it is not. A large Gallup poll has found that by almost any measure, people get happier as they get older, and researchers are not sure why.

It's because everything except the degeneration improves with time. Getting the most out of being human is a skill, just like any other, and practice makes perfect. I think that this comment from Glenn Reynolds is quite to the point:

Well, I’m certainly happier than I was in my 20s, or even 30s. But I’m not really feeling any physical effects of aging yet. I suggest, however, that this is a good argument for life extension - if people get happier as they live longer, and if that remains true even as their bodies fall apart, they’re likely to be happier still if they remain healthy.

Youth is wasted on the young, as they say - so why not work at making youth available to everyone? It's the horror of the human condition that just as we get to the point of being practiced and elegant, the rug is pulled out from under us. But engineered healthy longevity is a very possible, plausible goal for this present age of biotechnology. Like all good things it requires work to realize: the longer we hang around not working on it, the longer it'll take to arrive.

Psychological Stress, Exercise, and Telomere Length

Researchers continue to dig into the connection between psychological stress and telomere length: "Exercise can buffer the effects of stress-induced cell aging, according to new research ... A growing body of research suggests that short telomeres are linked to a range of health problems, including coronary heart disease and diabetes, as well as early death. ... Telomere length is increasingly considered a biological marker of the accumulated wear and tear of living, integrating genetic influences, lifestyle behaviors, and stress. ... Results support [the] discovery six years earlier in premenopausal women that psychological stress has a detrimental effect on immune cell longevity, as it relates to shorter telomeres. The new study showed, however, that when participants were divided into groups - an inactive group, and an active [group] - only the inactive high stress group had shorter telomeres. The active high stress group did not have shorter telomeres. In other words, stress predicted shorter telomeres in the sedentary group, but not in the active group."


The Aging of Arteries

A general interest article on the aging of blood vessels from the Wall Street Journal: "Over time, however, the effects of high blood pressure, cholesterol, blood sugar and tobacco smoke provide a toxic milieu that injures the endothelium. That causes an inflammatory response intended to heal the artery wall, but that in the face of continuous injury only makes things worse. The progressive result is an accumulation of fatty deposits called plaque that can rupture or have their caps shear off, causing clots that lead to heart attacks. In addition, artery walls can stiffen, transforming compliant arteries into conduits like 'Styrofoam tubes' [that] increase both blood pressure and the workload on the heart. ... Both high body mass, particularly belly fat that accounts for a person's bulging waist line, and diabetes have a pernicious effect on the health of adult blood vessels. ... Even if your weight is under control, high cholesterol, high blood pressure, smoking, sedentary living and stress all are culprits that can accelerate vascular age."