Fight Aging!

Even in the opening days of the modern era of regenerative medicine it was the case that repairing spinal cord injuries was up at the top of the to-do list. It still is: numerous research groups investigating nerve repair aim to reverse the paralysis and dysfunction produced when the spinal cord is damaged. This has proven to be more of a challenge than we'd like it to be, however: work on the regeneration of heart tissue is arguably much further ahead, and the creation of decellularized replacement organs will probably overtake nerve regeneration on the way to the widespread availability of practical and effective therapies.

This doesn't mean that progress is absent. Modest advances in nerve regeneration research show up every month these days, and far more is possible in the laboratory today than was the case ten years ago. You might look at these examples of publicity for recently published studies, representative of what is presently going on in laboratory research and clinical translation of that research:

SCI patients treated with own olfactory ensheathing cells realize neurologic improvement

A team of researchers in Poland who treated three of six paraplegics with spinal cord injury using transplanted olfactory ensheathing cells (OECs) found that the three treated patients showed neurological improvement and no adverse effects while the three control patients who did not receive transplants saw no improvement.

In a phase one of this non-randomized controlled study, the team of researchers treated the three patients with transplanted self-donated (autologous) OECs and fibroblasts isolated from olfactory mucosa combined with "intense" neuro-rehabilitation. They found the treatment "safe and feasible" one year after transplantation. There was no evidence of neurological deterioration, neuropathic pain, neuroinfection or tumor growth.

"Neurophysiological examinations showed improvement in spinal cord transmission and activity of lower extremity muscles in the surgically treated patients, but not in patients receiving only neuro-rehabilitation. We consider that the transplantation of OECs was the main factor contributing to the neurologic improvements in the three transplanted patients. Among the possible mechanisms for improvement is that the transplanted OECs may have mediated some restitution along white matter tracts in these patients."

Nerve Regeneration Restores Supraspinal Control of Bladder Function after Complete Spinal Cord Injury

A life-threatening disability after complete spinal cord injury is urinary dysfunction, which is attributable to lack of regeneration of supraspinal pathways that control the bladder. Although numerous strategies have been proposed that can promote the regrowth of severed axons in the adult [central nervous system], at present, the approaches by which this can be accomplished after complete cord transection are quite limited.

In the present study, we modified a classic peripheral nerve grafting technique with the use of chondroitinase to facilitate the regeneration of axons across and beyond an extensive thoracic spinal cord transection lesion in adult rats. The novel combination treatment allows for remarkably lengthy regeneration of certain subtypes of brainstem and propriospinal axons across the injury site and is followed by markedly improved urinary function. Our studies provide evidence that an enhanced nerve grafting strategy represents a potential regenerative treatment after severe spinal cord injury.

It isn't yet possible to fully regenerate or repair a severed spinal cord and all associated function in humans or other mammals, but it's a lot closer to being possible than it was just a handful of years ago.

An association between greater levels of high-density lipoproteins and lower mortality rates in old age showed up in studies of centenarians some years back, and has since been confirmed in other research. There is still the question of what this association means, however: correlation is not causation. Here is a little more on this topic:

Most coronary deaths occur in patients older than 65 years. Age associated alterations in the composition and function of high-density lipoproteins (HDL) may contribute to cardiovascular mortality. The effect of advanced age on the composition and function of HDL is not well understood. HDL was isolated from healthy young and elderly subjects. HDL composition, cellular cholesterol efflux/uptake, anti-oxidant properties and endothelial wound healing activities were assessed.

We observed a 3-fold increase of the acute phase protein serum amyloid A, an increased content of complement C3 and proteins involved in endopeptidase/protease inhibition in HDL of elderly subjects, whereas levels of apolipoprotein E were significantly decreased. HDL from elderly subjects contained less cholesterol but increased sphingomyelin. Most importantly, HDL from elderly subjects showed defective antioxidant properties, lower paraoxonase 1 activity and was more rapidly taken up by macrophages, whereas cholesterol efflux capability was not altered.

These findings suggest that aging alters HDL composition, resulting in functional impairment that may contribute to the onset/progression of cardiovascular disease.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23792422

If researchers have a good catalog of the biochemical differences between old and young stem cells, such as the ways in which the cell surface markers are different, then they can start act on those differences: measure the effects of rejuvenation therapies; attempt to change stem cell state to restore youthful appearance and activity; and so forth. This work is a step in the direction of that catalog:

A chemical code scrawled on histones - the protein husks that coat DNA in every animal or plant cell - determines which genes in that cell are turned on and which are turned off. [Researchers have now] identified characteristic differences in "histone signatures" between stem cells from the muscles of young mice and old mice. The team also distinguished histone-signature differences between quiescent and active stem cells in the muscles of young mice.

Stem cells in several tissues of older mice, including muscle, seemed to act younger after continued exposure to younger mice's blood. Their capacity to divide, differentiate and repopulate tissues, which typically declines with an organism's advancing age, resembled those of their stem-cell counterparts in younger animals. This naturally led to curiosity about exactly what is happening inside a cell to rejuvenate it. [One] likely place to look for an answer was histones, to see if changes in the patterns of the chemical marks on them might reveal any secrets, at the cellular level, of the aging process we all experience - and, perhaps, whether there might be anything we can do about it.

The differences between quiescent and activated cells [are] mirrored by those between young and old quiescent satellite cells. "With age, there's an uptick in repressive markers. A lot more genes are locked in the 'off' position. In a division-capable cell, as opposed to the nondividing, differentiated muscle cells that activated satellite cells may someday become, it may be important to maintain a high level of repression with age. Maybe this increase in repression is a kind of tumor-suppression mechanism, keeping aging satellite cells - which could have accumulated some dangerous mutations over the passing months and years - in check."

The description of the histone-code differences between young and old cells constitutes a yardstick allowing investigators to ask which of these differences are important in aging and in rejuvenation. "We don't have the answers yet. But now that we know what kinds of changes occur as these cells age, we can ask which of these changes reverse themselves when an old cell goes back to becoming a young cell" - as appeared to be the case when tissues of older mice were exposed to blood from younger mice.

Link: http://www.eurekalert.org/pub_releases/2013-06/sumc-ssd062413.php

Research runs rapidly these days. The tools of biotechnology are improving at a pace driven by the computing industry, where progress remains blisteringly fast. Today's researcher can achieve far more and at a much lower cost than the researcher of even ten years ago. Thus new knowledge is rolling in, and every part of the body is yielding up its secrets and surprises: unusually potent stem cells where none were thought to be, a better understanding of how mitochondria actually work, and so on. Amending the textbooks on any aspect of human molecular biology is a quarterly event these days.

Today I noticed two examples of what seem to be fairly significant discoveries in brain biochemistry, of importance to Alzheimer's disease and neurodegeneration in the broader sense. They are illustrative of just how much in the way of important processes may be still be left to discover and integrate into our understanding of our own biology.

In the case of this first study, you might read it while recalling that some researchers argue for Alzheimer's as a form of diabetes, a type 3 diabetes if you like. To the degree that this is the case, Alzheimer's is a largely avoidable fate for most people, just like type 2 diabetes, its prevalence a product of lifestyle choices such as becoming sedentary and putting on weight:

A second amyloid may play a role in Alzheimer's disease

A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta Αβ plaques that are associated with Alzheimer's disease. [The] study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer's disease, as well as combined deposits of amylin and plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer's.

"We've known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now. This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer's disease."

"We found that the amylin deposits in the brains of people with dementia are both independent of and co-located with the Aβ, which is the suspected cause of Alzheimer's disease. It is both in the walls of the blood vessels of the brain and also in areas remote from the blood vessels. It is accumulating in the brain and we found signs that amylin is killing neurons similar to Αβ. And that might be the answer to the question of 'What makes obese and type 2 diabetes patients more prone to developing dementia?'"

Brain's 'garbage truck' may hold key to treating Alzheimer's and other disorders

The body defends the brain like a fortress and rings it with a complex system of gateways that control which molecules can enter and exit. While this "blood-brain barrier" was first described in the late 1800s, scientists are only now just beginning to understand the dynamics of how these mechanisms function. In fact, the complex network of waste removal, which researchers have dubbed the glymphatic system, was only first disclosed by [scientists] last August.

The removal of waste is an essential biological function and the lymphatic system - a circulatory network of organs and vessels - performs this task in most of the body. However, the lymphatic system does not extend to the brain. [One] of the reasons why the glymphatic system had long eluded comprehension is that it cannot be detected in samples of brain tissue. The key to discovering and understanding the system was the advent of a new imaging technology called two-photon microscopy which enables scientists to peer deep within the living brain. Using this technology on mice, whose brains are remarkably similar to humans, [researchers] were able to observe and document what amounts to an extensive, and heretofore unknown, plumbing system responsible for flushing waste from throughout the brain.

One of the hallmarks of Alzheimer's disease is the accumulation in the brain of the protein beta amyloid. In fact, over time these proteins amass with such density that they can be observed as plaques on scans of the brain. Understanding what role the glymphatic system plays in the brain's inability to break down and remove beta amyloid could point the way to new treatments. Specifically, whether certainly key 'players' in the glymphatic system, such as astrocytes, can be manipulated to ramp up the removal of waste.

"The idea that 'dirty brain' diseases like Alzheimer may result from a slowing down of the glymphatic system as we age is a completely new way to think about neurological disorders. It also presents us with a new set of targets to potentially increase the efficiency of glymphatic clearance and, ultimately, change the course of these conditions."

Ames dwarf mice are among the longest lived longevity mutants so far created. They lack growth hormone, and this has a large effect on their metabolism, size, and pace of aging. Here researchers compare this extension of life with that produced by calorie restriction in mice:

Since 1996, aging studies using several strains of long-lived mutant mice have been conducted. Among these studies, Ames dwarf mice have been extensively examined to seek clues regarding the role of the growth hormone/insulin-like growth factor-1 axis in the aging process. Interestingly, these projects demonstrate that Ames dwarf mice have physiological characteristics that are similar to those seen with calorie restriction, which has been the most effective experimental manipulation capable of extending lifespan in various species. However, this introduces the question of whether Ames dwarf and calorie-restricted (CR) mice have an extended lifespan through common or independent pathways.

To answer this question, we compared the disease profiles of Ames dwarf mice to their normal siblings fed either ad libitum (AL) or a CR diet. Our findings show that the changes in age-related diseases between AL-fed Ames dwarf mice and CR wild-type siblings were similar but not identical. Moreover, the effects of CR on age-related pathology showed similarities and differences between Ames dwarf mice and their normal siblings, indicating that calorie restriction and Ames dwarf mice exhibit their anti-aging effects through both independent and common mechanisms.

It is worth noting that a similar mutant, in which growth hormone receptor is removed rather than growth hormone, has a corresponding small human population in which this mutation occurred naturally, a condition known as Laron syndrome. While the mice are exceedingly long-lived in comparison to their peers, people with Laron syndrome do not appear to exhibit significantly extended lives. They are, however, somewhat resistant to diabetes and cancer.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23799173

The immune system declines with age in part because it is limited in the number of cells it can support, and too many of those cells become specialized memory cells over time, unable to contribute to the fight against new pathogens. A variety of approaches might be developed to address this issue: remove the excess memory cells, generate new immune cells from stem cells and regularly infuse them into the patient, or cause the body to start producing more new immune cells than it otherwise would.

Immune cells are created in the thymus, an organ which atrophies and diminishes its output of cells quite early in life: its evolved job is to generate an effective immune system in youth, not to keep pumping out immune cells at a high pace throughout life. Rejuvenation of the thymus to youthful activity is thus a way to boost native immune cell production, and some work in this direction is funded by the SENS Research Foundation:

SENS Research Foundation has made substantial investments in research on regenerative therapies for the aging immune system, with the aim of maintaining and restoring youthful immune function throughout life, eliminating the disparate burden of morbidity and mortality from infectious disease that falls disproportionately persons over the age of 60. We have targeted research dollars toward developing rejuvenation biotechnologies to repair the two forms of aging damage that are the most widely accepted drivers of immunosenescence.

In the lab of Dr. Janko Nikolich-Žugich at the Arizona Center on Aging, we are funding a project testing the clearance of dysfunctional, "senescent" cytotoxic CD8⁺ T-cells - cells that exert suppressive effects on the expansion and response of other, functional T-cells. And at the Wake Forest Institute for Regenerative Medicine, SENS Research Foundation is supporting Dr. John Jackson's efforts to apply the decellularized scaffold tissue engineering technique to the engineering of a transplantable thymic neo-organ.

[Researchers have recently] derived functioning [thymic epithelial progenitor cells (TEP)] from [embryonic_stem_cells], and found a way to further develop TEP into [thymic tissue] capable of supporting the development of mature T-cells from T-lymphoid progenitor cells in vivo. The success of this new study is remarkable, not only for what the investigators achieved, but for what it suggests can be achieved when its relatively crude system of thymic epithelial cell derivation and transplantation is superseded by the engineeering of true thymic neo-organs, such as those that are in development in Dr. Jackson's SENS Research Foundation-funded lab at this writing.

Already, Dr. Jackson's lab team have succeeded in seeding epithelial cells onto decellularized mouse thymus scaffolds, and they are now in the process of completing the initial characterization proliferation and coverage of these cells on the scaffolds. Soon, the reseeding procedure will be completed by seeding bone marrow stem cells purged of T-cells onto the epithelial-seeded scaffold. Once this is achieved, the production of mature T-cells by the bioengineered neo-organs will be evaluated. Advances already achieved in bioengineering other organs with decellularized scaffolds suggest a successful outcome; moreover, the thymus scaffold specifically provides the structural elements necessary for the cells that are grown on it to assume the complex microenvironmental relationships of a mature thymus.

Link: http://www.sens.org/research/research-blog/first-glimpse-thymic-rejuvenation

A mountain of evidence points to the conclusion that bearing excess body fat, particularly visceral fat, is harmful to long-term health. The more visceral fat and the longer you have it the worse off you are. That fat tissue causes chronic inflammation, alters metabolism in ways that harm organs and important biological systems, and raises the risk of suffering all of the common age-related diseases, including those that erode the mind. In general: visceral fat tissue damages you, and degenerative aging is at root an accumulation of damage.

So if you want to live a shorter life with larger medical expenses, more pain and suffering, and less of an ability to do the things you like to do, then by all means let your weight go. It's easy to get fat in a society this wealthy: we are swimming in a sea of low-cost calories and exceedingly attractive foodstuffs, having achieved a state of security from hunger that our ancestors of a few hundred years past could only have dreamed of.

We work to build the world we desire, and we are hardwired by our evolutionary past to greatly desire food without limit. It's still your choice to become fat and suffer the consequences. Easy and hardwired are no excuse, and do not remove your ability to exercise free will in the pursuit of your goals. Thin people in wealthy countries are not thin because they have magic genes, but because they choose to be thin, and put in the necessary exercise of will to stay that way.

Here are a couple more items to add to the mountain of research linking visceral fat with ill health and shorter lives. The first is of interest for the methodology the scientists are using in order to work around the primary challenge of any human epidemiological study, which is how to show cause and effect rather than just correlation:

Overweight causes heart failure - large study with new method clarifies the association

These scientists studied whether a gene variant in the FTO gene, which regulates the appetite and thereby increases the individual's [body mass index, or BMI], is also linked to a series of cardiovascular diseases and metabolism. The risk variant is common in the population, and each copy of the risk variant increases BMI by an average of 0.3-0.4 units. Since an individual's genome is not affected by lifestyle and social factors, but rather is established at conception, when the embryo randomly receives half of each parent's genome, the method is thus called "Mendelian randomization". To achieve reliable results a large study material was needed, and nearly 200,000 individuals from Europe and Australia participated.

"Epidemiological studies look for associations in large populations, but it is usually difficult to reliably determine cause and effect - what we call causality. By using this new genetic method, Mendelian randomization, in our research, we can now confirm what many people have long believed, that increased BMI contributes to the development of heart failure."

The results show that an increase of one unit of BMI increases the risk of developing heart failure by an average of 20 per cent. Further, the study also confirms that obesity leads to higher insulin values, higher blood pressure, worse cholesterol values, increased inflammation markers, and increased risk of diabetes.

Exercise benefits patients with type 2 diabetes

Moderate-intensity exercise reduces fat stored around the heart, in the liver and in the abdomen of people with type 2 diabetes mellitus, even in the absence of any changes in diet. "Based on previous studies, we noticed that different fat deposits in the body show a differential response to dietary or medical intervention. Metabolic and other effects of exercise are hard to investigate, because usually an exercise program is accompanied by changes in lifestyle and diet."

For the new study, [researchers] assessed the effects of exercise on organ-specific fat accumulation and cardiac function in type 2 diabetes patients, independent of any other lifestyle or dietary changes. The 12 patients, average age 46 years, underwent MRI examinations before and after six months of moderate-intensity exercise totaling between 3.5 and six hours per week and featuring two endurance and two resistance training sessions. The exercise cycle culminated with a 12-day trekking expedition.

MRI results showed that, although cardiac function was not affected, the exercise program led to a significant decrease in fat volume in the abdomen, liver and around the heart, all of which have been previously shown to be associated with increased cardiovascular risk.

It is in fact possible to diet your way out of type 2 diabetes via a sustained low calorie intake, even at fairly late stages in the progression of the condition. That may operate partially through the mechanism of reducing the amounts of visceral fat tissue present in the body. All in all type 2 diabetes really is a self-inflicted and self-maintained medical condition for most people these days, now that it isn't just a disease of the very old and frail. With sufficient application of effort any non-frail patient can make his or her condition largely go away at any point before its end stages.

Hormesis is the way in which a minor amount of damage can be beneficial to an organism: it awakens cellular repair and maintenance mechanisms that fix that damage and then go on to more energetically fix other damage for an extended period of time. So the net result is a more robust, better maintained individual with a longer life expectancy. There are hormetic components to the benefits of exercise, calorie restriction, mild heat stress, and so on.

Mild radiation damage is one of the ways in which hormesis can be achieved, as examined in this review paper:

This paper assesses the capacity of ionizing radiation to extend the lifespans of experimental insect models based on the peer-reviewed literature. Ionizing radiation biphasically affects the lifespans of adult males and females for a broad range of insect models with high doses reducing lifespan whereas lower doses can enhance lifespan, typically in the 20-60% range.

The average adult insect lifespan can be increased when ionizing radiation exposure is administered during early developmental stages or during the adult stage. The effective dose inducing the average adult insect lifespan enhancement may vary considerably depending upon which life stage is exposed. Recent findings have identified specific genes affecting anti-oxidant defenses, DNA repair, apoptosis and heat shock proteins as well as several cell signaling pathways that mediate the longevity enhancing hormetic response.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23793937

Researchers here stop the reduction in number of sensory cells in the ear, one of the causes of progressive age-related deafness, by slowing the pace of programmed cell death (apoptosis). If employed as a general strategy for reducing losses in any important cell population this will probably lead to an increased risk of cancer: researchers are in effect making damaged cells work for longer. It is unclear at this point as to whether that is either true or a meaningful risk in any specific case, however, especially when small numbers of cells are involved:

Mcl-1 is an anti-apoptotic member of the Bcl-2 family that modulates apoptosis-related signaling pathways and promotes cell survival. We have previously demonstrated a reduction of Mcl-1 expression in aging cochleae. To investigate whether restoring Mcl-1 expression would reduce aging-related cochlear degeneration, we developed a rat model of Mcl-1 overexpression.

A plasmid encoding human Mcl-1/enhanced green fluorescent protein was applied to the round window of the cochlea. This in vivo treatment transfected both the sensory and supporting cells of the cochlear sensory epithelium and enhanced Mcl-1 expression at both the mRNA and the protein level. The upregulation of Mcl-1 expression reduced the progression of age-related cochlear dysfunction and sensory cell death. Furthermore, the transfection of Mcl-1 exerted its protective effect by suppressing cochlear apoptosis at the mitochondrial level. This study demonstrates that the genetic modulation of Mcl-1 expression reduces the progression of age-related cochlear degeneration.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23790646

This is the question posed and not answered by a recent paper from a German institution, accompanied by a very tersely worded abstract:

Do we age because we have mitochondria?

The process of aging remains a great riddle. Production of reactive oxygen species (ROS) by mitochondria is an inevitable by-product of respiration, which has led to a hypothesis proposing the oxidative impairment of mitochondrial components (e.g., mtDNA, proteins, lipids) that initiates a vicious cycle of dysfunctional respiratory complexes producing more ROS, which again impairs function. This does not exclude other processes acting in parallel or targets for ROS action in other organelles than mitochondria.

Given that aging is defined as the process leading to death, the role of mitochondria-based impairments in those organ systems responsible for human death (e.g., the cardiovascular system, cerebral dysfunction, and cancer) is described within the context of "garbage" accumulation and increasing insulin resistance, type 2 diabetes, and glycation of proteins.

The processes involved in mitochondria-based impairments are very similar across a large range of organisms. Therefore, studies on model organisms from yeast, fungi, nematodes, flies to vertebrates, and from cells to organisms also add considerably to the understanding of human aging.

Would we age without mitochondria? Certainly. Mitochondrial damage and dysfunction is only one of the most likely fundamental differences between young tissue and old tissue. Other similarly fundamental differences include the build up of amyloids, lipofuscin, and cross-linked proteins (the glycation of proteins mentioned in the abstract above), and there is no reasonable case to be made for those aspects of aging to be dependent on mitochondrial function. If all our mitochondria were removed and replaced with black box nanomachines that performed the same tasks for an indefinite period of time without wear or failure, then we would still suffer degenerative and eventually fatal aging due to the other forms of accumulated damage that harm our tissues.

(Replacing our mitochondria with something that doesn't fall apart and progressively sabotage us is actually a very plausible and desirable goal for the future of medicine. But the first strides in the that direction will probably take the form of simple replacement: introduce new mitochondria or new mitochondrial DNA to take up the slack).

Why do we age at all? There are plenty of species that age far less visibly than we do, suffering little reduction in vigor and resistance until very late in the game. But they have mitochondria too, so I don't think we can lay the roots of aging at the feet of mitochondrial biology. If there were no mitochondria, then the forces of natural selection would still result in the vast majority of species consisting of individuals that age to death. The only differences would be in the details of how eventually fatal damage arises and progresses. The world changes, and that favors aging as an outcome of successful strategies in evolutionary competition.

When conditions change, a senescent species can drive immortal competitors to extinction. This counter-intuitive result arises from the pruning caused by the death of elder individuals. [While] senescence damages the individuals and has an evolutionary cost, it has a benefit of its own. It allows each lineage to adapt faster to changing conditions.

This is all natural, but not good. It is natural like anthrax, dying of exposure, plague, and famine. Our ancestors toiled hard to defeat the aforementioned line items, very successfully in recent centuries, and research and development efforts continue today. Here and now we can also choose to do something about the causes of aging, an option that wasn't available until the present time: mitochondrial damage, amyloids, and the other causes of aging can all be addressed with the tools of the biotechnology revolution. So we should get on with it, and those of us without the necessary skills to work in the laboratory should help to fund those who do.

Advanced glycation endproducts (AGEs) are one of the root causes of aging. Many different types of AGE are created as a byproduct of ordinary metabolic operation and also arrive in the diet. Their levels rise and fall over time depending on circumstances and the body's efforts to clear out these unwanted compounds. The hardiest forms of AGE are a challenge, however: they lurk in your tissues in growing amounts as the years pass, disrupting important biological machinery, provoking chronic inflammation, and altering cellular behavior for the worse. Of these various types of AGE the most important by far in human tissues is glucospane, but very little attention is given to finding ways to break down and clear glucosepane from the body despite the consensus that this is a desirable goal.

So the SENS Research Foundation funds work on developing a glucosepane-clearing therapy, and is one of only two or three research organizations in the world to do so - and none of those programs are particularly large or active. The SENS work might be the largest glucosepane research program in the world at this point. Still, it looks like at least some other researchers are knowledgeable enough in this area to issue their own calls to action, and that is welcome, even when those calls to action are mild in comparison to those of the SENS program. A greater diversity of funding and more research groups focused on glucosepane can only be a good thing:

Advanced glycation end products (AGEs) represent a family of protein, peptide, amino acid, nucleic acid and lipid adducts formed by the reaction of carbonyl compounds derived directly or indirectly from glucose, ascorbic acid and other metabolites such as methylglyoxal. AGE formation in diabetes is of growing importance for their role as markers and potential culprits of diabetic complications, in particular retinopathy, nephropathy and neuropathy.

Development of sensitive and specific assays utilizing liquid chromatography mass spectrometry with isotope dilution method has made it possible to detect and quantitate non-UV active AGEs such as carboxymethyl-lysine and glucosepane, the most prevalent AGE and protein crosslink of the extracellular matrix.

The results of [studies on AGE formation in two skin biopsies] show that while several AGEs are associated and predict complication progression, the glucose/fructose-lysine/glucosepane AGE axis is one of the most robust markers for microvascular disease, especially retinopathy, in spite of adjustment for past or future average glycemia. Yet overall little biological and clinical information is available on glucosepane, making this review a call for data in a field of growing importance for diabetes and chronic metabolic diseases of aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23787467

Earlier this month, I pointed out a series of articles that examined how we might go about developing the means to gradually replace neurons in the brain with nanomachines that serve the same purpose and integrate fully with the remaining natural neurons. If the pace of that process is slow, on a par with natural levels of neurogenesis and cell turnover, then we could argue that you remain you even though the end result is a completely artificial brain: the self is preserved.

This sort of process is a necessary precondition to live for much longer than a few thousand years following the development of rejuvenation biotechnology that can indefinitely prolong healthy, youthful life. Accidents happen, and the best way to reduce the chance of a fatal accident to negligible levels is to switch out the body and brain for more durable machinery.

Following on from that, here is a consideration of some of the details of replacing just portions of a cell with artificial components that perform the same function, but are immune by design to the degraded function known to occur in aging:

In this essay I argue that technologies and techniques used and developed in the fields of Synthetic Ion Channels and Ion-Channel Reconstitution, which have emerged from the fields of supramolecular chemistry and bio-organic chemistry throughout the past 4 decades, can be applied towards the purpose of gradual cellular (and particularly neuronal) replacement to create a new interdisciplinary field that applies such techniques and technologies towards the goal of the indefinite functional restoration of cellular mechanisms and systems.

In earlier essays I identified approaches to the synthesis of non-biological functional equivalents of neuronal components (i.e., ion-channels, ion-pumps, and membrane sections) and their sectional integration with the existing biological neuron. It has only recently come to my attention that there is an existing field emerging from supramolecular and bio-organic chemistry centered around the design, synthesis, and incorporation/integration of both synthetic/artificial ion channels and artificial bilipid membranes (i.e., lipid bilayer). The potential uses for such channels commonly listed in the literature have nothing to do with life-extension, however, and the field is, to my knowledge, yet to envision the use of replacing our existing neuronal components as they degrade (or before they are able to).

I argue here that the very technologies and techniques that constitute the field (Synthetic Ion Channels and Ion-Channel/Membrane Reconstitution) can be used towards the purposes of indefinite longevity and life-extension through the iterative replacement of cellular constituents so as to negate the molecular degradation they would have otherwise eventually undergone.

Link: http://www.rationalargumentator.com/index/blog/2013/06/intimations-of-imitations/

Targeting is the future of cancer treatment. The fact that treatments can be targeted to cancer cells with even a moderate level of precision is the important factor, not the nature of the mechanism used to destroy those cells. Targeting means few or no side effects, which in turn means that more potent attacks can be conducted on cancerous cells: no more will cancer therapy be a matter of finely juggling whole-body chemical infusions to kill as much of the cancer as possible without killing or crippling the patient.

Many different cell killing mechanisms have been demonstrated in the laboratory in conjunction with forms of targeting - there are any number of ways to sabotage a cell to the point at which it self-destructs, such as by dumping in enough heat, or radiation, or toxic molecules, or carefully selected sabotaging proteins that throw a spanner into cellular machinery. When nanoparticles are used as the delivery platform, researchers can even load them up with old-school chemotherapy drugs: minute amounts attached to each nanoparticle, but enormous doses for each individual cancer cell in comparison to what would be received in the standard form of presently widespread chemotherapy.

Here are two examples of other methods of targeting cancer presently under development: a gene therapy delivered by engineered virus, and altered immune cells that are programmed to attack and destroy cells with cancerous surface markers.

Targeted viral therapy destroys breast cancer stem cells in preclinical experiments

A promising new treatment for breast cancer [has] been shown in cell culture and in animal models to selectively kill cancer stem cells at the original tumor site and in distant metastases with no toxic effects on healthy cells, including normal stem cells. Melanoma differentiation associated gene-7 (mda-7), also known as interleukin (IL)-24, has been shown to directly impact two forms of cell suicide known as apoptosis and toxic autophagy, regulate the development of new blood vessels and also play a role in promoting cancer cell destruction by the immune system. In the present study, the researchers used a recombinant adenovirus vector, an engineered virus with modified genetic material, known as Ad.mda-7 to deliver the mda-7/IL-24 gene with its encoded protein directly to the tumor.

Since discovering the mda-7/IL-24 gene, Fisher and his team have worked to develop better ways to deliver it to cancer cells, including two cancer "terminator" viruses known as Ad.5-CTV and Ad.5/3-CTV. Cancer terminator viruses are unique because they are designed to replicate only within cancer cells while delivering immune-modulating and toxic genes such as MDA-7/IL-24. Coupled with a novel stealth delivery technique known as ultrasound-targeted microbubble destruction (UTMD), researchers can now systemically deliver viruses and therapeutic genes and proteins directly to tumors and their surrounding tissue (microenvironment) at both primary and metastatic tumor sites. UTMD uses microscopic, gas-filled bubbles that can be paired with viral therapies, therapeutic genes and proteins, and imaging agents and can then be released in a site and target-specific manner via ultrasound. Fisher and his colleagues are pioneering this approach and have already reported success in experiments utilizing UTMD technology and mda-7/IL-24 gene therapy in prostate and colorectal cancer models.

Modified immune cells seek and destroy melanoma

All cells express a complex known as the proteasome, which acts as the garbage disposal for the cell. There are two types of proteasomes: constitutive proteasomes (cPs), which are found in normal tissues, and immunoproteasomes (iPs), which are found in stressed or damaged cells. In a damaged cell, the iP generates protein fragments that are displayed on the surface of the distressed cells, triggering recognition by dendritic cells and subsequent destruction by the immune system.

Most cancers, including melanoma, exclusively express cPs, making it impossible for them to express the protein fragments that are recognized by the immune system. To make it easier for the immune system to find cancer cells, [researchers] engineered a specific type of immune cell, known as a dendritic cell, that recognizes protein fragments of cancer specific antigens made by cPs. The engineered dendritic cells were then injected into patients that were in remission from melanoma.

The trial consisted of 4 patients that were vaccinated with regular dendritic cells, 3 patients that received cells that underwent a control treatment, and 5 patients that received dendritic cells that recognized cancer-made protein fragments. Vaccination with all three types of dendritic cells elicited an immune response, which peaked after 3-4 vaccinations with dendritic cells. Patients that received the specially modified dendritic cells had a longer lasting immune response and fewer circulating melanoma cells. Of the two patients that had active disease, treatment with modified dendritic cells resulted in a partial clinical response in one and a complete clinical response in the other.

A number of other forms of targeting are further ahead in the process of development than the two examples above: there is a lot of variety in the approaches used, and that is a very good thing. Competition drives progress. It is not unreasonable to think that cancer will be a controllable part of our biology twenty years from now, gone the way of tuberculosis to become something that can only seriously harm you if you do not have access to clinical medicine.

A number of lines of research have suggested that telomere length and mitochondrial damage are linked in some way. The research result below is noted with the caveat that it is very easy to find correlations in aging, however, as aging is a global process in which everything declines.

Both telomere length and mitochondrial function are accepted as reflective indices of aging. Recent studies have shown that telomere dysfunction may influence impaired mitochondrial biogenesis and function. However, there has been no study regarding the possible association between telomere and mitochondrial function in humans. Therefore, the purpose of the study was to identify any relationships between mitochondrial and telomere function. The present study included 129 community-dwelling, elderly women. The leukocyte mitochondrial DNA copy number and telomere length were measured using a quantitative real-time polymerase chain reaction method.

Leukocyte mtDNA copy number was positively associated with telomere length. With a stepwise multiple regression analysis, telomere length was found to be an independent factor associated with leukocyte mtDNA copy number after adjustment for confounding variables including age [and] body mass index. Our findings suggest that telomere function may influence mitochondrial function in humans.

Link: http://dx.doi.org/10.1371/journal.pone.0067227

A simplistic view of telomere length seems to be percolating into the public view of aging, judging by some of the recent discussions on the topic I've encountered. The average disinterested fellow in the street might now have the idea that telomeres somehow get shorter and in doing so cause aging. I expect that this mistaken echo from the halls of science will be reinforced as new telomere assessment services flush with venture funding continue to publicize themselves via the mainstream media.

In fact, telomere length is fairly dynamic and varied, and a lot of uncertain remains in its role in aging. In immune cells the average telomere length seems to correlate well with general health on a statistical basis across a population, being on average shorter in ill people. There are ways to measure telomere length in some animal species that do a good job of predicting likely life expectancy. Delivering additional telomerase, the enzyme that lengthens telomeres, to mice increases their life span. Nonetheless, it's very much up in the air as to whether reduced telomere length is a cause of aging versus a secondary effect of other processes that nonetheless causes some harm of its own, versus just being a marker of the progression of degenerative aging. That telomerase therapy might be extending life through some unrelated function of telomerase, perhaps one involving reducing the level of mitochondrial damage in cells.

Of the mechanisms of aging cataloged in the SENS rejuvenation research proposals, only cancer prevention involves telomeres. All of the other ways in which your metabolism becomes damaged over time have nothing much to do with telomere length. But here is a recent article on science and longevity that focuses on telomeres:

[Telomeres are] tiny structures at the ends of your chromosomes that keep them from fraying and losing crucial bits of genetic information. What interests researchers who study aging is that when cells divide, their telomeres get shorter. Once they get too short, cells stops dividing and may die. Played out across the whole body, there's mounting evidence that shorter telomeres translate into increased susceptibility to diseases and the gradual wearing out of tissues that is the hallmark of old age.

It's tempting to think of our telomeres as the cellular equivalents of the grim reaper's hourglass, counting out our predetermined life spans. But the hourglass can get periodic refills - thanks to an enzyme called telomerase, which acts to build telomeres back up. And the rise of telomere testing for consumers is also pegged to evidence that telomere length is not just an inherited inevitability but may be influenced by factors such as stress, exercise and nutrition. The thinking is, if you can regularly monitor your telomere length, you'll be more apt to do the right things to slow the rate at which they're burning away.

Despite media reports, telomeres do not actually tell you how long you are going to live. That's because there's a huge variation between individuals. A teenager can have shorter telomeres than a 70-year-old, yet that teenager is far more likely to still be around in 20 years. The correlation between telomere length and lifespan is something that emerges when larger numbers of individuals are analyzed as a group.

With the field still trying to figure out exactly how telomeres relate to aging and health, some researchers express strong reservations about telomere testing for health assessment - and taking tests at face value. "It's easy to get correlations in aging, because many, many things are affected as you get older," says David Harrison, a gerontologist at the Jackson Laboratory in Bar Harbor, Me. While he doesn't rule out that telomeres play a role in aging, he is not persuaded that their role is clear or that telomere testing is meaningful. And he is wary, he says, when researchers in the field have a commercial interest in the testing technology.

Link: http://www.theglobeandmail.com/life/health-and-fitness/health/how-science-plans-to-helps-us-live-to-150-and-soon/article12754905/?page=all

Exercise is good for you: there is a big difference in likely long term health between moderate regular exercise and being sedentary. Exercise seems to be roughly on a par with calorie restriction when it comes to improving health and extending average life span, but interestingly it doesn't extend maximum life span in the way that calorie restriction does in animal studies. There is that intriguing disconnect between improved long-term health and maximum observed longevity that someone, one day, will be able to explain: from a naive perspective that considers aging to be accumulated damage, you'd expect it that any improvement in health over the long term would tend to push out maximum life span.

While the difference between no exercise and moderate exercise (the traditionally recommended 30 minutes of aerobic exercise a day that every doctor will tell you about) is well supported by the evidence, it's harder to say that more is better, or that some exercise is better than other exercise. Human data shows us that athletes are longer lived than the rest of us on average, for example, but it's far from clear that they are long-lived because they exercise, versus there being a bias towards athletics as a career for more robust individuals who would have lived longer anyway.

Going by the published research, the 80/20 win for personal health involves taking the 30 minutes a day at this point. A recent paper suggests that it doesn't matter how you rack up the time so long as it's somewhat regular:

Total amount of exercise important, not frequency, research shows

[Researchers] studied 2,324 adults from across Canada to determine whether the frequency of physical activity throughout the week is associated with risk factors for diabetes, heart disease and stroke. "The findings indicate that it does not matter how adults choose to accumulate their 150 weekly minutes of physical activity. For instance, someone who did not perform any physical activity on Monday to Friday but was active for 150 minutes over the weekend would obtain the same health benefits from their activity as someone who accumulated 150 minutes of activity over the week by doing 20-25 minutes of activity on a daily basis."

So in general keep in mind that the outcomes with exercise are much better than those without it. Living a sedentary life is a matter of stabbing yourself in the back thirty years down the line: making your future more expensive, more painful, and shorter. Perhaps the pace of medical science will keep up with you and you'll be rescued by new medical technologies - but why take risks that you don't have to?

Exercise training as a preventive tool for age-related disorders: a brief review

There is structural and functional deterioration of almost all physiological systems during aging, even in the absence of discernible disease, resulting in reduced independence and increased incidence and progression of chronic diseases in older adults.

However, regular participation in physical activity and/or exercise training programs can minimize the physiological alterations that occur during aging and may contribute to improvements in health and well-being. Numerous studies have shown that exercise training programs improve the muscle strength, balance, cardiorespiratory fitness, metabolism, glucose tolerance, daily living activities and psychological health of elderly people, even those in their 80s or 90s. Accordingly, national and international agencies have recommended regular physical activity or exercise participation to promote older adult health and disease prevention.

In this context, avoiding a sedentary life style by performing any type or level of daily exercise is a prudent recommendation to follow as it will reduce the impact of aging on some physiological functions, reduce the risk of developing chronic disease and prevent premature mortality, regardless of age.

Ultimately, of course, you can't treadmill your way out of aging to death. What you can do is make life more likely to be pleasant and longer by a handful of years. The studies that compare those who exercise with those who don't suggest that the value of being active is 5 to 10 years of life expectancy, a bonus above and beyond the health benefits. If you want to live longer than that, and with greater certainty of a long future ahead, then the development of new medical technology is the only viable way forward. The earlier you start helping to make foreseeable technologies of human rejuvenation a reality, the more likely it is that they will exist in time to save you from the frailty, suffering, and death caused by degenerative aging.

The two extremes of theorizing on the process of aging might be seen as (a) arguing that aging is damage that causes metabolism to react, alter its processes, and ultimately fail, and (b) arguing that aging is a harmful programmed change in the operation of metabolism, the result of evolved processes that are beneficial in youth continuing past the point at which natural selection operates strongly and progressively becoming ever more damaging to the individual. The views held by researchers tend towards one side of the aisle or the other, largely favoring aging as damage, but it's not a black and white thing: it's perfectly possible to think that some portions of aging are spawned by damage while other portions are programmed, or that the answer is different in different species.

This paper leans towards the programmed side of the house in discussing GSK-3 in the context of the biology of aging. It's a study that only shows accelerated aging, however. This is always less convincing as an argument that a particular gene or protein is related to longevity because researchers can create what appears to be accelerated aging by breaking any number of important biological mechanisms so as to cause more damage and dysfunction in an organism. Very few of those changes can be turned in the opposite direction and shown to extend life, however - and extending life rather than shortening it is the crucial test of relevance:

Very few enzymes exert as broad a regulatory influence on cellular functions as do the two isoforms of GSK-3(α and β). The substrates that are phosphorylated by GSK-3s can be classified into four categories: metabolic enzymes, signaling molecules, structural proteins, and transcription factors, typically involved in regulating cell proliferation and differentiation; cellular metabolism, cell survival and cell cycle regulation. Additionally, GSK-3 has been linked to several chronic diseases, including diabetes and Alzheimer disease. Nevertheless, it was not clear whether GSK-3 might regulate aging.

Our recent work seems to clearly implicate GSK-3, and specifically the α isoform, in aging. Through targeting GSK-3α in the mouse, we found accelerated development of age-related pathologies in multiple organ systems. These included accelerated aging in the bone/skeletal system, leading to severe degenerative joint disease that was accompanied by increased inflammatory cytokines. The gut and liver also showed clear signs of accelerated aging. But the most striking findings were seen in the heart and skeletal muscle (i.e. striated muscle). These organ systems developed profound hypertrophy and dysfunction.

Notably, [we] saw innumerable structurally abnormal organelles, in particular (but not limited to) disrupted mitochondria. The profound nature of this suggested that the [mice] were unable to clear these damaged organelles, possibly implicating dysfunctional autophagy. We confirmed that [knockout] of GSK-3α markedly activated mTOR, and knowing that mTOR suppresses autophagy, we asked if autophagy was dysregulated. We confirmed that it was.

The key remaining question was whether this dysregulation of autophagy was leading to (or at least contributing to) the abnormalities of striated muscle. We employed a second generation inhibitor of mTORC1, everolimus, and found that both cardiac contractile abnormalities and skeletal muscle abnormalities were largely corrected. It remains to be seen whether the numerous other organ systems that we found to be dysfunctional in the absence of GSK-3α will also be corrected by mTORC1 inhibition.

I'd be inclined to read this as simply a confirmation that GSK-3 sits in the same general set of aging-related mechanisms as mTOR, and that autophagy, once again, is shown to be a very important aspect of health and longevity.

Link: http://impactaging.com/papers/v5/n6/full/100568.html

Research into sirtuins in relation to longevity has consumed a great deal of money over the past decade, more than enough to fully implement the Strategies for Engineered Negligible Senescence in mice, and yet there is very little to show for it aside from an increased knowledge of one small area of metabolism in a range of species. A drug to slightly slow the pace of aging in humans might yet result in the future, but if it does emerge then it is unlikely to provide greater benefit than, say, the practice of calorie restriction.

This is absolutely characteristic of present mainstream research into interventions in aging: expensive, slow, unlikely to produce results, and the plausible future outcomes if successful will be of limited benefit. Yet so much money has flowed into work on sirtuins that it has inertia now: research and attempts at development will continue until someone finds a way to shoehorn sirtuin activating drugs into a marginal therapy for something. This is a great pity: there are far better ways forward, more productive research plans for therapies to treat aging and age-related disease.

Here is a familiar refrain on sirtuins, nothing that we haven't heard before: a combination of interesting new details on metabolism relating to sirtuins and beating the drum with promises of future treatments under the implicit assumption of further funding for present research.

A gene called SIRT1, previously shown to protect against diseases of aging, plays a key role in controlling circadian rhythms. [Researchers] found that circadian function decays with aging in normal mice, and that boosting their SIRT1 levels in the brain could prevent this decay. Conversely, loss of SIRT1 function impairs circadian control in young mice, mimicking what happens in normal aging. Since the SIRT1 protein itself was found to decline with aging in the normal mice, the findings suggest that drugs that enhance SIRT1 activity in humans could have widespread health benefits. "If we could keep SIRT1 as active as possible as we get older, then we'd be able to retard aging in the central clock in the brain, and health benefits would radiate from that."

[Researchers] created genetically engineered mice that produce different amounts of SIRT1 in the brain. One group of mice had normal SIRT1 levels, another had no SIRT1, and two groups had extra SIRT1 - either twice or 10 times as much as normal. Mice lacking SIRT1 had slightly longer circadian cycles (23.9 hours) than normal mice (23.6 hours), and mice with a 10-fold increase in SIRT1 had shorter cycles (23.1 hours). In mice with normal SIRT1 levels, the researchers confirmed previous findings that when the 12-hour light/dark cycle is interrupted, younger mice readjust their circadian cycles much more easily than older ones. However, they showed for the first time that mice with extra SIRT1 do not suffer the same decline in circadian control as they age.

"I think we should look at every aspect of the machinery of the circadian clock in the brain, and any intervention that can maintain that machinery with aging ought to be good. One entry point would be SIRT1, because we've shown in mice that genetic maintenance of SIRT1 helps maintain circadian function." Some SIRT1 activators are now being tested against diabetes, inflammation and other diseases, but they are not designed to cross the blood-brain barrier and would likely not be able to reach the [suprachiasmatic nucleus that controls circadian cycles]. However, [researchers believe] it could be possible to design SIRT1 activators that can get into the brain.

Link: http://www.eurekalert.org/pub_releases/2013-06/miot-tlb061913.php

This year's Global Future 2045 conference took place earlier this week. The focus, as for other aspects of the 2045 Initiative, is on creating artificial bodies and minds and the many technologies needed to support that goal. There is also a fair-sized chunk of social utopianism driving the Initiative's founder, Dmitry Itskov, and that shows in the way he presents his vision for a machine humanity: not just a proposal to eliminate the death and suffering caused by aging and disease, but also to undermine as much as possible of the basis for man's ongoing inhumanity to man.

We shall see how well that plays. Certainly analogous and admired visions have emerged from the past few decades of transhumanist writing, such as the Hedonistic Imperative: technology shackled primarily to the goal of ending pain and suffering, with the defeat of aging and disease merely one necessary line item along the way. But this is more or less the opposite way round from the way in which I usually think of these things: I say focus on building the technologies of rejuvenation and disease control first, second, and last of all, and let society sort itself out. Creating the means to reduce suffering and involuntary death is a worthy goal to focus on regardless of how people choose to behave towards one another.

A couple of press items on the Global Futures 2045 conference have emerged in the past few days, and some of them manage to avoid the eye candy robotics in favor of noting more interesting items. In the first case below, that means getting the essence of Aubrey de Grey's SENS proposals wrong, but such is life.

Dmitry Itskov's Immortal Robots Hit the Big Stage, in Name Only

There's a broader question that's yet to be broached: If we're searching for immortality, do we really need to become robots? Conference attendee Aubrey de Grey, the biologist and longevity scientist known for his colorful interviews and wizard beard, thinks the biological solution to eternal life will be available first as it is "easier" to achieve. Much of de Grey's research revolves around solving the free radical problem, through which rogue molecules accumulate inside and randomly damage our cells, which in turn make us age. As biological robots, our bodies should be able to repair themselves indefinitely, but free radicals prevent cells from doing this after you reach a certain age.

The prospect of his research failing to find a cure for aging before Itskov's timeline plays out doesn't phase Grey one bit. When asked how he would feel about his work becoming obsolete if the goals of the 2045 initiative come to fruition, Grey responded with a smile and "good, the sooner the better."

This is what the world will look like in 2045

"It's not so hard to predict the future, but it's sometimes hard to connect the dots." In the opening of his lecture to the Global Futures 2045 Congress, famed geneticist Dr. George Church neatly summed up what being a futurist is all about, though he was reminding the audience rather than the other speakers assembled at Alice Tully Hall in New York City this past weekend. Gathered there by a young Russian tech tycoon on a mission to do nothing less than achieve immortality through technology, a who's-who of renowned technologists, scientists, futurists, and entrepreneurs painted a sometimes terrifying, sometimes electrifying picture of what the world is going to look like in the decades to come, describing how technology is going to drastically alter economies, biologies, and perhaps even consciousness itself.

'Mind Uploading' and Digital Immortality May Be Reality By 2045, Futurists Say

By 2045, "based on conservative estimates of the amount of computation you need to functionally simulate a human brain, we'll be able to expand the scope of our intelligence a billion-fold," Kurzweil said. Itskov and other so-called "transhumanists" interpret this impending singularity as digital immortality. Specifically, they believe that in a few decades, humans will be able to upload their minds to a computer, transcending the need for a biological body. The idea sounds like sci-fi, and it is - at least for now. The reality, however, is that neural engineering is making significant strides toward modeling the brain and developing technologies to restore or replace some of its biological functions.

I shouldn't have to repeat myself to say that the 2045 timeline seems overly ambitious, and for all the same reasons as Ray Kurzweil's projections seem overly ambitious. For so long as we are still essentially human, it takes a certain minimum amount of time to organize a business, raise funding, process and assimilate new knowledge into the entrepreneurial and scientific zeitgeist, and so on. The technological capabilities discussed at Global Futures 2045 will come to pass, but not for at least another few decades, I think.

That said, nothing wrong with aiming high if you're in the business of working on the problem rather than just talking about it. It's just a pity that working towards machines to replace biology is highly unlikely to be of greater benefit over the next thirty years than working on rejuvenation biotechnology after the SENS model. Progress on the problem of aging in the next thirty years is critical for those of us in middle age today: it determines whether we make it or not, whether we live for as long as our parents, or we live for thousands of years in a golden future of ever-increasing technological capabilities.

There are a good number of genes with quirky names, and sonic hedgehog might not even be the quirkiest. Here researchers increase levels of the protein produced by this gene to roll back some of the loss of muscle regenerative capacity that occurs with aging:

Sonic hedgehog (Shh) is a morphogen regulating muscle development during embryogenesis. We have shown that the Shh pathway is postnatally recapitulated after injury and during regeneration of the adult skeletal muscle and regulates angiogenesis and myogenesis after muscle injury. Here, we demonstrate that in 18-month-old mice, there is a significant impairment of the upregulation of the Shh pathway that physiologically occurs in the young skeletal muscle after injury. Such impairment is even more pronounced in 24-month-old mice.

In old animals, intramuscular therapy with a plasmid encoding the human Shh gene increases the regenerative capacities of the injured muscle, in terms of Myf5-positive cells, regenerating myofibers, and fibrosis. At the molecular level, Shh treatment increases the upregulation of the prototypical growth factors, insulin-like growth factor-1 and vascular endothelial growth factor. These data demonstrate that Shh increases regeneration after injury in the muscle of 24-month-old mice and suggest that the manipulation of the Shh pathway may be useful for the treatment of muscular diseases associated with aging.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23781099

MicroRNA molecules are a part of the complex machinery of gene expression that builds proteins from the blueprints encoded in DNA. This machinery determines levels of specific proteins in a cell. By doing so it steers cell processes, and is in turn steered by the structures and activities of those proteins. A cell is an enormously intricate feedback loop.

Individual differences in longevity exist for entities living in very similar environments, and these differences have to arise from some collection of mechanisms - such as the differences in gene expression between individuals. Here researchers move from checking global gene expression levels to checking microRNA levels in much the same way: to see if they can find correlations between specific microRNA molecules and individual longevity. No amazing results yet, but these are early days:

In the round worm Caenorhabditis elegans, genetically identical animals exhibit large differences in their lifespan with associated declines in motor skills and pathogen resistance. We have previously shown that aging behavioral phenotypes in individual worms are associated with statistically significant changes in gene expression. We hypothesized that the distinct age dependent gene expression profiles that exist between genetically identical individuals are likely to be mediated through variations in gene regulatory networks. miRNAs represent likely candidates for mediating some of this variation in expression as they are known modulators of gene expression, which have been shown to act to facilitate the robustness of such networks.

We measured the abundance of 69 miRNAs expressed in individual animals at different ages [and] found that miRNA abundance was highly variable between individual worms raised under identical conditions and that expression variability generally increased with age. To identify expression differences associated with either reproductive or somatic tissues, we analyzed wild type and mutants that lacked germlines. miRNAs from the mir-35-41 cluster increased in abundance with age in wild type animals, but were nearly absent from mutants lacking a germline, suggesting their age-related increase originates from the germline. Most miRNAs with age-dependent levels did not have a major effect on lifespan, as corresponding deletion mutants exhibited wild-type lifespans. The major exception to this was mir-71, which increased in abundance with age and was required for normal longevity. Our genetic characterization indicates that mir-71 acts at least partly in parallel to insulin/IGF like signals to influence lifespan.

Link: http://impactaging.com/papers/v5/n6/full/100564.html

Naked mole rats are exceedingly long lived in comparison to similarly sized rodents, and furthermore appear to be immune to cancer. A number of researchers are engaged in uncovering the reasons why the species has these characteristics. On the longevity front, differences in the composition of vulnerable cell membranes is one candidate, making cells more resistant to the more important forms of oxidative damage to protein machinery that accumulate over time. Cancer immunity on the other hand seems to be connected to the p16 gene and cellular reactions to overcrowding:

Like many animals, including humans, the mole rats have a gene called p27 that prevents cellular overcrowding, but the mole rats use another, earlier defense in gene p16. Cancer cells tend to find ways around p27, but mole rats have a double barrier that a cell must overcome before it can grow uncontrollably.

Neighboring species of blind mole rat may also be immune to cancer, but appear to have evolved a different mechanism to achieve the same end.

The modern research community being what it is, I expect that the years ahead hold a lot more work on the cancer angle than on aging and longevity. There is much more money in cancer research, and it is actually possible in the present regulatory environment to take new discoveries straight into development and clinical trials. No such luck for potential ways to treat aging: the FDA doesn't recognize aging as a disease, and therefore there is no path to gaining approval for a way to treat aging. Hence there is little funding for research like that organized by the SENS Research Foundation, aimed at plausible near future paths to human rejuvenation.

In investigating naked mole rat cancer immunity researchers are following the normal script, which is to find any important part of the biological mechanisms of interest - such as by removing genes until they find one that is necessary for the process to work - and then from that starting point move along the chains of protein interactions in an effort to understand how it all fits together. So starting from p16, researchers have moved on to identify a role for hyaluronan. The full paper isn't open access, unfortunately, but the publicity materials give a fair overview:

Biologists Identify the Chemical Behind Cancer Resistance in Naked Mole Rats

[Researchers] discovered that these rodents are protected from cancer because their tissues are very rich with high molecular weight hyaluronan (HMW-HA). The biologists' focus on HMW-HA began after they noticed that a gooey substance in the naked mole rat culture was clogging the vacuum pumps and tubing. They also observed that, unlike the naked mole rat culture, other media containing cells from humans, mice, and guinea pigs were not viscous. [They] identified the substance as HMW-HA, which caused them to test its possible role in the naked mole rat's cancer resistance.

When HMW-HA was removed, the cells became susceptible to tumors, confirming that the chemical did play a role in making naked mole rats cancer-proof. [The] team also identified the gene, named HAS2, responsible for making HMW-HA in the naked mole rat. Surprisingly, the naked mole rat gene was different from HAS2 in all other animals. In addition naked mole rats were very slow at recycling HMW-HA, which contributed to the accumulation of the chemical in the animals' tissues.

[Previously researchers] showed that the p16 gene in naked mole rats stopped the proliferation of cells when too many of them crowd together. In their latest work, the two biologists identified HMW-HA as the chemical that activates the anti-cancer response of the p16 gene.

The next step will be to test the effectiveness of HMW-HA in mice. If that test goes well, [researchers] hope to try the chemical on human cells. "There's indirect evidence that HMW-HA would work in people. It's used in anti-wrinkle injections and to relieve pain from arthritis in knee joints, without any adverse effects. Our hope is that it can also induce an anti-cancer response. We speculate that naked mole rats have evolved a higher concentration of HA in the skin to provide skin elasticity needed for life in underground tunnels. This trait may have then been co-opted to provide cancer resistance and longevity to this species."

A little early to be seeking out and stockpiling hyaluronan, I think - unless you have an aggressive cancer, in which case it doesn't seem like there's all that much to lose given the present safety profile. There are all sorts of reasons why hyaluronan may not have the same effect in anything other than naked mole rats: if the presence of hyaluronan is unusual in this species, then why not the reaction to it as well? So wait for the mouse studies before getting excited.

A reader was kind enough to dig up a few interesting papers on hyaluronan from past years and send over the links earlier today. The stem cell biology connection is interesting in connection with naked mole rat longevity, but that's really just speculation on my part:

• Genome integrity, stem cells and hyaluronan
• Hyaluronan suppresses epidermal differentiation in organotypic cultures of rat keratinocytes
• Hyaluronan inhibits osteoclast differentiation via Toll-like receptor 4

Researchers here propose an interesting use for genetic data obtained from the many centenarians now known to the scientific community from past studies of genetics and longevity:

In the last ten years the scientific community has devoted a consistent effort to identify the genetic basis of the most common age-related diseases, as they represent one of the most important public health and socio-economical burden all over the world and particularly in Western Countries. This challenge was mainly faced up by genome wide association studies (GWASs) based on microarray technology that allows the simultaneous analyses of hundred thousands of single nucleotide polymorphisms (SNPs), within the framework of the "common variant common disease" theory.

So far, more than 1,000 published GWASs reported significant associations of ~4,000 SNPs for more than 200 traits/diseases. GWASs of age-related, chronic human diseases often suffer from a lack of power to detect modest effects, which can to some extent explain why the identified genetic effects comprise only a small fraction of the estimated trait heritability. These limitations can be overcome simply by ever increasing sample size in order to achieve the necessary statistical power to detect variants with small effects, which is not always feasible.

Here we propose an alternative approach of including healthy centenarians as a more homogeneous and extreme control group. As a proof of principle we focused on type 2 diabetes (T2D) and assessed genotypic associations of 31 SNPs associated with T2D, diabetes complications and metabolic diseases and SNPs of genes relevant for telomere stability and age-related diseases. We hypothesized that the frequencies of risk variants are inversely correlated with decreasing health and longevity. We performed association analyses comparing diabetic patients and non-diabetic controls followed by association analyses with extreme phenotypic groups (T2D patients with complications and centenarians). Results drew attention to rs7903146 (TCF7L2 gene) that showed a constant increase in the frequencies of risk genotype (TT) from centenarians to diabetic patients who developed macro-complications and the strongest genotypic association was detected when diabetic patients were compared to centenarians. We conclude that robust and biologically relevant associations can be obtained when extreme phenotypes, even with a small sample size, are compared.

Link: http://impactaging.com/papers/v5/n5/full/100562.html

Neural plasticity is the ability of the brain to remodel and adapt, and one of the necessary mechanisms supporting this process is neurogenesis, the creation of new neurons. The practice of calorie restriction has been shown to slow the age-related decline in numerous mechanisms in the brain, which is to be expected since it slows near every measurable aspect of aging in the course of producing extended life in laboratory species.

Production of new neurons from stem cells is important for cognitive function, and the reduction of neurogenesis in the aging brain may contribute to the accumulation of age-related cognitive deficits. Restriction of calorie intake and prolonged treatment with rapamycin have been shown to extend the lifespan of animals and delay the onset of the age-related decline in tissue and organ function.

Using a reporter line in which neural stem and progenitor cells are marked by the expression of green fluorescent protein (GFP), we examined the effect of prolonged exposure to calorie restriction (CR) or rapamycin on hippocampal neural stem and progenitor cell proliferation in aging mice. We showed that CR increased the number of dividing cells in the dentate gyrus of female mice. The majority of these cells corresponded to nestin-GFP-expressing neural stem or progenitor cells; however, this increased proliferative activity of stem and progenitor cells did not result in a significant increase in the number of newborn neurons [with markers of precursor cells]. Our results suggest that restricted calorie intake may increase the number of divisions that neural stem and progenitor cells undergo in the aging brain of females.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23773068

The SENS Research Foundation advocates, organizes, and funds rejuvenation research based on the Strategies for Engineered Negligible Senescence (SENS) program. The aim is to produce the means to repair and reverse the fundamental known differences between young tissue and old tissue, things like damaged mitochondrial DNA and a build up of various forms of hardy metabolic waste product that impair cellular functions. This isn't so far away as you might thing: some of the presently envisaged approaches are within a couple of years of practical technology demonstrations in laboratory animals, given sufficient funding.

The SENS Research Foundation remains the only easy way to donate funds that will go towards research very likely to produce meaningful extension of healthy life when complete. There is no other group that has yet proceeded as far down the road of building a network within the longevity science community, establishing an organization, and gathering support for a research strategy devoted to effective ways to reverse the course of aging in the old. We'd like to see that change in the future: the SENS Research Foundation budget is growing but still small, and it will take hundreds of millions of dollars over the next decade or two to complete SENS or something like SENS. The SENS Research Foundation must continue to grow, but it will be good to see other SENS-like groups following the same path and working on many of the same problems. Competition makes the world go round, and more funding speeds progress.

Given that the SENS Research Foundation is growing (the annual budget has increased from $1 million to $3 million in the past couple of years) you might not recognize many of the new staff. The Foundation puts out the occasional post to feature members of the research team, coordinators, and affiliated scientists, and here are four noted in recent weeks:

New Staff Spotlight: Ehud Goldin, PhD

Dr. Ehud Goldin has recently joined SENS Research Foundation as head of the Research Center's A2E degradation project. Dr. Goldin [worked] with Fabry disease before joining the NIH's National Human Genome Research Institute as a staff scientist. There, he developed models for high-throughput drug discovery and conducted drug development studies for Gaucher's and Parkinson's diseases.

These numerous experiences have given Dr. Goldin over eighty publications, along with a deep understanding of lysosomal storage diseases. He brings this expertise to the SRF Research Center's own lysosomal storage work: his new project is to enable the lysosomes of retinal pigment epithelial cells to degrade A2E. A successful treatment that follows this strategy could prevent or even cure age-related macular degeneration. Dr. Goldin hopes to bring this project into an animal model, and follow it with more work on the various forms of lipofuscin that build up in lysosomes and drive age-related diseases.

Dr. Gregory Chin: SRF's new Director of Education

One of the best parts of my outreach positions was always working with student researchers. Research mentors will work alongside the SRF interns at the bench, but I am excited to play a role in developing presentation and data interpretation skills via feedback on reports and presentations. Being around education all my life, I couldn't help but love to learn. The variety of research that the SENS Research Foundation supports is astounding. It's going to be fun learning more about these projects through my work with the interns and through the upcoming online seminar series that will highlight the work of some of the top aging-related research labs in the world.

Intern Spotlight: Ali Crampton

Ali returns to the SRF Research Center this summer to work on the problem of damage to mitochondrial genes. Mitochondrial genes are prone to damage from by-products of cellular respiration, which leads to a loss of cell function. Ali's 2013 summer project will be to investigate two possible methods of supplying proteins to the affected mitochondria, in order to restore proper function. This fall, Ali will begin the next chapter of her career as a Biomedical Engineering graduate student at the University of Minnesota.

SENS6 Speaker Highlight: Dr. Eric Lagasse

The work that has come to define Dr. Lagasse's career began with an NIH Director's Transformative R01 Award in 2009. Lagasse had proposed a radical new idea: that transplanted cells from organs like the liver might be able to develop, grow, and function within the lymph nodes of living organisms. The miniature organs produced in this way would have the potential to save the lives of patients waiting for an organ transplant, or even to cure some conditions outright. Within three years, Dr. Lagasse had published his team's success in Nature Biotechnology. The results were striking. Not only could mice be saved from a deadly liver disease with hepatic cells transplanted to the lymph nodes, but diabetic animals could have their blood sugar brought back to normal using pancreatic islet cells. Mice lacking a proper immune system could similarly be saved using cells from the thymus. Dr. Lagasse will discuss this very project during SENS6's ninth session, "Beyond organ transplantation." We're looking forward to learning more about his work, his latest results, and his plans for the future.

As I've said numerous times in the past, helping the SENS Research Foundation to grow, gather more support, and prosper is the best present path to speed the development of methods of human rejuvenation. A strong Foundation will drag the rest of the aging research field along with it as the research proceeds, and competitors and cooperative projects will naturally arise along the way. This is all a vital part of the sea change in aging research that must take place over the years ahead: to move away from useless and expensive tinkering with drug discovery to slightly slow aging, and towards targeted implementations of new technologies that repair specific forms of damage that cause aging.

If this change happens, we have a shot at living far longer than the present human life span: the old will have access to rejuvenation therapies. If this change falters, then the only outcome of enormously expensive research programs two or three decades from now will be drugs that slightly slow down aging, and do next to nothing for people already old. That would be a grand failure indeed. So support the SENS Research Foundation: it's very much in your own self-interest.

Researchers are working on technology that is analogous to dialysis machines, but provides one of the functions of the spleen instead of the kidney. This sort of thing is a very early step on the road that eventually leads to machines capable of reproducing every necessary function of the body's major organs:

Taking advantage of recent advances in nanotechnology and microfluidics, researchers have made significant progress toward a device that could be used to rapidly remove pathogens from the blood of patients with sepsis, a potentially life-threatening condition that occurs when an infection is distributed throughout the body via the bloodstream. The new system effectively acts as an artificial spleen, filtering the blood using injectable magnetic nanobeads engineered to stick to microorganisms and toxins. After the beads are injected, blood is removed and run through a device that uses a magnetic-field gradient to extract the nanobead-bound germs. Then the blood is returned to the body.

[Researchers] looked to the human immune system - specifically, at a class of proteins in the blood that attach to potentially harmful microorganisms or toxins and mark them as targets for other immune cells. The group genetically engineered one such protein - known to bind to over 90 different pathogens, including bacteria, fungi, viruses, parasites, and toxins - so that it functions as a coating for magnetic nanobeads, giving them the ability to collect infectious agents in the bloodstream.

Following an injection of the beads, a patient's blood is run through an external device that contains a system of microfluidic channels, the design of which is inspired by the spleen. In the device, which the inventors call a "spleen-on-a-chip," contaminated blood flows through the channels alongside a saline solution. A magnetic-field gradient is then used to pull the nanobeads and their bound pathogens into that solution.

Link: http://www.technologyreview.com/news/515886/artificial-spleen-offers-hope-for-faster-sepsis-diagnosis-and-treatment/

Researchers involved in one of the very the early portions of drug discovery, in which as many types of molecule are tested as possible, have discovered a way to improve memory in mice:

Memory improved in mice injected with a small, drug-like molecule discovered [by] researchers studying how cells respond to biological stress. The memory-boosting chemical was singled out from among 100,000 chemicals screened at the Small Molecule Discovery Center at UCSF for their potential to perturb a protective biochemical pathway within cells that is activated when cells are unable to keep up with the need to fold proteins into their working forms.

The chemical acts within the cell beyond the biochemical pathway that activates this unfolded protein response, to more broadly impact what's known as the integrated stress response. In this response, several biochemical pathways converge on a single molecular lynchpin, a protein called eIF2 alpha. "Among other things, the inactivation of eIF2 alpha is a brake on memory consolidation." The chemical identified by the UCSF researchers is called ISRIB, which stands for integrated stress response inhibitor. ISRIB counters the effects of eIF2 alpha inactivation inside cells.

In one memory test included in the study, normal mice were able to relocate a submerged platform about three times faster after receiving injections of the potent chemical than mice that received sham injections. The mice that received the chemical also better remembered cues associated with unpleasant stimuli - the sort of fear conditioning that could help a mouse avoid being preyed upon. "It appears that the process of evolution has not optimized memory consolidation; otherwise I don't think we could have improved upon it the way we did in our study with normal, healthy mice."

Evolution has failed to optimize many individually desirable and arguably advantageous aspects of mouse biology, such as life span, for example. That tells us something about the details of the way in which natural selection operates.

Link: http://www.newswise.com/articles/memory-boosting-chemical-is-identified-in-mice

LongeCity has been around for a while, and is home to an energetic community interested in health and longevity. There is as much talk of supplements, frivolous stuff to my eyes, as there is of serious longevity science aimed at rejuvenation, such as the Strategies for Engineered Negligible Senescence, but over the years the folk there seem to have made that work in a sustainable way. The LongeCity crowd are more biased towards supporting rejuvenation research than any other health-focused community you're likely to find out there.

One of the other distinctions of LongeCity is that they have spent some years raising funds from the community for small research projects. They have been doing that for some time longer than the current crop of science crowdfunding startups have existed, for example. Making this work is a hard nut to crack, both from the point of view of practical administration and from convincing people to donate, but plenty of $20-40,000 sized projects exist in longevity-related life science research that are both useful and feasible to undertake. So the LongeCity administrators have established an ongoing grant scheme under which they solicit applications, raise funds, and monitor the progress of projects such as evaluating the effects of transplanting young microglia cells into old mice to see if such a procedure can slow or reverse neurodegeneration.

This ongoing set of initiatives and the efforts of crowdfunding startups like Microryza are just the opening notes in the near future symphony of community science funding. There will be a great deal more open fundraising and many more people helped to advance their own favored causes by careful funding of specific small research projects. Like medical tourism, this is still at the stage of shaking out an industry with standards, best practices, and approaches that work. Growth is yet to come: the foundation work is still underway.

On this topic I noticed a recent post that looks over the LongeCity crowdfunding activities and projects of past years:

Help Conquer Death with Grants and Research Funding from LongeCity!

LongeCity has been doing advocacy and research for indefinite life extension since 2002. With the Methuselah Foundation and the M-Prize's rise in prominence and public popularity over the past few years, it is sometimes easy to forget the smaller-scale research initiatives implemented by other organizations. Anyone can have a great idea, and there are many low-hanging fruits that can provide immense value and reward to the field of life extension without necessitating large-scale research initiatives, expensive and highly-trained staff or costly laboratory equipment.

In the past LongeCity has raised funding by matching donations made by the community to fund a research project that used lasers to ablate (i.e. remove) cellular lipofuscin. LongeCity raised $8,000 dollars by the community which was then matched by up to $16,000 by SENS Founation. LongeCity's second successfully funded research initiative was mitochondrial uncoupling. LongeCity's 3rd success was their project on Microglia Stem Cells in 2010. This project studied the benefits of transplanting microglia in the aging nervous system. LongeCity's fourth research-funding success was on Cryonics in 2012, specifically uncovering the mechanisms of cryoprotectant toxicity.

These are real projects with real benefits that LongeCity is funding. Even if you're not a research scientist, you can have an impact [by helping to fund a] small-scale research grant from LongeCity.

Something like a third of medical research funding comes from government sources. It is the most transparent and easily quantified source, so it is the one most often discussed. The incentives put upon researchers competing for these funds steer them towards largely mundane, low-risk, low-reward work, and greatly favor large institutions over smaller research groups. This is a proven way to edge out the sort of research that tends to occasionally produce meaningful or even spectacular results, in favor of research that is essentially make-work or pointless in comparison to what could be done. It's why you shouldn't expect much from massive public spending on research: the yield of meaningful work is very low.

The private funding world is mostly for-profit research, and that has its own issues that are driven by the enormous imposed costs of regulation and short time horizons. So as a general rule near all of the really interesting and potentially game-changing research programs in aging and the broader life sciences were started by and are still largely funded by philanthropists. Consider the SENS Research Foundation, for example, or the Glenn Laboratories, or the points made by Peter Thiel's radical philanthropy initiative: too much funding is biased towards the incremental and the meaningless, while ignoring the tremendous possibilities of the near future. So progress is far slower than it might be.

Here are a few comments on the public funding environment from a discussion on the Gerontology Research Group list:

One of the main reasons for a lack of serious anti-aging basic science [is] the current and recent funding climate of academia. As a scientist currently in the middle of the funding rat race, I can tell you why not a lot of scientists want to work on aging. The NIH/NIA/NCI want preliminary data. They want it on every single grant application. If you don't have it, they won't fund it, and this is a relatively new phenomenon (and the definition of "preliminary data" has become significantly more burdensome). Effectively, in order to get new work funded, it has to be partially (or in some cases nearly entirely) complete, meaning that you have to have some other funding source and a functional laboratory *before you get the grant*.

This shifts risk from the funding agency to the investigator, such that if you are using your current funding, left over from some already completed grant or tangentially related to a grant in progress on a new project, you want to be sure that the new project will work, because if it doesn't, you're out of funding and have exhausted the most precious resource you have in securing new funding - your old funding! You won't do things that are hard or risky unless you're a very rich lab (which tend to be entrenched in certain fields that aren't hard or risky, because that's how they got to be a rich lab), because hard and risky things can fail, and then your career is over. Aging research is hard and risky.

There's too much focus on low hanging fruits because of the pressure to publish and get grants. My lab is no exception on this, but the fact is that all my high-risk, high-reward grant applications have been rejected (my more conservative grants also often get rejected, but at least sometimes they are funded). Some years ago I asked a well-known biogerontologist why his lab was doing a certain series of experiments that, while getting results and papers, seemed to beat around the bush of understanding aging. His answer was: "Because I've got a mortgage to pay."

Link: http://postbiota.org/pipermail/tt/2013-June/013563.html

Ten years from now blood donation might be a thing of the past in wealthier regions of the world:

Researchers based at the Scottish Centre for Regenerative Medicine (SCRM) in Edinburgh hope to use stem cells to manufacture blood on an industrial scale to help end shortages and prevent infections being passed on in donations. The UK's Medicines and Healthcare products Regulatory Agency (MHRA) has now granted a licence so scientists can make blood from stem cells which can be tested in humans - the first step towards large-scale clinical trials, which will hopefully lead to the routine use of blood created in this way.

As well as the blood research, the licences will also allow scientists in the coming years to create stem-cell products to treat patients who have suffered a stroke and people with Parkinson's disease, diabetes and cancer. But much of the attention has focused on how stem cells could be harnessed to create blood products - seen by many as the "holy grail" of blood research.

A key difference in their work going forward would be the use of stem cells derived from adult tissue - known as induced pluripotent stem cells. "In the first part of the project we used human embryonic stem cell lines and one of the problems with using those lines is you can't choose what the blood group is going to be. Over the last few years there has been a lot of work on induced pluripotent stem cells and with those an adult can donate a small piece of skin or a blood sample and the technology allows for stem-cell lines to be derived from that sample. This makes our life a lot easier in some ways because that means we can identify a person with the specific blood type we want and get them to donate a sample from which we could manufacture the cell lines."

Link: http://www.scotsman.com/the-scotsman/health/scots-scientists-to-trial-synthetic-human-blood-1-2948081

Calorie restriction is definitely good for you, provided that you maintain an optimal intake of micronutrients in your smaller diet. There is a tremendous weight of evidence for the benefits of calorie restriction in animals and a large weight of evidence for benefits in humans: it improves near all short term measures of health, slows down the progression of near every measure of degenerative aging, and extends healthy life in most species. Research publications are usually more understated in their evaluation of calorie restriction, of course. See this, for example:

Caloric Restriction: Implications for Human Cadiometabolic Health

Evidence from animal studies and a limited number of human trials indicates that calorie restriction has the potential to both delay cardiac aging and help prevent atherosclerotic cardiovascular disease via beneficial effects on blood pressure, lipids, inflammatory processes, and potentially other mechanisms.

The candidate list of mechanisms by which calorie restriction likely delivers its benefits include reduced visceral fat, increased levels of autophagy, altered mitochondrial function, and metabolic changes caused by reduced levels of methionine in the body. All of these on their own have been shown to extend life and improve measures of health in animal studies. Many other measurable changes result from calorie restriction, but identifying which of them are definitively primary and which are definitively secondary is still a work in progress.

Methionine is one of the essential amino acids that your metabolism doesn't manufacture. You have to obtain it in the diet, and it's an essential component for the cellular manufacture of new protein machinery. There are all sorts of studies in mice and rats showing that if you keep the same dietary calorie level but strip out much of the methionine then the animals involved live longer, and exhibit many of the same changes in metabolism as occur from reduced calorie levels. Here is a recent example:

Methionine restriction affects oxidative stress and glutathione-related redox pathways in the rat

Lifelong dietary methionine restriction (MR) is associated with increased longevity and decreased incidence of age-related disorders and diseases in rats and mice. A reduction in the levels of oxidative stress may be a contributing mechanistic factor for the beneficial effects of MR. To examine this, we determined the effects of an 80% dietary restriction of Met on different biomarkers of oxidative stress and antioxidant pathways in blood, liver, kidney and brain in the rat.

Male F-344 rats were fed control (0.86% methionine) or MR (0.17% methionine) diets for up to six months. Blood and tissues were analyzed for [levels of the natural antioxidant] glutathione (GSH). related enzyme activities and biomarkers of oxidative stress. MR was associated with reductions in oxidative stress biomarkers [and] erythrocyte protein-bound glutathione after one month with levels remaining low for at least six months.

Levels of free GSH in blood were increased after 1-6 months of MR feeding whereas liver GSH levels were reduced over this time. In MR rats, GSH peroxidase activity was decreased in liver and increased in kidney compared with controls. No changes in the activities of GSH reductase in liver and kidney and superoxide dismutase in liver were observed as a result of MR feeding. Altogether, these findings indicate that oxidative stress is reduced by MR feeding in rats, but this effect cannot be explained by changes in the activity of antioxidant enzymes.

You might compare the comments above with the two calorie restriction research papers I pointed out earlier today - you'll quickly see the similarities, such as the fact that the behavior of antioxidants and oxidants in metabolism is complex and hard to tie to the observed benefits in health and longevity. All in all it is convincing to argue that methionine sensing is at the heart of the metabolic changes that produce the benefits of calorie restriction:

• Calorie Restriction Versus Resveratrol Treatment
• Reviewing the Literature on Calorie Restriction and Oxidative Stress

From the practical standpoint of day to day effort and willpower, I'd say that that there isn't much difference between eating a calorie restricted diet and a methionine restricted diet. The latter is harder by far to organize, I think. You certainly couldn't do it without a lot of research, extra food preparation, and meal planning, and there are few resources out there to help you short-cut the process. Calorie restriction, on the other hand, just requires you to keep count and be sensible, plus of course to have a willingness to be hungry for some time every day. It's that latter item that most people find a challenge, in this age of ubiquitous, cheap, tasty food. Calorie restriction also has a far greater weight of supporting evidence for benefits to health in humans, which is probably the most important factor of those mentioned here, but every choice you make has trade-offs.

Researchers here compare the effects of calorie restriction and dietary resveratrol on the pace of sarcopenia, the age-related loss of muscle mass and strength. What I take away from this is that calorie restriction produces meaningful results on this front, albeit modest in comparison to what we'd like to see, and resveratrol doesn't.

Aging is associated with a loss in muscle known as sarcopenia that is partially attributed to apoptosis. In aging rodents, caloric restriction (CR) increases health and longevity by improving mitochondrial function and the polyphenol resveratrol (RSV) has been reported to have similar benefits. In the present study, we investigated the potential efficacy of using short-term (6 weeks) CR (20%), RSV (50 mg/kg/day), or combined CR+RSV (20% CR and 50 mg/kg/day RSV), initiated at late-life (27 months) to protect muscle against sarcopenia by altering mitochondrial function, biogenesis, content, and apoptotic signaling in both glycolytic white and oxidative red gastrocnemius muscle (WG and RG, respectively) of male Fischer 344 x Brown Norway rats.

CR but not RSV attenuated the age-associated loss of muscle mass in both mixed gastrocnemius and soleus muscle, while combined treatment (CR+RSV) paradigms showed a protective effect in the soleus and plantaris muscle. Sirt1 protein content was increased by 2.6-fold in WG but not RG muscle with RSV treatment, while CR or CR+RSV had no effect. PGC-1α levels were higher (2-fold) in the WG from CR-treated animals when compared to ad-libitum (AL) animals but no differences were observed in the RG with any treatment.

These data suggest that short-term moderate CR, RSV, or CR+RSV tended to modestly alter key mitochondrial regulatory and apoptotic signaling pathways in glycolytic muscle and this might contribute to the moderate protective effects against aging-induced muscle loss observed in this study.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23747682

Oxidative theories of aging place the blame for the damage of aging on reactive oxidizing molecules, generated most notably in the mitochondria of your cells, and which tend to break the protein machinery they react with. Oxidative stress is the term given to ongoing damage (and efforts to repair it) caused by the presence of oxidative molecules in and around cells. Levels of oxidative stress can alter as a result of heat, exposure to ionizing radiation, the details of diet, and all sorts of other environmental influences.

The relationship between oxidative stress and the pace of aging is far from straightforward, however. There is more oxidative stress with age, but this is an expected result of carrying a high level of cellular and molecular damage. Some very long-lived species, such as naked mole rats, show very high levels of oxidative stress but don't appear to be particularly harmed by it. Mild oxidative stress can be beneficial, triggering increased cellular maintenance for a time to produce a net benefit. Oxidative compounds are also widely used in our biochemistry for necessary signaling purposes.

You can see the nature of this complex relationship between oxidative stress and aging by looking at what happens in interventions that reliably slow aging and extend life, such as calorie restriction in rodents:

Oxidative stress is observed during aging and in numerous age-related diseases. Dietary restriction (DR) is a regimen that protects against disease and extends lifespan in multiple species. However, it is unknown how DR mediates its protective effects. One prominent and consistent effect of DR in a number of systems is the ability to reduce oxidative stress and damage. The purpose of this review is to comprehensively examine the hypothesis that dietary restriction reduces oxidative stress in rodents by decreasing reactive oxygen species (ROS) production and increasing antioxidant enzyme activity, leading to an overall reduction of oxidative damage to macromolecules.

The literature reveals that the effects of DR on oxidative stress are complex and likely influenced by a variety of factors, including sex, species, tissue examined, types of ROS and antioxidant enzymes examined, and duration of DR. [In] a majority of studies, dietary restriction had little effect on mitochondrial ROS production or antioxidant activity. On the other hand, DR decreased oxidative damage in the majority of cases. Although the effects of DR on endogenous antioxidants are mixed, we find that glutathione levels are the most likely antioxidant to be increased by dietary restriction, which supports the emerging redox-stress hypothesis of aging.

While thinking about antioxidants and their effect on aging, it's important to remember that location matters immensely. Ingested antioxidants of the sort you can buy in the store are convincingly demonstrated to do nothing for your health, and there is evidence to suggest that they are actually mildly harmful - for example by blocking some of the oxidant-based signaling mechanisms the body uses to dial up cellular housekeeping and muscle growth responses after exercise. Meanwhile researchers are demonstrating benefits in mice by targeting designed antioxidant compounds to the mitochondria in cells, the place that most oxidants are generated. Those antioxidants are not yet available for the rest of us, however. The antioxidant pills from the store don't deliver their contents to your mitochondria, and are thus not terribly helpful.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23743291

It is usually the case that the first knee-jerk reaction in opposition to increased human longevity is based on the mistaken belief that life extension technologies would lead to people being ever more frail and decrepit for a very long time. This is far from the case, and it's probably not even possible to cost-effectively engineer a society of long-lived frail people - even if that was the goal to hand. If you are frail and decrepit then you have a high mortality rate due to the level of age-related cellular and molecular damage that is causing the failure and degeneration of your body and its organs. You won't be around for long. No, the only way to engineer longer healthy life is extend the period of youth and vitality, a time in which you have little age-related damage and your mortality rate is very low. Most present strategies are aimed to prolong that period of life, either by slowing the rate at which damage occurs (not so good) or finding ways to periodically repair the damage and thus rejuvenate the patient (much better).

Once people grasp that longevity science is the effort to make people younger for far longer, then the second knee-jerk objection arises. This is the belief that a very long-lived individual would become overwhelmed by boredom: they would run out of interest and novelty. This is by far the sillier objection, and there is absolutely no rational basis for it. Even a few moments of thought should convince you that there is far more to do and learn that you could achieve in a thousand life spans - and it's a little early in the game to be objecting to enhanced longevity on the basis that you can't think of what to do with life span number number 1001.

Considering boredom, futility, meaningless, and related matters, I noticed what appears to be an argument by induction in the article below. Mathemetical induction is a tool used in formal proofs wherein if you can prove that something is generally true for n and n+1 (where n is a natural number), and then show that it is true for 1, then you can conclude it must be true for all natural numbers. If it is true for 1, then it must be true for 1+1 = 2, and true for 2+1 = 3, and so on.

Life Extension Leads to Meaningless Days? NO!

Person X lives a fulfilling and meaningful life for X number of years before that life is terminated by a sudden, massive heart attack.Now, imagine another person whom we shall label (not too creatively) 'Person 2′. Person 2′s life follows the same general path as person 1 with one exception: It is one day longer than person 1′s was. Now ask yourself: Is there any reason to suppose that this day, let us assume it is aTuesday, strikes person 2 as being meaningless despite the fact that all Tuesdays (and indeed every other day in person 2′s past) seemed worth living?

OK, so now imagine yet another person who goes by the label of... yes, you guessed it, Person 3. You can probably also guess that Person 3 lives one day longer than person 2. Once again, I can think of no reason why, where we have two people who live meaningful lives but one lives one day longer, that extra day would not seem worth experiencing. Put another way: If possible would persons 2 and 1 rather not be dead on Wednesday (the last day for person 3) when Monday and all preceding days were worth experiencing? So far as I can see, the answer to that question is, 'yes'. There seems to be no reason why this argument should not hold for any number of hypothetical people, each one of which lives one day longer than the last.

Unfortunately you can't prove conjectures about aspects of human nature with induction (or not yet, at least). What you can do is use it, as above, to mount a more convincing argument. This one is somewhat akin to one of the standard lines in any debate between a person who is in favor of greatly extending healthy life versus someone who isn't.

Advocate: So you are fine with aging and dying?

Deathist: Yes.

Advocate: So you are fine with dying right now, done and finished?

Deathist: Well, no.

Advocate: Why would you think any differently ten days, or a hundred days, or decades from now, if you still had your health and vigor?

Deathist: Um...

There seems to be a strange disconnect in many people's minds, in which they are vigorously in favor of being alive right this instant or next week, but they nonetheless believe that their future self of years ahead will be of a different opinion and want to die. Now if you're on the downhill slope of aging, in great pain, and your body is falling apart, desiring a stopping point is not unreasonable. (With the best of present options for those in that position being cryonics). But in a world of rejuvenation therapies, in which older life is just as healthy, low-risk, and full of possibility as younger life, what mysterious thing is going make people want to die?

Young mammals, and occasionally adults, can regenerate lost fingertips. This seems like a good place to learn more about the mechanisms of regeneration, gaining insight into why it is that mammals cannot replicate the feats of limb and organ regeneration exhibited by species such as salamanders and zebrafish. More importantly, researchers hope to find that it is practical to adjust human biology to allow this sort of exceptional regeneration:

If a salamander loses its leg, it can grow a new one. Humans and other mammals are not so fortunate, but we can regenerate the tips of our digits, as long as enough of the nail remains. This was first shown some 40 years ago; today researchers finally reveal why it is that nails are necessary. Working with mice, [researchers] have identified a population of stem cells lying beneath the base of the nail that can orchestrate the restoration of a partially amputated digit. However, the cells can do so only if sufficient nail epithelium - the tissue that lies immediately below the nail - remains.

The process is limited compared with the regenerative powers of amphibians, but the two share many features, from the molecules that are involved to the fact that nerves are necessary. "I was amazed by the similarities. It suggests that we partly retain the regeneration mechanisms that operate in amphibians."

The nail base contains a small population of self-renewing stem cells, which sustain the nail's continuous growth. This ongoing growth depends on signals carried by the Wnt family of proteins - if this signalling pathway is disrupted, mouse nails cannot form. The team found that the same pathway is involved in the regeneration of lost mouse toe tips. After amputation, the Wnt pathway is activated in the epithelium underlying the remaining nail and attracts nerves to the area. Through a protein called FGF2, the nerves drive the growth of mesenchymal cells, which restore tissues such as bone, tendons and muscle. Within five weeks, the digit is good as new.

However, none of this can happen if the digit is amputated too far back, and too much nail epithelium is lost. In such cases, the Wnt pathway is never activated, the nerves do not extend and the other tissues cannot regenerate.

Link: http://www.nature.com/news/how-nails-regenerate-lost-fingertips-1.13192

Researchers have produced an improvement in methods of gene therapy used to treat some rare forms of blindness, and which may allow the use of gene therapy in the treatment of more common forms of degenerative blindness that occur in old age:

Three groups of researchers have successfully restored some sight to more than a dozen people with a rare disease called Leber's congenital amaurosis. [They] achieved this by inserting a corrective gene into adeno-associated viruses (AAV), a common but benign respiratory virus, and injecting the viruses directly into the retina. The photoreceptor cells take up the virus and incorporate the functional gene into their chromosomes to make a critical protein that the defective gene could not, rescuing the photoreceptors and restoring sight.

Unfortunately, the technique cannot be applied to most blinding diseases because the needle often causes retinal detachment, making the situation worse. Yet the standard AAV used in eye and other types of gene therapy cannot penetrate into tissue to reach the photoreceptors and other cells, such as retinal pigment epithelium, that need to be fixed.

[Researchers] set out to find a way to "evolve" AAV to penetrate tissues, including eye and liver, as a way to deliver genes to specific cells. [They have] generated 100 million variants of AAV - each carrying slightly different proteins on its coat - [and] selected five that were effective in penetrating the retina. "Building upon 14 years of research, we have now created a virus that you just inject into the liquid vitreous humor inside the eye and it delivers genes to a very difficult-to-reach population of delicate cells in a way that is surgically non-invasive and safe. It's a 15-minute procedure, and you can likely go home that day."

The engineered virus works far better than current therapies in rodent models of two human degenerative eye diseases, and can penetrate photoreceptor cells in the eyes of monkeys, which are like those of humans. [This] could greatly expand gene therapy to help restore sight to patients with blinding diseases ranging from inherited defects like retinitis pigmentosa to degenerative illnesses of old age, such as macular degeneration.

Link: http://www.eurekalert.org/pub_releases/2013-06/uoc--rde061213.php

Cryonics is the industry and technologies that can provide long-term low-temperature storage of your body and mind following death. The balance of evidence presently favors the supposition that vitrification of cryoprotectant-infused tissue, avoiding ice-crystal formation, preserves the fine structure of neural cells in which the data of the mind is stored. That is the core of the matter: whether cryonics preserves the mind well enough to allow future technologies to repair and revive suspended people. If you are going to die prior to the advent of rejuvenation biotechnology, and this is a significant risk for most of us, then cryonics and its uncertainties are the only shot at a longer life in the future. It's a very reasonable wager, all told: a bet that the future of technological progress will continue, versus the certainty of oblivion found in the grave.

Cryopreservation is modestly expensive if you pay in a lump sum: usually more than $100,000, depending on which provider you go with and the details of your arrangements. Most people fund this service via life insurance, however. If you obtain a policy early enough in life the monthly payments are very cheap. It's not a terribly large amount of money even if you start in mid life.

Cryonics should be far more popular than it is. The cost is reasonable, any number of other businesses with multi-decade customer lifetimes prosper, and the potential upside is considerable. Four decades after its emergence from amateur practice into professional practice it remains a niche industry, while billions have gone to the grave over that same span of time. You might compare this with the same puzzling lack of interest in extending life through medical technology: at times one is forced to conclude that most people just don't care about living longer.

A generally favorable, well-researched, long article on the cryonics community recently emerged in the alternative online press. I think it's worth your time to read it all, and if you are presently trying to persuade anyone to see the merits of cryonics, then this would an excellent piece to pass along:

Are We Warming Up to Cryonics?

Some things should not be left to the last minute. For instance, having yourself frozen. The act of being preserved in a giant thermos cooled by liquid nitrogen in the hopes that the scientists of the future will figure out how to revive you and repair whatever it was that drove you to require freezing in the first place is no small matter. There are insurance policies to settle upon. Legal documents to notarize. Relatives to appease. And all of this must be done far enough in advance that arrangements can be made for a field response team to reach you on your deathbed and stand by until a doctor declares you medically deceased, at which time they will leap into action and begin your cryopreservation.

Legally speaking, cryonics is okay because it's considered an extravagant funeral practice. Its few practitioners would not argue with the notion that the procedure would be more effective if started before the heart has taken its final beats, but to do so would be illegal, even if the soon-to-be-deceased is a willing participant. Thus, the process waits for death, and the longer after death it begins, the worse off you are. This is why the Alcor Life Extension Foundation really doesn't like to accept last-minute cases.

One thing to note is this news of funding and initiatives presently in the works. You might not be keeping up with this sort of behind the scenes progress if you're merely interested in cryonics rather than being an insider:

If ever a group is going to coalescence behind the idea of obviating death as we know it, it's the one currently ruling Silicon Valley, which came of age at a time when it really felt like the right combination of smart people and money could solve any problem. And the most intriguing name to sniff around cryonics publicly is Peter Thiel, the billionaire investor who co-founded [PayPal] and was the first outside investor in Facebook. Thiel, who has made no secret of his belief in experimental science, and of his interest in technologies that could suspend or eliminate aging, has a separate fund set up to invest in more outré scientific endeavors. And Breakout Labs, as it's known, has provided seed capital to two cryonics-related start-ups founded by former Alcor employees.

Thiel (who declined an interview request) was also part of the conversation that laid the groundwork for a cryonics X-Prize that is currently in development. The prize, as constructed, would challenge applicants to freeze and then thaw a human organ so that it returns to a viable state. This would enable organ banks, potentially solving a huge global problem - the shortage of organs for transplant - and would be the first proof-of-concept that large, complex collections of tissue could be stored indefinitely at low temperatures without damage. It's not a huge leap from there to imagine the same thing being done with a whole organism.

Here is a recent article from the local Los Angeles press, in which the author manages to touch on a broader range of the pro-human-longevity community than is usually the case:

What researchers do know is that there are limits to how far we can naturally extend the human life span. L. Stephen Coles, a UCLA lecturer and executive director of the Gerontology Research Group, documents and studies "supercentenarians" - people who live to 110 or longer. When he started tracking the longest-lived humans around 2000, "the oldest [known] person in history was a Frenchwoman named Jeanne Calment, who died in 1997 at the age of 122," Coles says. "I thought that because average life expectancy had increased significantly over the last hundred years, it meant someone would break her record." But that hasn't happened. "It's been more than 15 years, and no one has come close."

Even if scientists do find a way to create more supercentenarians, should they? Blogging for The Huffington Post last year, unofficial Hollywood Conscience Jamie Lee Curtis declared that any attempt to conquer aging was an affront to nature. "I am appalled that the term we use to talk about aging is 'anti,' " she wrote. "Aging is as natural as a baby's softness and scent. Aging is human evolution in its pure form. Death, taxes, and aging."

But she's missing the point, says Maria Entraigues, the L.A.-based outreach coordinator for the SENS Research Foundation, a Northern California nonprofit that focuses on longevity research. "I always tell people, Why is it not 'natural' to get sick?" Entraigues says. "Why do we go to the doctor? Aging is the same thing. If there's something we can do about it, we should."

Aubrey de Grey, a Cambridge University computer scientist turned antiaging theorist, launched SENS, short for Strategies for Engineered Negligible Senescence, in 2009. Fifty years old with a Rasputinesque beard, de Grey has gained fame through his appearances at TED talks and on The Colbert Report, among other venues, making the case that aging can be vanquished. He's proposed that seven specific types of damage cause human beings to deteriorate over time, including cellular mutations, an accumulation of "junk" inside and between cells, and a gradual loss of important cells in the brain and other organs. If it were possible to fix all or even some of these problems, he argues, the diseases and frailty that come with old age could be postponed or even reversed. And he believes it's possible that aging itself will be brought under medical control - via maintenance treatments of gene therapies, stem cell therapies, and immune stimulants - within our lifetimes.

Link: http://www.lamag.com/citythink/wellbeing/2013/06/10/forever-young

Mitochondria are the swarming powerplants of the cell, a bacteria-like herd of self-replicating machines that produce the chemical energy stores that power cellular processes. They bear their own DNA, and damage to this mitochondrial DNA (mtDNA) damage is important in aging. Per the mitochondrial free radical theory of aging, some types of mitochondrial DNA damage spread throughout the population of mitochondria in a cell, subverting the quality control mechanisms that normally destroy damaged mitochondria. This leads to harmfully altered mitochondrial function and malfunctioning cells that export damaging reactive compounds into the surrounding tissues.

At this point the fastest way to confirm theories on aging and mitochondrial DNA damage is to implement one of the ways to replace or repair mitochondria DNA. There are a range of potential methods that might result in therapies. In the future, people will probably have their mitochondrial DNA globally refreshed every few decades, removing this contribution to degenerative aging.

Here researchers argue that the spread of mitochondrial DNA damage to all the mitochondria in a cell can't be just random, and thus has be driven by some advantage in selection - such as the ability to fool quality control mechanisms, as is proposed in mitochondrial theories of aging. If damaged mitochondria are culled by the cell less often, they will eventually out-compete undamaged mitochondria.

Mitochondrial DNA deletions accumulate over the life course in post-mitotic cells of many species and may contribute to aging. Often a single mutant expands clonally and finally replaces the wild-type population of a whole cell. One proposal to explain the driving force behind this accumulation states that random drift alone, without any selection advantage, is sufficient to explain the clonal accumulation of a single mutant.

Existing mathematical models show that such a process might indeed work for humans. However, to be a general explanation for the clonal accumulation of mtDNA mutants, it is important to know whether random drift could also explain the accumulation process in short-lived species like rodents. To clarify this issue, we modelled this process mathematically and performed extensive computer simulations to study how different mutation rates affect accumulation time and the resulting degree of heteroplasmy. We show that random drift works for lifespans of around 100 years, but for short-lived animals, the resulting degree of heteroplasmy is incompatible with experimental observations.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23742009

One of the emerging themes over the past few years of stem cell research is that various forms of pluripotent stem cell can be found in adult tissues. Pluripotency in a stem cell is the ability to differentiate to form lineages of any cell type in the body. The well known types of adult stem cell that researchers have cataloged over the past few decades are only multipotent, meaning that they are limited in the type of cell lineages they can create. A multipotent stem cell supports a particular tissue type made up of a few types of cell.

Why does this matter? It's all about the efficiency and cost of research and development of regenerative therapies based on the use of stem cells. If researchers must locate and understand specific multipotent cell populations in order to regenerate a specific type of tissue, then a great deal of work remains on the way to a comprehensive regenerative medicine toolkit. Every type of multipotent stem cell has its own distinct behaviors and mechanisms, and requires a different environment to grow in useful numbers outside the body. Discovering how to make use of any specific type of multipotent stem cell has proven to be a slow process of trial, error, and educated guesswork. On top of that, researchers haven't yet reliably identified multipotent stem cells in all types of tissue, and most of the known populations are far from well understood. There are hundreds of cell types in the human body, and much left to accomplish.

If researchers can obtain a reliable, low-cost source of pluripotent stem cells, however, then that single resource can be used to generate any type of cell you want, starting from the same shared baseline. It greatly cuts down the complexity and work required to move forward with regenerative medicine. This is why the research community is so focused on embryonic stem cells and the reprogramming of ordinary cells into induced pluripotent stem cells. Pluripotent cells obtained directly from an patient's tissues, especially those that are easily accessed such as skin and fat, may be even better than induced pluripotent stem cells in terms of cost-effectiveness. Such a resource cuts out yet another step in the process of obtaining broadly useful patient-matched cells for research and regenerative therapies.

In recent years a few research groups have claimed the identification of pluripotent stem cells in adult tissue. They have given the cells various different names, such as very small embryonic-like stem cells (VSELs), but they might all be talking about the same thing - or they might not. Biology is always more complex than you think it is. Why shouldn't there be all sorts of variously potent cell types hiding away in our bodies in larger or smaller numbers?

Here is an open access publication from another research group to have isolated pluripotent stem cells in adult tissue. From a long term perspective, the more of this that happens the better, I think. It suggests that over the next decade or two regenerative research will move more rapidly than would otherwise have been the case:

Awakened by Cellular Stress: Isolation and Characterization of a Novel Population of Pluripotent Stem Cells Derived from Human Adipose Tissue

Recently, a new stem cell population has been isolated from mesenchymal tissues such as human skin fibroblasts and bone marrow stromal cells under cellular stress conditions. These cells, termed Multilineage Differentiating Stress-Enduring (Muse) Cells, are of mesenchymal stem cell origin and comprise 1-3% of the entire cell population. Muse cells exhibit characteristics of both mesenchymal and pluripotent stem cells. They are double positive for CD105, a mesenchymal stem cell marker, and stage specific embryonic antigen-3 (SSEA3), well known for the characterization of undifferentiated human embryonic stem cells (ES) from bone marrow aspirates or from cultured mesenchymal cells such as bone marrow stromal cells and dermal fibroblasts. They express pluripotency markers including [those used to create induced pluripotent stem cells], differentiate into cells of ectodermal, endodermal, and mesodermal lineages both in vitro and in vivo, and have the ability to self-renew.

Advantageously, Muse cells do not appear to undergo tumorigenic proliferation, and therefore would not be prone to produce teratomas in vivo, nor do they induce immuno-rejection in the host upon autologous transplantation. In addition, Muse cells are shown to home into the damage site in vivo and spontaneously differentiate into tissue specific cells according to the microenvironment to contribute to tissue regeneration when infused into the blood stream. Therefore, they exhibit the potential to make critical contributions to tissue regeneration in the absence of restrictions attributed to the difficult extraction of bone marrow stromal cells and human skin fibroblasts, and time-consuming purification methods such as cell sorting. In order to increase the viability of Muse cells as a source of tissue regeneration, a more accessible supply must be utilized.

Harvesting human adipose tissue by lipoaspiration is a safe and non-invasive procedure, and hundreds of millions of cells can be isolated from 1-2 liters of lipoaspirate material. Therefore, adipose tissue could prove the ideal source for Muse cell isolation as opposed to bone marrow or dermis. Using lipoaspirate material, we developed a novel methodology for the isolation of a population of human Muse cells under severe cellular stress conditions (long term incubation with proteolytic enzyme, 4°C, serum deprivation, and hypoxia). Purification of human Muse cells derived from adipose tissue (Muse-ATs) does not require the use of cell sorting, magnetic beads or special devices.

Researchers are digging deeper into the mechanisms underlying the loss of bone that accompanies aging. A complete understanding of how imbalances occur between ongoing bone creation and destruction that takes place at the cellular level should eventually lead to ways to manipulate that process:

By analyzing biopsy specimens from patients with postmenopausal osteoporosis and primary hyperparathyroidism, investigators have begun to pay increasing attention to "reversal cells," which prepare for bone formation during bone remodeling. The hope is that these reversal cells will become critical therapeutic targets that may someday prevent osteoporosis and other bone disorders.

In adults, bones are maintained healthy by a constant remodeling of the bone matrix. This bone remodeling consists of bone resorption by osteoclasts and bone formation by osteoblasts. A failure in the delicate balance between these two processes leads to pathologies such as osteoporosis. How these two processes are coupled together is poorly understood. "Reversal cells may represent the missing link necessary to understand coupling between bone resorption and formation and to prevent osteoporosis."

Reversal cells actually cover more than 80% of the resorbed bone surfaces. Using histomorphometry and immunohistochemistry on human bone biopsies, researchers found that the reversal cells colonizing the resorbed bone surfaces are immature osteoblastic cells which gradually mature into bone forming osteoblasts during the reversal phase, and prepare the bone surface for bone formation. Researchers also found that some reversal cells display characteristics that suggest an "arrested" physiological status. These arrested reversal cells showed no physical connection with bone forming surfaces, a reduced cellular density, and a reduced expression of osteoblastic markers.

Biopsies from postmenopausal patients with osteoporosis showed a high proportion of arrested cells, but no such cells were found in biopsies from patients with primary hyperparathyroidism, in which the transition between bone resorption and formation is known to occur optimally. [Larger] arrested cell surfaces were associated with bone loss. "Our observations suggest that arrested reversal cells reflect aborted remodeling cycles which did not progress to the bone formation step. We therefore propose that bone loss in postmenopausal osteoporosis does not only result from a failure of bone formation as commonly believed, leading to incomplete filling of resorption cavities, but also from a failure at the reversal phase, uncoupling bone formation from resorption."

Link: http://www.eurekalert.org/pub_releases/2013-06/ehs-rcm060413.php

Long term administration of rapamycin has been demonstrated to slow aging in mice, and here one aspect of that outcome is examined in more detail:

Elderly mice suffering from age-related heart disease saw a significant improvement in cardiac function after being treated with the FDA-approved drug rapamycin for just three months. The research, led by a team of scientists at the Buck Institute for Research on Aging, shows how rapamycin impacts mammalian tissues, providing functional insights and possible benefits for a drug that has been shown to extend the lifespan of mice as much as 14 percent.

Researchers at the Mayo Clinic are currently recruiting seniors with cardiac artery disease for a clinical trial involving low dose treatment with rapamycin.

In this study, rapamycin was added to the diets of mice that were 24 months old - the human equivalent of 70 to 75 years of age. Similar to humans, the aged mice exhibited enlarged hearts, a general thickening of the heart wall and a reduced efficiency in the hearts ability to pump blood. The mice were examined with ultrasound echocardiography before and after the three-month treatment period - using metrics closely paralleling those used in humans. Buck Institute [researchers] said age-related cardiac dysfunction was either slowed or reversed in the treated mice.

"Rapamycin affected the expression of genes involved in calcium regulation, mitochondrial metabolism, hypertrophy and inflammation. We also carried out behavioral assessments which showed the treated mice spent more time on running wheels than the mice who aged without intervention."

It sounds a lot like increased exercise has as much to do with the outcome as direct effects of the drug. Exercise, like calorie restriction, has a powerful influence on all aspects of health.

Link: http://www.eurekalert.org/pub_releases/2013-06/bifa-ldg061013.php

Some of the folk at the University of Oxford Future of Humanity Institute recently engineered a little publicity for cryonics. It's always pleasing to see good press for the cryonics industry, especially when those interviewed take the time to present membership with a cryonics provider like Alcor or the Cryonics Institute as a sensible and rational choice.

What is cryonics? It is the collection of technologies and service providers that offer long-term low-temperature preservation of the brain (vital) and body (probably not so vital). The goal is a chance at future resuscitation, once medicine, nanotechnology, and related fields have advanced to the point at which a stored person can be brought back to active life. It doesn't much matter whether this takes fifty or a hundred years or even longer: while preserved a patient has time to wait. If technology is advanced enough to restore a preserved individual, so the thinking goes, then it is also advanced enough to restore an aged brain to youthful function and repair the age-damaged body, or provide a tissue engineered replacement if you chose not to have your body preserved. Some people are even fine with a copy their brain running as software via future methods of whole brain emulation. That doesn't much help you yourself, the entity associated with your physical brain, but all too many people are fine with the other way of looking at things, which is that a copy of the self is also the self.

In short, cryonics is the only chance at a longer life in the future for those people who will not live long enough to benefit from rejuvenation biotechnology presently under development. Death by aging will one day be a thing of the past, but all too many people will still be claimed by aging between now and the advent of the first rejuvenation therapies. Cryonics is also a good backup plan: you never know how early you might be struck down by age-related disease, cancer in particular. Cryonics, like the life insurance usually used to pay for it, and like saving for retirement, is something that is best organized a fair way in advance.

It's worth noting that cryopreservation is not freezing, and in fact is distinguished by the many efforts taken to avoid freezing of any tissue, especially in the brain where the data of the mind is stored. Freezing damages cells through ice crystal formation, but infusion with cryoprotectant chemicals combined with low temperatures is used to produce a state of vitrification in cryopreserved tissues.

Oxford academics hope to be brought back to life

Three professors from England's Oxford University are paying to have their bodies frozen so they can be thawed out and brought back to life in the future. Philosophy professor Nick Bostrom and neuroscientist Anders Sandberg have signed up to pay nearly $79,000 to have their heads filled with "antifreeze" chemicals and stored in liquid nitrogen at -196C in the US after they die. Their colleague Stuart Armstrong has chosen to have his entire body frozen.

The men, who are the lead researchers at the Future of Humanity Institute, have reportedly set up monthly life insurance policies and pay about $40 a month to be frozen.

Three senior Oxford University academics will pay to be deep frozen when they die so they could one day be 'brought back to life'

Previous acolytes of cryonics have often been dismissed as head-in-the-clouds cranks, sci-fi buffs who have watched too much TV or victims of vanity. Britney Spears and Paris Hilton have both waxed lyrical about being frozen. Simon Cowell is believed to be among several dozen Britons who have joined a cryonics programme, although several hundred have reportedly shown interest.

But most of them are ordinary people - usually retirees who are thinking about defeating death. The science may be sketchy but the principle is simple: nothing ventured, nothing gained. But Prof Bostrom and his colleagues are young, highly educated specialists who have devoted their careers to humanity. If they are signing up for cryonics, one might think, perhaps we should all pay attention.

That latter reaction is exactly why it's a good thing to see well-publicized advocacy for cryonics from noted researchers. In many ways this is far better than any celebrity endorsement. To the fellow in the street scientists are the arbiters of truth, the people that tell you what is, the people who know best the nature of the world. Celebrities are just celebrities.

The tissue engineering of large blood vessels is a very different matter from growing the intricate networks of small blood vessels needed to support tissue. The former goal is far less challenging, for one thing, and researchers are thus further along in bringing the creation of new veins and arteries to the clinic. Here is news of progress on that front:

In a first-of-its-kind operation in the United States, a team of doctors at Duke University Hospital helped create a bioengineered blood vessel and implanted it into the arm of a patient with end-stage kidney disease. The procedure, the first U.S. clinical trial to test the safety and effectiveness of the bioengineered blood vessel, is a milestone in the field of tissue engineering. The new vein is an off-the-shelf, human cell-based product with no biological properties that would cause organ rejection.

Using technology developed at Duke and at a spin-off company it started called Humacyte, the vein is engineered by cultivating donated human cells on a tubular scaffold to form a vessel. The vessel is then cleansed of the qualities that might trigger an immune response. In pre-clinical tests, the veins have performed better than other synthetic and animal-based implants.

Clinical trials to test the new veins began in Poland in December with the first human implantations. The U.S. Food and Drug Administration recently approved a phase 1 trial involving 20 kidney dialysis patients in the United States, followed by a safety review. Duke researchers enrolled the first U.S. patient and serve as study leaders. The initial trial focuses on implanting the vessels in an easily accessible site in the arms of kidney hemodialysis patients. More than 320,000 people in the United States require hemodialysis, which often necessitates a graft to connect an artery to a vein to speed blood flow during treatments.

If the bioengineered veins prove beneficial for hemodialysis patients, the researchers ultimately aim to develop a readily available and durable graft for heart bypass surgeries, which are performed on nearly 400,000 people in the United States a year, and to treat blocked blood vessels in the limbs.

Link: http://www.sciencedaily.com/releases/2013/06/130606110026.htm

David Murdock is one of the few billionaires interested enough in human longevity to talk about it in public and work towards doing something about it. Unfortunately he is focused only on diet and thus will fail to achieve his own stated goal of living far longer than any man has ever done, and will fail to help anyone else to do the same. You can't eat your way to an extremely long life, no matter how good your diet might be. Most of the healthiest people die before reaching Murdock's advanced age of 90, and he is fortunate to have lived as long as he has. In a world of billions, random chance will deliver a small population of people who are very wealthy, interested in ineffective means of living longer, and who also, coincidentally, live for a long time.

Diet only affects your health - which is a good enough reason to try for a sensible diet and lifestyle. It isn't the key to extreme longevity, however. It remains the case that only way to enable people to reliably live far longer than they would otherwise have done is the development of new medical science focused on repairing the cellular and molecular causes of aging.

David Murdock, at age 90, has the look and energy of a man many years younger. The chairman of Dole Foods, the world's largest marketer of fruits and vegetables, has stated that he expects to live to 125, thanks to his lifestyle, diet and exercise regimen. In the early 1980s, about the same time Murdock bought a controlling interest in the conglomerate of which Dole was a part, his wife, Gabriele, was ill with advanced-stage ovarian cancer. The couple spent nearly two years traveling the world seeking information about potential cures. After Gabriele died in 1985, at age 43, Murdock stuck with many of the healthy lifestyle habits the couple discovered during their quest.

Murdock, whose net worth is estimated by Forbes to be $2.4 billion, has also committed more than $500 million toward the creation of the North Carolina Research Campus and David H. Murdock Research Institute in Kannapolis, N.C. There, researchers from government, industry, non-profit groups and eight universities can take advantage of advanced technology and agricultural resources to collaborate on studies that explore the potential health benefits of plants in boosting longevity and warding off what the institute calls "lifestyle-related disorders," like diabetes, obesity, Alzheimer's disease and cancer. The campus also supports public campaigns to promote healthy choices.

Murdock's commitment to biotechnology research is admirable and a far better legacy than most high net worth individuals manage. The focus of this work will have next to no impact on human longevity, however.

Link: http://www.forbes.com/sites/nextavenue/2013/06/07/90-year-old-billionaire-david-murdock-doles-out-advice-on-longevity/

In the near future it will be possible to build artificial bodies, and some decades after that it will become possible to gradually replace the biology of our brains with more durable and capable nanomachinery. A diverse industry of brain-computer interfaces and artificial intelligences will arise and come to maturity along the way. Will we in fact largely become a species of intelligent machines within the next few centuries? By this I mean designed machines, as opposed to the evolved machines we presently are: entities that are human, but very distant from our present forms, functions, and limitations. When you design the machinery, rather than just working with what you have been given, an enormous range of possibilities open up. For one thing, even very complex machines can be designed to be far more robust and easily maintained than our biology, allowing a person-turned-machine-intelligence the option of an extremely long life expectancy.

Will there be a population-scale rush away from biology towards the new and better options for bodies and brains as soon as they become a practical concern? Some people think so, and I believe it is an inevitable transition given the far greater capabilities that could be provided by being more than merely biological. Perhaps not a rush, but a transition over time, leaving behind a disparate collection of Amish-like groups and poor communities that coexist and trade with the transitioned human societies. On the large scale people follow incentives: they buy the new tools that improve life, boost economic output, and add new options at an affordable price. Those groups with the greatest economic output grow to become the cultural mainstream over time. There's no reason to think that any of this will change, no matter whether society is running on silicon or neurons. Here is an interesting thought, though:

Aubrey de Grey on Ending Aging and the Human Future

I spoke with Aubrey briefly on the topic of the future of humanity, and the potential scenarios (often discussed in the world of transhumanism and futurism) that might involve moving our human conscious into other substrates, giving us long-lasting silicon bodies and potentially moving our minds into computers that are more durable and reliable that our current biological grey matter.

It is Aubrey's belief that the desire to leave our biological substrate will diminish as the "down-sides" of remaining purely biological go down. In other words, when we can more-or-less live forever in our present bodies, Aubrey believes that we will likely not wish to remove ourselves from them. The negative aspects of "being made of meat" - as he aptly put it - would be mitigated by an absence of disease and an absence of the recurring damage which is the origin of aging itself.

Another way of looking at the incentives of moving from biology to machinery is that it is not just a matter of chasing something better, but also a matter of leaving something undesirable. Discomfort is a great motivator, and evading the terrible suffering and death caused by aging is important to many of those who look with hope to a transhumanist future. Given an industry of rejuvenation medicine and complete control over aging, disease, and pain, however, being a standard issue biological human begins to look like an indefinitely comfortable existence - barring rare fatal accidents, of course, but who goes through life thinking that will happen to them?

So the argument here is that medicine, and specifically the defeat of degenerative aging, will alter the incentive landscape in a way that leads more people to choose to remain biological, even when it is possible to become a machine intelligence with greater capabilities and durability. My estimate of the timelines is that rejuvenation will be a going concern a long way prior to the point at which slow, safe replacement of the brain's neurons with nanomachinery is possible. It's possible that the increased comfort provided by the removal of age-related suffering and death will slow down progress towards ways to move biology to machinery.

But we shall see. It is interesting to think about these things, but important not to lose sight of the fact that researchers still need to build the means to reverse degenerative aging. There are detailed plans to show what needs to be done in order to rejuvenate the old, there are plenty of researchers ready to jump in and perform the work if given funding, but resources and public interest are - as ever - lacking. The future only stays fascinating if you remain alive to see it, so consider helping to speed progress towards the means of human life extension.

It is good that scientists are now more willing than in past years to talk about human longevity and the prospects for reversing aging through medical science. That change in attitudes is a necessary part of creating an environment in which rejuvenation research programs like SENS can thrive.

This particular group of researchers holds a different view as to which of the known changes in old cells and tissues are fundamental and thus cause aging: in the SENS outline telomere shortening is a secondary effect and nuclear DNA damage is only a cause of cancer rather than aging, but this paper puts them front and center as primary causes of aging. These researchers are also as yet unwilling to explicitly talk about rejuvenation rather than simply slowing aging, but a rising tide floats all boats.

All in all I'm very pleased to see scientists independently following the SENS model by producing a work that combines (a) specific descriptions of the changes proposed to cause aging and (b) specific proposals on how to use this information to build therapies that will address aging. The paper is open access for the moment at least, so you might take a look:

For some species, living twice as long in good health depends on no more than a few genes. When this fact was revealed by studies on worms three decades ago, it ushered in a golden age of ageing studies that has delivered numerous results, but also sown some confusion. [Researchers are now] publishing an exhaustive review of the subject that aims to set things straight and "serve as a framework for future studies." All the molecular indicators of ageing in mammals - the nine signatures that mark the advance of time - are set out in its pages. And the authors also indicate which can be acted upon in order to prolong life, while debunking a few myths like the belief that antioxidants can delay aging.

The authors are Spanish scientists Maria Blasco (Spanish National Cancer Research Centre, CNIO), Carlos López-Otín (University of Oviedo), and Manuel Serrano (CNIO), along with Linda Partridge (Max Planck Institute for Biology of Ageing) and Guido Kroemer (Paris Descartes University). Their inspiration came from a classic 2000 paper, The Hallmarks of Cancer, [which] marked a watershed in cancer research.

[This] removes the "frivolity" with which aging research is often approached: "It's not about not having wrinkles or living to be a hundred at any cost, but about prolonging disease-free life." [The] scientists are explicit about their final goal, which is "to identify pharmaceutical targets to improve human health during aging."

Another milestone of the paper is that it not only defines the nine molecular hallmarks of aging but orders them into primary hallmarks - the triggers; those that make up the organism's response to these triggers; and the functional defects resulting. This hierarchy is important, because different effects can be achieved by acting on one or other of these processes. By acting on just one mechanism, if it numbers among the primaries, we can delay the aging of many organs and tissues.

There are four primary causes of aging: genomic instability; the shortening of telomeres; epigenetic alterations; and loss of proteostasis.

Genomic instability refers to the defects the genes accumulate over time, due to intrinsic or extrinsic causes. The shortening of telomeres - the protective caps over the ends of chromosomes - is one such defect, but so important a one that it stands as a hallmark in its own right. Epigenetic alterations are the result of lived experience - our exposure to the environment.

Loss of proteostasis has to do with the non-elimination of defective proteins, whose accumulation promotes age-related diseases. With Alzheimer's, for instance, neurons die because plaques form of a protein that should have been eliminated.

The organism responds to these triggers with mechanisms that try to correct the damage, but which can themselves turn deleterious if they become exacerbated or chronic. This is the case of cellular senescence: the cell is induced to stop dividing, and thus prevent cancer, when too many defects are built up, but if the effect is overdone, the tissues - and the body - age.

One therapeutic strategy tested successfully in mice is to stop the telomeres from shortening. "The process can be halted and even reversed in mice," remarks Blasco, an expert in the area, who is convinced that, by and large, "we still have ample room for manoeuver to combat aging and enjoy more years of both life and health."

For López-Otín, "We have diverse opportunities to extend longevity in the not too distant future. Treatments aimed at reducing or correcting the genomic damage that occurs with time are still a distant prospect, but those focusing on metabolic regulation systems may be much more achievable. We don't aspire to immortality, just to the possibility of making life a little better for us all."

Link: http://www.eurekalert.org/pub_releases/2013-06/cndi-srw060313.php

It was once thought that the brain did not generate new neurons in adult life, but the evidence for ongoing neurogenesis was found a few decades ago. Levels of neurogenesis in humans have been hard to pin down, but knowing the degree to which it happens naturally has some relevance to attempts to induce a higher rate of neuron creation with the aim of reversing age-related loss of cognitive function. Here researchers find a way to quantify the level of cell turnover in at least one part of the brain:

The birth of new neurons in the adult brain sharpens memory in rodents, but whether the same holds true for humans has long been debated. A [study] reveals that a significant number of new neurons in the hippocampus - a brain region crucial for memory and learning - are generated in adult humans. The researchers used a unique strategy based on the amount of carbon-14 found in humans as a result of above-ground nuclear testing more than half a century ago. The findings suggest that new neurons are born daily in the human hippocampus, offering the tantalizing possibility that they may support cognitive functions in adulthood.

Due to technical limitations, until now it was not possible to quantify the amount of neurogenesis in humans. To overcome this hurdle, [researchers] developed an innovative method for dating the birth of neurons. This strategy takes advantage of the elevated atmospheric levels of carbon-14, a nonradioactive form of carbon, caused by above-ground nuclear bomb testing more than 50 years ago. Since the 1963 nuclear test ban treaty, atmospheric levels of "heavy" carbon-14 have declined at a known rate. When we eat plants or animal products, we absorb both normal and heavy carbon at the atmospheric ratios present at that time, and the exact atmospheric concentration at any point in time is stamped into DNA every time a new neuron is born. Thus, neurons can be "carbon dated" in a similar way to that used by archaeologists.

By measuring the carbon-14 concentration in DNA from hippocampal neurons of deceased humans, the researchers found that more than one-third of these cells are regularly renewed throughout life. About 1,400 new neurons are added each day during adulthood, and this rate declines only modestly with age.

Link: http://www.eurekalert.org/pub_releases/2013-06/cp-ntf053113.php

Of the billions presently alive, some fraction will go on to live for thousands of years. The age of rejuvenation therapies is just around the corner, and new approaches to medicine will enable the old to be made young again. This will happen within a few decades, perhaps soon enough for those in middle age today in wealthier regions, perhaps not. Whatever the timeline turns out to be - and we have the opportunity to accelerate it - the fundamental forms of cellular and molecular damage that cause aging will become just another set of chronic medical conditions that are kept under control with regular treatments: periodically repaired, so as to maintain youth and indefinitely postpone age related disease.

In this future people will still die, however. The current mortality rate due to fatal accidents, if maintained, would give an ageless, disease-free person a life expectancy of a few thousand years. If you want to live longer than that, then you require either (a) the means of greatly reducing the occurrence and severity of accidents, or (b) to ability to change yourself to be less vulnerable. Those people alive today who are still alive ten thousand years from now, and some will be, will most likely have altered themselves dramatically, abandoning flesh and the human form in favor of far more robust machinery.

It should not be terribly controversial to suggest that a hundred years from now replacing your body with an artificial chassis will be a very feasible, cost-effective option. The manufacturing and design technologies of that era will involve mature artificial intelligence and precise atomic construction. An artificial body should be a simple undertaking by that point, and there's more than enough time to wait for that technology if you survive today's first hurdle of living long enough to benefit from the first wave of rejuvenation biotechnologies.

When it comes to transforming yourself into an entity likely to survive for longer than recorded human history to date, the body is a trivial matter, however, hardly worth putting much thought into at this point. Almost any easily replaceable, mobile, and very robust machinery will do. The more interesting questions relate to the brain and the self: how can you switch out the intricate biology of the brain for more durable machines without killing yourself in the process? All that is you is encoded as data in the fine structure of brain tissue. Making a copy of your mind to run as software seems like a feasible undertaking, something that can be envisaged even today: it's possible to speculate in a useful fashion as to how that might be accomplished within the next few decades. But a copy of you is its own entity, not you, and there are many other questions and doubts relating to the continuity of the self associated with an intelligence running as software.

The best approach to replacing the brain while retaining your self is a slow process of replacing each neuron with machinery that serves exactly the same purpose and integrates with the rest of the brain in exactly the same way as the neuron did. The brain creates and loses neurons on an ongoing basis already - though a plausible replacement methodology would run many times faster than that process, and would replace neurons that are normally never replaced. Some of those cells last a lifetime.

This gradual neural replacement is a fine thing to talk about in abstract, but how would it even work in practice? How would a neuron machine be constructed? How do you assure continuity of the self when doing this for real? Some people have put a fair amount of thought into this topic, even though it is a far future prospect and we still have to sort out the first step of not aging to death in the bodies and brains we have now. Over at the Rational Argumentator you'll find an eleven part series on the important parts of the path to replacing the brain with machinery. There's quite a lot of reading material there, and I make no warranty as to the quality and rigor of the work, but I think you'll find it interesting.

1. The Moral Imperative and Technical Feasibility of Defeating Death
2. Immortality: Material or Ethereal? Nanotech Does Both!
3. Concepts for Functional Replication of Biological Neurons
4. Gradual Neuron Replacement for the Preservation of Subjective-Continuity
5. Wireless Synapses, Artificial Plasticity, and Neuromodulation
6. Mind as Interference with Itself: A New Approach to Immediate Subjective-Continuity
7. Neuronal 'Scanning' and NRU Integration
8. Squishy Machines: Bio-Cybernetic Neuron Hybrids
9. Choosing the Right Scale for Brain Emulation
10. Maintaining the Operational Continuity of Replicated Neurons
11. Immortality: Bio or Techno?

If we seek to replace biological neurons with artificial equivalents, once we have a simulation of a given neuron in a computer outside the body, how is that simulated neuron to communicate with the biological neurons still inside that biological body, and vice versa? My solution was the use of initially MEMS (micro-electro-mechanical systems) but later NEMS (nano-electro-mechanical-systems) to detect biophysical properties via sensors and translate them into computational inputs, and likewise to translate computational output into biophysical properties via electrical actuators and the programmed release of chemical stores (essentially stored quantities of indexed chemicals to be released upon command). While the computational hardware could hypothetically be located outside the body, communicating wirelessly to corresponding in-vivo sensors and actuators, I saw the replacement of neurons with enclosed in-vivo computational hardware in direct operative connection with its corresponding sensors and actuators as preferable.

I didn't realize until 2010 that this approach - the use of NEMS to computationally model the neurons, to integrate (i.e., construct and place) the artificial neurons and translate to biophysical signals into computational signals and vice versa - was already suggested by Kurzweil and conceptually developed more formally by Robert Freitas, and when I did, I felt that I didn't really have much to present that hadn't already been conceived and developed.

However, since then I've come to realize some significant distinctions between my approach and Brain-Emulation, and that besides being an interesting story that helps validate the naturality of Immortalism's premises (that indefinite longevity is a physically realizable state, and thus technologically realizable - and what can be considered the "strong Immortalist" claim: that providing people the choice of indefinite longevity if it were realizable is a moral imperative), I had several novel notions and conceptions which might prove useful to the larger community working and thinking on these topics.

I believe it's a grand waste of time to try to optimize your health through presently available methods. It's very easy to get the 80/20 best expected outcome: exercise regularly, practice calorie restriction with optimal nutrition, and refrain from methods of self-harm such as smoking, jumping off tall buildings, and so on. This is not rocket science.

There is no scientific support for going beyond this to tinker with types of exercise, esoteric supplements, and the like, however. There's no way to link your future life expectancy with your activities, and there is no good weight of evidence to suggest that any of the thousands of available options are better or worse for life expectancy than the 80/20 approach. There is always someone out there pushing a new fad, but that doesn't make it right, useful, or legitimate. Maybe you'll improve your life span by a few percentage points, and maybe you won't. There is no way to tell, and the time and money easily wasted on that endeavor is better put to other uses that are far more likely to extend your healthy life span - such as supporting the research needed to produce rejuvenation biotechnology.

That all said, it's possible to go too far in the direction of doing little but the basics for your health - if you are thinking of letting it all go and doing nothing for your health, that will have consequences. This view is illustrated in the post quoted below, wherein the author rejects calorie restriction on the basis that the present consensus view is that it won't extend healthy life in humans by all that much. This ignores the amazing health benefits demonstrated in human studies to date - calorie restriction may or may not extend human life by more than a few years, but it certainly greatly improves measures of health and lowers risk of age-related disease. It seems silly to reject something shown to produce larger benefits for basically healthy people than can be gained by any presently available medical technology.

I want to live longer and help others do the same. I assumed the most effective way to do that is by understanding the science of aging and then engineering solutions to extend human lifespan. That is why I became a biomedical researcher and over the past several years I have pursued this goal almost single-mindedly.

When a 2004 study showed that reducing the calorie intake in mice extended their life by 42%, I enthusiastically embraced the results and even put myself on a calorie restricted diet. But, subsequently, a 2012 study showed that long-term calorie restriction may not have the promised benefits. On the contrary, fewer calories without the required nutrients might actually cause harm.

Calorie restriction is not the first such "promising" route that eventually did not live up to the promise, and it will not be the last. Antioxidants showed promise in holding back diseases caused by aging, but now we know that antioxidant supplements are more likely to shorten your life.

Earlier in May, researchers showed that reducing a protein called NF-kB in mouse brains modestly improved their lifespan. I am not holding out for this result either. Before too long, I'm sure there will be reports of severe side effects of manipulating levels of NF-kB.

Looking at the data I have come to the conclusion that "doing nothing" may be the best option in most cases. This may not be as pessimistic as it sounds and it is definitely not to say that research in fighting aging must not be carried out. When I say "do nothing", I am assuming that you do not smoke or drink too much alcohol, and have access to medical care in case of injury. Such measures are bound to increase your lifespan.

But currently, not intervening in the aging process is more likely to help you live longer than trying any of the methods I've mentioned, not by a few months but by many years. Trying any of those interventions may actually cause harm, and will do so for the foreseeable future.

I agree with the basic thesis here, which is to be a late adopter and refrain from chasing the latest fads and data - this is an aspect of what I am arguing with my view on the futility of trying to optimize health past the 80/20 basics. But again, you can take it too far and throw the baby out with the bath water. Calorie restriction with optimal nutrition has an enormous weight of evidence gathered over decades backing its benefits and safety, and the same goes for regular exercise.

Link: http://lifeboat.com/blog/2013/05/do-nothing-to-live-long

Here is an interview in Russian with with researcher Alexei Moskaliev, associated with the Science for Life Extension Foundation. The Russian gerontology community's view of aging has a somewhat different slant from that of the English language world - there is more of a tendency towards the programmed aging viewpoint, for one thing, in which aging is thought to be a genetic program that leads to damage rather than damage that causes epigenetic changes in response.

Automated translation of Russian remains terrible, I should note, so be prepared to have to interpret the output where it becomes confusing:

Stress leads to substantial deviations of the external and internal parameters of the optimum life span of cells (concentration of nutrients, pH, oxygen level and temperature). Oxidative stress, genotoxic stress, mitochondrial stress, endoplasmic reticulum stress - different kinds of complex intracellular processes leading to the accumulation of damaged cellular structures. Damaged cells cope worse with the problems, and are not able to participate in physiological functions and tissue regeneration.

Gerontologists often talk about the fundamental difference between aging "carts" and aging "horses." The cart accumulates damage and ceases to perform its function. The horse is actively opposing internal failure at the level of each cell for as long as these arrangements do not themselves fail, and this is called stress tolerance. Mechanisms involving DNA damage response proteins, membrane lipids, and detoxification of toxins work with reduced effectiveness with advancing age. Therefore, the real cause of aging is not actually the accumulation of cell damage but rather the loss of mechanisms to combat injuries.

Many diseases are characterized by an exponential growth with increasing age, indicating that their direct connection with aging. This suggests that aging is the cause of most of these diseases (many types of cancer, cardiovascular disease, retinopathy, cataracts, type II diabetes, etc.) and an important risk factor for other causes of death (viral diseases, accidents, etc.). Some authors believe that it's time to talk about aging as a disease, and age-related pathologies are its manifestations or biomarkers. The adoption of this approach would change modern medicine.

In struggling with specific manifestations (individual age-related pathologies) doctors reach only short-term success. By suppressing the causes of aging, including age-related decline in the activity of stress-resistance genes we may expect much more progress in both prolonging life and improving quality of life.

Link: http://translate.google.com/translate?u=www.gazeta.ru/health/2013/05/29_a_5360833.shtml

The near future of human longevity will be determined by progress in medical technology. This is the only thing that might result in the option to live in good health for decades or more beyond the span of years enjoyed by your grandparents: there's no other way to extend healthy life to this degree. It's new medicine or nothing, and the critical factor is whether proposed forms of rejuvenation biotechnology such as those described in the SENS proposals are developed rapidly or slowly. At present the pace is slow, but we may yet manage to obtain the funding and attention needed to turn rejuvenation into a field as large and energetic as cancer research or stem cell medicine.

Present day good health practices cannot greatly extend your life, and they cannot even reliably ensure that you reach extreme old age in good shape, or indeed at all. Most exceptionally healthy people don't make it to 90 - but of course the toll is far worse among those who are sedentary, fat, and smoke. The consensus from various studies appears to be that you can give yourself the expectancy of five to ten additional years above the average through regular exercise, and you can drop five to ten years or more below the average through being obese or smoking. Calorie restriction may or may not be as good as exercise for human life expectancy, though it is expected by the research community to extend life. The benefits to short term measures of health are arguably far better than those produced by exercise, but it's hard to find a big enough study population for calorie restriction to produce the same sorts of quality statistic data as are available for exercise.

Taking the 80/20 approach to being healthy isn't just a quality of life and lower medical expense thing nowadays, however. It was in the past, because there was no possibility of radical life extension through medical technology on the horizon. Now, however, rejuvenation biotechnology is within a few decades of implementation, with that countdown starting just as soon as the funding ramps up to appreciable levels. How long will it take to generate the funds and interest? No one knows.

So who will make it to survive into the era of rejuvenation and the defeat of degenerative aging? Certainly most of the people born within the past decade. But those of us presently in the middle of life are looking at a great deal less certainty. For hundreds of millions of people a decade one way or another will be the difference between death and living to be young again, for as long as you care to keep going. Are you one of the people in that zone of uncertainty? Perhaps - but you'll never know until it's too late. That's why the whole healthy lifestyle thing is important: it's one of the only two ways in which you can shift the odds in a favorable direction, with the other being to help accelerate research and development.

With this in mind, here are a few recent research results on the topic of health and lifestyle. They are a reminder that a better lifestyle is a good thing from the point of view of your likely length of life, medical expenditures, and the risk of suffering age-related medical conditions.

Vegetarian Diets Associated With Lower Risk of Death

Vegetarian diets are associated with reduced death rates in a study of more than 70,000 Seventh-day Adventists with more favorable results for men than women. There were 2,570 deaths among the study participants during a mean (average) follow-up time of almost six years. The overall mortality rate was six deaths per 1,000 person years. The adjusted hazard ratio (HR) for all-cause mortality in all vegetarians combined vs. nonvegetarians was 0.88, or 12 percent lower, according to the study results. The study notes that vegetarian groups tended to be older, more highly educated and more likely to be married, to drink less alcohol, to smoke less, to exercise more and to be thinner.

Evidence mounts that 4 lifestyle changes will protect heart, reduce your risk of death

A large, multi-center study led by Johns Hopkins researchers has found a significant link between lifestyle factors and heart health, adding even more evidence in support of regular exercise, eating a Mediterranean-style diet, keeping a normal weight and, most importantly, not smoking. The researchers found that adopting those four lifestyle behaviors protected against coronary heart disease as well as the early buildup of calcium deposits in heart arteries, and reduced the chance of death from all causes by 80 percent over an eight-year period.

Healthy Lifestyle Choices Mean Fewer Memory Complaints

To examine the impact of these lifestyle choices on memory throughout adult life, UCLA researchers and the Gallup organization collaborated on a nationwide poll of more than 18,500 individuals between the ages of 18 and 99. Respondents were surveyed about both their memory and their health behaviors, including whether they smoked, how much they exercised and how healthy their diet was.

"We found that the more healthy lifestyle behaviors were practiced, the less likely one was to complain about memory issues." In particular, the study found that respondents across all age groups who engaged in just one healthy behavior were 21 percent less likely to report memory problems than those who didn't engage in any healthy behaviors. Those with two positive behaviors were 45 percent less likely to report problems, those with three were 75 percent less likely, and those with more than three were 111 percent less likely.

Adiponectin is one of many signaling proteins generated by fat cells and has been showing up of late in research aimed at better understanding the ways in which the operation of metabolism determines the pace of aging. Visceral fat tissue is very active in terms of determining the operating state of your metabolism as a whole. Carrying more visceral fat is associated with worse long-term health and a shorter life expectancy, thought to be achieved through mechanisms such as raised levels of chronic inflammation. Studies in mice show that removing visceral fat extends life. Altered levels of adiponectin and related proteins may be one of the ways in which excess fat (adipose tissue) sabotages your health, but given the evidence from studies of the metabolism of long-lived individuals it's probably not a simple relationship:

Adipose tissue is an active metabolic organ secreting adipocytokines which are involved in the energy homeostasis and regulation of glucose and lipid metabolism. Aging is associated with fat redistribution, which is characterized by loss of peripheral subcutaneous fat and accumulation of visceral fat. Visceral adipose tissue is more involved in the development of metabolic diseases than subcutaneous adipose tissue.

Aging also alters the function, proliferation, size, and number of adipose cells which leads to alterations in the secretion, synthesis and function of the adipocytokines. Adiponectin is an insulin sensitizing, anti-inflammatory, and antiathoregenic adipokine. Centenarians have higher adiponectin levels associated with longevity. However, in older individuals ‑ age 65 or more ‑ adiponectin is associated with higher mortality. Dysregulation of adiponectin in older individuals may be due to loss of function of circulating adiponectin or a response to increased inflammatory process. Longitudinal increase in adiponectin levels with aging rather than genetically high adiponectin levels may translate to increased mortality in older patients.

The adipocytokine leptin is traditionally viewed as a product of adipocytes that can exert endocrine effects. There have been conflicting reports of not only the effects of aging on leptin, but also the effects of leptin on age-related diseases including sarcopenia, Alzheimer's disease and cardiovascular diseases. Aging is also associated with resistance to leptin and/or to a decrease of receptors for this hormone.

Link: http://www.ncbi.nlm.nih.gov/pubmed/23732375

Aging causes bone to deteriorate, as is the case for all types of tissue in our bodies. This open access paper reviews what is known of the higher level mechanisms involved in bone aging, but it remains the case that little work is done to link these mechanisms with specific forms of age-related damage, such as those outlined in the SENS research and development proposals. Most researchers work towards linking specific outcomes in aging to the secondary results of damage, such as changes in gene expression and rising levels of oxidative stress:

With advancing age, the amount of bone resorbed by the osteoclasts is not fully restored with bone deposited by the osteoblasts and this imbalance leads to bone loss. Thus, aging and osteoporosis are intimately linked.

Similar to other tissues, oxidative stress increases in bone with age. This article reviews current knowledge on the effects of the aging process on bone and its cellular constituents, with particular emphasis on the role of reactive oxygen species (ROS). FoxOs, sirtuins and the p53/p66shc signaling cascade alter osteoblast number and bone formation via ROS-dependent and -independent mechanisms.

Specifically, activation of the p53/p66shc signaling increases osteoblast/osteocyte apoptosis in the aged skeleton and decreases bone mass. FoxO activation in osteoblasts prevents oxidative stress to preserve skeletal homeostasis. However, while defending against stress FoxOs bind to β-catenin and attenuate Wnt/T-cell cell factor transcriptional activity and osteoblast generation. Thus, pathways that impact longevity and several diseases of ageing might also contribute to age-related osteoporosis.

Link: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3659822/

A broad range of future medicine will be based on ways and means of ever more precisely controlling cells. Many scientists are engaged in the process of developing the necessary knowledge and tools: finding out how to instruct cells to take particular actions, change their internal state, or even shift between cell types; understanding cellular processes well enough to be able to adjust or repair them when they are broken; learning how to steer vast numbers of cells in the collaborative work of maintaining tissue function and building new tissue. Progress is incremental, as there are hundreds of different cell types in the body and while they are all built on the same chassis, as it were, they are nonetheless very different from one another. Specialist research groups tend to work with just a few types of cell, making small steps forward year after year in understanding cell signals and behaviors well enough to manipulate them.

The recent research publicity releases quoted below are examples of the sort of work that will be taking place for decades yet. This is the foundation of regenerative medicine: the small projects and narrowly focused advances that will together form the basis for future therapies. It's a lot of work, as cell biology is enormously complex.

A step closer to artificial livers

The liver can indeed regenerate itself if part of it is removed. However, researchers trying to exploit that ability in hopes of producing artificial liver tissue for transplantation have repeatedly been stymied: Mature liver cells, known as hepatocytes, quickly lose their normal function when removed from the body. "It's a paradox because we know liver cells are capable of growing, but somehow we can't get them to grow" outside the body.

Now, [researchers] have taken a step toward that goal. [They] previously developed a way to temporarily maintain normal liver-cell function after those cells are removed from the body, by precisely intermingling them with mouse fibroblast cells. For this study, [the] research team adapted the system so that the liver cells could grow, in layers with the fibroblast cells, in small depressions in a lab dish. This allowed the researchers to perform large-scale, rapid studies of how 12,500 different chemicals affect liver-cell growth and function. [After] screening thousands of liver cells from eight different tissue donors, the researchers identified 12 compounds that helped the cells maintain those functions, promoted liver cell division, or both.

Two of those compounds seemed to work especially well in cells from younger donors, so the researchers [also] tested them in liver cells generated from induced pluripotent stem cells (iPSCs). Scientists have tried to create hepatocytes from iPSCs before, but such cells don't usually reach a fully mature state. However, when treated with those two compounds, the cells matured more completely. [Other] researchers are now testing them in a variety of cell types generated from iPSCs. In future studies, [the] team plans to embed the treated liver cells on polymer tissue scaffolds and implant them in mice, to test whether they could be used as replacement liver tissues. They are also pursuing the possibility of developing the compounds as drugs to help regenerate patients' own liver tissues.

Penn Research Shows Way to Improve Stem Cells' Cartilage Formation

"The broad picture is trying to develop new therapies to replace cartilage tissue, starting with focal defects - things like sports injuries - and then hopefully moving toward surface replacement for cartilage degradation that comes with aging. Here, we're trying to figure out the right environment for adult stem cells to produce the best cartilage. As we age, the health and vitality of cartilage cells declines, so the efficacy of any repair with adult chondrocytes is actually quite low. Stem cells, which retain this vital capacity, are therefore ideal."

The first step in growing new cartilage is initiating chondrogenesis, or convincing the mesenchymal stem cells to differentiate into chondrocytes, which in turn generate the spongy matrix of collagen and sugars that cushions joints. One challenge in prompting this differentiation is that, despite the low density of adult chondrocytes in tissues, the actual formation of cartilage begins with cells in close proximity. "In typical hydrogels used in cartilage tissue engineering we're spacing cells apart, so they're losing that initial signal and interaction. That's when we started thinking about cadherins, which are molecules that these cells use to interact with each other, particularly at the point they first become chondrocytes."

To simulate that environment, the researchers used a peptide sequence that mimics these cadherin interactions, which they bound to the hydrogels used to encapsulate the mesenchymal stem cells. "While the direct link between cadherins and chondrogenesis is not completely understood, what's known is that if you enhance these interactions early during tissue formation, you can make more cartilage, and, if you block them, you get very poor cartilage formation. What this gel does is trick the cell into thinking it's got friends nearby."

A reminder from the SENS Research Foundation staff that the early registration and abstract submission deadlines for this year's SENS6 conference are coming up on June 15th:

You are cordially invited to participate in the sixth Strategies for Engineered Negligible Senescence (SENS) Conference, which will be held from 3rd - 7th September, 2013 at Queens' College, Cambridge. June 15th is the deadline for discounted registration and abstract submission. After this deadline, all registration fees rise by £150.00. Also, after that date, we cannot guarantee that submitted abstracts will be considered for oral presentation or that they will be included in the conference abstract book.

All details of the conference, including forms for abstract submission and online registration, are at the conference website. The conference program features 47 confirmed speakers so far, all of them world leaders in their field. As with previous conferences hosted by SENS Research Foundation, the emphasis of this meeting is on the design and implementation of rejuvenation biotechnologies - applications of regenerative medicine to age-related disease. Such biomedical interventions may jointly constitute a comprehensive panel of therapies that is sufficient to prevent or cure the diseases of aging, ensuring robust health for all.

Link: http://www.sens.org/files/newsletters/sens6-invite.html

The American Aging Association (AGE) held its 2013 meeting a few days ago. The program was a mix of old-school and irrelevant research such as the effects of specific foods on parameters of aging, nothing that's going to help us meaningfully extend life there, and the new and interesting such modulating autophagy to slow the effects of aging in specific tissues. Here are some notes from an attendee:

Several talks involved growth hormone one way or another. Growth hormone is hyped as an anti-aging remedy by many supplement sources, but its benefits are likely to be short-term, and there is substantial risk that it actually increases mortality risk in the long run. Holly Brown-Borg made this point quite explicitly. Her research is centered on two strains of mice, a dwarf strain which has a genetic defect for growth hormone, and lives 50% longer, the other is genetically engineered to have extra growth hormone, and it lives 50% shorter than ordinary lab mice. The dwarf mice are super-healthy and don't get cancer, but you can make them sick by giving them growth hormone.

There were several major presentations at the conference focused on rapamycin. Rapamycin binds to two sites, called TORC1 and TORC2 (TOR stands for "target of rapamycin"). Joe Bauer reported his theory that TORC2 holds most of the benefits, and TORC1 most of the dangers of rapamycin, and he is working to separate the two effects. Arlan Richardson offered an hour-long advertisement for rapamycin as a cancer treatment, for cardiac health and prevention of cognitive decline. He reluctantly admitted that it also causes cataracts, slows healing, and contributes to Type 2 diabetes. Conference consensus (including this author) is that rapamycin is an exciting new vehicle for studying aging, but as a general tonic, it's not ready for prime time.

I've been attending these meetings for several years, and I continue to find that the meetings are small, there are almost no MDs, and the research seems to occupy a backwater between bench science and medical research. Compared to cancer research or heart or lung disease, the field is way underfunded. Still, research in anti-aging medicine is growing, as policy-makers realize it is a way to address many diseases of old age with a powerful new paradigm.

Link: http://joshmitteldorf.scienceblog.com/2013/06/03/short-takes-from-the-2013-age-meeting-baltimore-june-1-3/

Greatly extending the healthy human life span has always been one of the core goals advocated by transhumanist authors. Degenerative aging and the suffering and death that it causes are limits, and the philosophy of transhumanism is to develop the technological means to make limits optional - to create choice where no choice is presently possible. As a species we have greatly changed the human condition to date by improving our surroundings and our tools, but in the future we will change it by improving ourselves. To create medical technologies that enable the choice not to age, suffering, and die is the most important of all goals. The personal relevance of everything else that the future might bring depends upon being alive to see it, after all.

Transhumanist research and development takes place all around us, and the human condition changes a little every year as a result, but research into the means of extending healthy life is very sparsely funded. The public at large seems in the most part indifferent to the prospect of longer lives. Does this mean that we are doing too poor a job in advocacy and fundraising, or that good progress over the past few decades has taken place in the face of a widespread lack of interest and even hostility towards longevity science? It's certainly the case that there is more deliberate funding and advocacy for rejuvenation research today than ten years ago, even though it's still small in comparison to other fields of medical science.

Everyone has an opinion on what we might do differently to persuade more people to support scientific research aimed at the reversal of aging. To follow on from last week's post on advocacy and the lack of funding for rejuvenation research, I thought I'd point out a few thoughts from Maria Konovalenko of the Science of Life Extension Foundation. They are presented beneath this banner:

How can Transhumanism Win?

The topics of horror of death and despair of aging are poorly exposed in tranhumanist rhetoric. In the 14th century, in the plague times, death used to be one of the main topics of visual arts. Nowadays the topic of horror of death struggles its way to the surface only on cigarette packs in a few countries of the world. There is an unspoken ban on documentary demonstration of the moment of human death. Death itself is often embellished, heroized and named necessary for striving of other people.

We claim that there is nothing more dreadful than death, and our main goal is to fight it. We understood that one of the most powerful impact tools are not the rational arguments, but visual images. We are interested in creating the new art that describes the horrors of aging and death with the aim of increasing the motivation of people to fight for radical life extension, for immortality. So, if you happen to know some artists, tell them about tranhumanist ideas and about the urgent need of new art that will help defeat death.

People don't like to talk about death, and in my experience can become very resistant or even hostile when the topic of rejuvenation research, cryonics, or other ways in which we can try to address death are brought up in the course of conversing about death. The death of older public or private figures should be teaching moments for longevity science, but in practice turn out to be a good opportunity to make people angry. This is an interesting response but not very helpful. People rarely want to talk about death in any detail at other times, and when it cannot be avoided as a topic they often react angrily to any thought of avoiding death through science and research.

So I think there's something to be said for giving death a 14th century prominence. Perhaps fewer people will choose to bury their heads in the sand. Konovalenko offers up some other points and opinions as well, which you may or may not agree with but which are all worth at least a little thought. One of these days someone will figure out the key to open the floodgates of support for extended healthy life and rejuvenation research, but that won't happen without a diversity of effort aimed at a better way forward.

Many in the mainstream research community still believe that the only viable way forward to extend life is to slow aging by manipulating metabolism - such as by trying to replicate the effects of calorie restriction through drugs. In their view, this is a long, hard, slow project that is unlikely to produce meaningful results within our lifetimes, and when it does produce results they will only induce a modest extension of healthy life.

These researchers do not yet acknowledge the potential of repair-based strategies that aim to reverse the forms of age-related cellular damage that most likely cause aging - the known fundamental differences between old tissue and young tissue - and thus produce rejuvenation. This should be less expensive and faster in addition to producing a better end result, such as indefinite extension of healthy life.

Extending life by slowing aging has been accomplished in many different species and in many different ways, but rejuvenation research is a younger, underfunded field that has yet to advance to the point at which it can boast the same panoply of demonstrations. All we have so far are examples of rejuvenation achieved in some aspects or mechanisms of some tissues, and not so many of those either. Even in the scientific community, people tend to believe in what they can see rather than what is plausible but not yet in evidence:

In an age of breakneck technological and scientific progress, it can seem at times like anything's possible. [For] all the exponential advances, though, some technologies remain firmly in the realm of science fiction. We can't engineer genius babies. We're never getting our hoverboards. And, perhaps most dispiritingly of all, we haven't figured out a way to cheat death.

It isn't for lack of trying. Research centers around the world have teams devoted to the study of human longevity, and scientists have been working furiously for years to uncover the secrets of long life in everything from mice to yeast to hydra. In fact, they're making a lot of progress, and there's good reason to be optimistic that they'll someday hit on a breakthrough that will allow people to live significantly longer than they do today. But if you're sitting around waiting for the singularity, you might want to stand up and go for a jog instead.

One problem is that humans are a lot harder to study than mice. A [study] found that mice injected with a substance that inhibited a molecule known as NF-KB lived longer than normal. Mice injected with NF-KB itself died young. That seems like compelling evidence that the molecule, which is involved in the body's response to stress, plays a role in how mice age. But what works in mice doesn't necessarily work in humans. And who's going to approve the study that injects people with an NF-KB inhibitor and to see how soon they die?

No one - especially since the FDA doesn't recognize aging as a disease. That makes regulations and approvals trickier for potential anti-aging treatments. And some researchers in the field complain that it makes it harder to get funding for big studies. The bigger-picture problem is that human longevity is a confluence of so many factors - genes, nutrition, lifestyle, luck - interacting in so many complex ways that there is unlikely ever to be a surefire way to live to 120.

Link: http://www.slate.com/articles/health_and_science/superman/2013/05/human_longevity_research_on_animals_and_centenarians_shows_promise_on_extending.html

The forthcoming Global Futures 2045 conference is attracting media attention to Dmitry Itskov's 2045 Initiative. The technological aim of the program is to move out of our biology and into durable, ageless machine bodies and minds as quickly as possible - though of course an upload of you is not you, but rather a distinct copy. That will not prevent people from choosing to create uploaded copies of themselves when the option becomes available, and will not diminish the enthusiasm of those who belief that a copy of you is you. Moving from a biological mind to a machine mind without copying or destroying yourself would have to be a much more gradual process, perhaps by a slow replacement of individual neurons and synapses with more resilient nanomachines that serve the same purpose.

The technologies needed to enable these goals are distant but not implausible - there is a lot of work between here and there. To my eyes this all seems like a harder and slower track to agelessness than the biological path of rejuvenation biotechnology as championed by the SENS Research Foundation. We don't have all the time in the world to wait for the future until researchers can repair the various known underlying causes of aging, and sorting that out in the biology we have today seems more viable than building a new home for the mind.

It is hard to imagine a day when the ideas championed by Mr. Itskov, 32, a Russian multimillionaire and former online media magnate, will not seem strange, or at least far-fetched and unfeasible. His project, called the 2045 Initiative, for the year he hopes it is completed, envisions the mass production of lifelike, low-cost avatars that can be uploaded with the contents of a human brain, complete with all the particulars of consciousness and personality. [He] has the attention, and in some cases the avid support, of august figures at Harvard, M.I.T. and Berkeley and leaders in fields like molecular genetics, neuroprosthetics and other realms that you've probably never heard of.

Mr. Itskov's role in the 2045 Initiative is bit like that of a producer in the Hollywood sense of the word: the guy who helps underwrite the production, shapes the script and oversees publicity. He says he will have spent roughly $3 million of his own money by the time the [forthcoming Global Futures 2045 conference] is over, and though he is reluctant to disclose his net worth - aside from scoffing at the often-published notion that he's a billionaire - he is ready to spend much more.

For now, he is buying a lot of plane tickets. He flies around the globe introducing himself to scientists, introducing scientists to one another and prepping the public for what he regards as the inevitable age of avatars. In the span of two weeks, his schedule took him from New York (for an interview), to India (to enlist the support of a renowned yogi), home to Moscow, then to Berkeley, Calif. (to meet with scientists), back to Moscow and then to Shanghai (to meet with a potential investor).

Mr. Itskov says he will invest at least part of his fortune in such ventures, but his primary goal with 2045 is not to become richer. In fact, the more you know about Mr. Itskov, the less he seems like a businessman and the more he seems like the world's most ambitious utopian. "We need to show that we're actually here to save lives. To help the disabled, to cure diseases, to create technology that will allow us in the future to answer some existential questions. Like what is the brain, what is life, what is consciousness and, finally, what is the universe?"

I might not believe that Itskov's vision is the best way forward towards greater longevity, but I do think that we would all benefit from the existence of a good many more ambitious utopians of this sort.

Link: http://www.nytimes.com/2013/06/02/business/dmitry-itskov-and-the-avatar-quest.html?pagewanted=all