Fight Aging! Newsletter, July 15th 2013

July 15th 2013

The Fight Aging! Newsletter is a weekly email containing news, opinions, and happenings for people interested in aging science and engineered longevity: making use of diet, lifestyle choices, technology, and proven medical advances to live healthy, longer lives. This newsletter is published under the Creative Commons Attribution 3.0 license. In short, this means that you are encouraged to republish and rewrite it in any way you see fit, the only requirements being that you provide attribution and a link to Fight Aging!

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  • Limits on Cell Life Span Have Little To Do With Limits on Organism Life Span
  • An Interview With Vladimir Skulachev
  • Calorie Restriction and Alternate Day Fasting in Ames Dwarf and GHRKO Mice
  • Cell Fusion in Functional Regeneration of the Mouse Retina
  • Latest Headlines from Fight Aging!
    • Less Frailty in GHRKO and Calorie Restricted Mice
    • Working on Artificial Replacements for Nerve Grafts
    • Correlating Rate of Aging With Metabolism in Infancy
    • IGF-1 Induced Longevity Accompanied by Reduced Protein Translation and Increased Autophagy
    • Examining the Mechanisms Behind Loss of Insulin Sensitivity in Sedentary Individuals
    • A Spanish Language Interview With Aubrey de Grey
    • Thoughts on Maintaining the Self While Upgrading the Brain to Machinery
    • Surf1 Knockout Mice Live Longer, Have Better Memories
    • Creating Inner Ear Structures from Stem Cells
    • Improved Outcomes for Long-Lived Individuals Born in 1915 Versus Those Born in 1905


Higher organisms like we humans are made of cells, of several hundred distinct types if you exclude all of the symbiotic bacterial species that we carry along with us. The vast majority of cells have short finite life spans: they stop reproducing and self-destruct or become senescent after a number of reproductive divisions. You might be familiar with the Hayflick limit in relation to this topic: it is the number of times a cell divides before it removes itself from the cell cycle to a fate of destruction or senescence. Similarly you have probably heard of telomeres, the repeating DNA sequences at the end of our chromosomes. The length of telomeres shortens with each cell division, forming a sort of countdown clock, and too-short telomeres is one of mechanisms by which cell division is halted.

The reality on the ground is much more complex than this simple view of a cell division countdown. Some cells don't divide and last you a lifetime, such as many of those in the central nervous system. Other cells, such as stem cell populations, have their telomeres repeatedly extended by the enzyme telomerase. Different cells in different parts of the body have very different life spans, and the complex array of processes that determine those life spans is highly variable, reacting to the environment and to each other.

None of this really has much direct bearing on the life span of an organism, however. You can't just wave a wand that would extend the life of all cells, and expect to see a similar extension of life in the organism - whether that happens or not depends on the intricate details of how cells relate to organs and systems. The life span of cells is all the way down there in the depths of the machine, details internal to low-level components that are decoupled from how the machine behaves in aggregate. There is no particular reason for cell life spans to have anything to do with how long the machine as a whole can last. Some of our tissues are designed to cycle through and replace all of their cells very rapidly, in a matter of days. Other cells are never replaced and live as long as we do.

Cell behavior is subordinate to the needs of the organ or system that they are a part of. The cells of a given type evolved to have their present behavior and typical life spans because, when acting as a system in conjunction with other cell types, they produce a working organ or system that provides some evolutionary advantage. If that can be done with lots of cell turnover and short cell life spans, it will be. If it can be done with little cell turnover and long cell life spans, it will be also - but either path can produce a long-lived and reliably functional organ. This point is one that a recent article comes to eventually, after a tour of the Hayflick limit and telomere biology:

Lust for life: Breaking the 120-year barrier in human aging

It is true that as we get older our telomeres shorten, but only for certain cells and only during certain times. Most importantly, trusty lab mice have telomeres that are five times longer than ours but their lives are 40 times shorter. That is why the relationship between telomere length and lifespan is unclear.

Apparently using the Hayflick limit and telomere length to judge maximum human lifespan is akin to understanding the demise of the Roman empire by studying the material properties of the Colosseum. Rome did not fall because the Colosseum degraded; the Colosseum degraded because the Roman Empire fell.

Within the human body, most cells do not simply senesce. They are repaired, cleaned or replaced by stem cells. Your skin degrades as you age because your body cannot carry out its normal functions of repair and regeneration.

The processes that cause degenerative aging occur at the level of cells and specific protein machinery within cells, harming their ability to perform as they should. Old, damaged cells produce more old, damaged cells when they divide. Old, damaged stem cells simply fail to keep up with their tasks of tissue maintenance. Long-lived cells become progressively more damaged and incapable, or die back, either of which causes very visible issues when it happens in the nervous system and brain.

Aging is simply a matter of damage. But how that damage translates into system failure is not a straightforward matter of cells living longer or cells dying sooner - except when it is for some long-lived cell types. Every tissue fails through the same general processes, but those processes produce a very wide range of failure modes, depending on the character of the tissue and the cells that make it up. Go beyond the comparative simplicity of the root causes of aging, and everything becomes progressively ever more complex as you move towards describing the highly varied biology of fatal age-related diseases. This is why intervening in the root causes is absolutely the best and most cost-effective strategy, the only one likely to produce meaningful progress towards human rejuvenation in our lifetimes.

As a final note, for my money, I'd wager that forms of amyloidosis are the present outermost limiting condition on human life span. The evidence suggests that this is what ultimately kills supercentenarians, the resilient individuals who have made it past the age of 110, avoiding or surviving all of the fatal age-related medical conditions that claimed their peers.


I recently noticed a two-part interview with researcher Vladimir Skulachev on a Russian language medical news site. Long-time readers will recognize the name in connection with work on plastoquinone-based mitochondrially targeted antioxidants: Skulachev's group produces the SkQ series of compounds that in recent years have been shown to generate benefits and extend life in mice. These are noteworthy for working though dietary intake, rather than requiring injection like the SS class of mitochondrially targeted antioxidants.

Mitochondrially targeted antioxidants are thought to work by soaking up a usefully large portion of the reactive oxygen species (ROS) produced by mitochondria in cells at their source, before they can cause harm to cellular structures - and especially before they can damage mitochondrial DNA. Progressively accumulated oxidative damage to mitochondrial DNA is widely considered to be an important contribution to degenerative aging, per the mitochondrial free radical theory of aging.

Like many Russian biogerontologists, Skulachev is on the programmed aging side of the fence, seeing aging as more of an evolved genetic program that causes damage rather than as a matter of accumulated damage that causes systems to change as they head down the path toward failure. This is far from a trivial difference, as it informs the strategies that researchers adopt in attempts to remove degenerative aging from the human condition - the wrong choice leads down an expensive and largely ineffective path. For my part, I think that the evidence points towards damage rather than programs.

As always I should note that automated translation of Russian has a way to go yet: we can put men on the moon and make stem cells dance to our tune, but moving a few verbs around remains beyond us. Thus the quoted materials below have been tidied up with guesswork and interpolation; errors are probably mine where they appear:

Can I live a few hundred years?

Interviewer: Is there a limit to growth? How long, in principle, a person can expect to live?

Skulachev: I think that there is no limit, and sooner or later people will come to practical immortality. Before, I was afraid to say so, because it sounded too provocative, but now, perhaps, it is already possible. The development of biology is such fantastic pace, after 100 years it will be completely realistic to talk of changing human nature ... This, of course, will never be immortality in its idealized form - when a person, for example, is beneath a falling concrete slab, we will not have a way to return him to his former state. But if we exclude such an absolute disaster, it is possible to assume the reality of a Methuselah-like near future, the life of a few centuries.

In principle we have not reached a point where people could die from wear and tear of the body. So far, I'm sure that people die because of orders received from the genome - for evolution it is enough to live and then give a place to others. This is a purely evolutionary mechanism, not necessary for modern man who has ceased to adapt to the environment and began to adapt the environment to his needs. How it will end and how dangerous this situation is - that is another question.

Interviewer: If everyone would live like Methuselah, does not have the resources ...

Skulachev: A typical error. In fact, there are a lot of resources and those resources are growing in proportion to human knowledge. But I would again like to emphasize that our goal is not immortality. We set ourselves a much simpler task: to transfer humans from the category of aging organisms into the category of non-aging organisms. Non-aging organisms exist in nature, both animal and plant. But perhaps the most striking example is the naked mole rat: they do not suffer from cancer, cardiovascular and infectious diseases, and their life expectancy is extremely high for small rodents - more than 30 years. So, the recent work of biochemists show that naked mole rats turn off a number of regulatory systems that are active in genetically close relative species. And it is very likely that as a result they have interrupted signals that trigger the mechanism of aging.

Abolish age

Last year, the Russian market launched a brand new ophthalmic drug based on SkQ1 for the treatment of dry eye syndrome - an old man's disease is considered incurable. Droplets containing SkQ1 as active ingredient, resulted in the disappearance of disease symptoms in 60% of patients after three weeks of treatment. Now research is ongoing in eight clinics in Russia and two in Ukraine. There is reason to think that the positive effect of a more prolonged use SkQ1 can be even greater.

It can treat some cancers, we have found in animal experiments. But no evidence of carcinogenicity caused by SkQ has been received. There are two aspects to this result. First, the very low therapeutic concentrations of SkQ - thanks to the targeted effect the substance is effective in minute doses. And the second - it quickly breaks down in the body.

Now begins the process of registering our medicines in the United States. Because the clinical trials that need to be carried out in America are very expensive we started with the orphan disease of uveitis. This will reduce the number of participants and therefore costs. Uveitis is an extremely unpleasant condition in which the tissues of the eye are being targeted by the patient's own immune system. It is treated by large doses of steroid hormones with very serious adverse consequences. Now three independent labs in Minneapolis, Andover and Sunny Vale (USA) have already confirmed our experiments previously carried out on animals in Russia.

We have already completed clinical trials on glaucoma and cataracts, which took place in Russia. The results are being published. In the near future are going to get the permission of Ministry of Health to study SkQ1 for the treatment of macular degeneration. It is hoped to complete this process in the winter of this year. It should be noted that initially the Ministry met our project with great skepticism. Too unusual results ... But, fortunately, we are guided by the principles of evidence-based medicine, and can always explain how and why our product works.

So all in all it looks like we'll be seeing the use of mitochondrially targeted antioxidants to treat numerous conditions over the next decade. Given that the substances are going through clinical trials, it seems unlikely that they'll be easily available - regulated and controlled as drugs, with harsh penalties for anyone using them outside the system. Still, broader usage can only result in it becoming easier for DIYbio and home chemistry amateurs to synthesize their own supplies should they feel so inclined, and should the evidence warrant making the effort versus just giving the funds to the SENS Research Foundation instead.


There has been an injection of greater rigor into mainstream mouse studies of longevity in recent years, possibly prompted by a growing realization that many studies of past decades were fatally undermined by a failure to consider the possibility of inadvertent calorie restriction, among other issues. So even well-trafficked areas such as the biology of long-lived lineages like Ames dwarf and growth hormone receptor knockout (GHRKO) mice presently see a steady progression of new and ever more careful studies of the basics. Not that there is any shortage of new ground to cover in something as complex as the biology of a mammal. There are unknowns enough to last for decades at the present pace of discovery.

These two papers take a new look at how some of the long-lived mouse breeds react to calorie restriction and the similar method of alternate day fasting, both of which are shown to extend life in ordinary non-engineered laboratory mice. There is far more evidence for the benefits of calorie restriction than there is for forms of intermittent fasting, as it has been studied for longer and by more research groups. Interestingly, some studies have shown alternative day fasting to extend life to some degree even when the overall level of calories consumed is not reduced. Other studies show that calorie restriction and alternate day fasting produce notably different patterns of gene expression - sets of overlapping but different changes.

The end goal behind this sort of work is to pin down the shared mechanisms by which life is extended, and thereby do a better job of identifying exactly what they are and how they work. If you find two methods of life extension that don't stack - as appears to be the case for GHRKO and calorie restriction - then that's a good place to start looking for these shared root causes.

Metabolic Alterations Due to Caloric Restriction and Every Other Day Feeding in Normal and Growth Hormone Receptor Knockout Mice

Mutations causing decreased somatotrophic signaling are known to increase insulin sensitivity and extend life span in mammals. Caloric restriction and every other day (EOD) dietary regimens are associated with similar improvements to insulin signaling and longevity in normal mice; however, these interventions fail to increase insulin sensitivity or life span in growth hormone receptor knockout (GHRKO) mice.

To investigate the interactions of the GHRKO mutation with caloric restriction and EOD dietary interventions, we measured changes in the metabolic parameters oxygen consumption (VO2) and respiratory quotient produced by either long-term caloric restriction or EOD in male GHRKO and normal mice.

GHRKO mice had increased VO2, which was unaltered by diet. In normal mice, EOD diet caused a significant reduction in VO2 compared with ad libitum (AL) mice during fed and fasted conditions. In normal mice, caloric restriction increased both the range of VO2 and the difference in minimum VO2 between fed and fasted states, whereas EOD diet caused a relatively static VO2 pattern under fed and fasted states. No diet significantly altered the range of VO2 of GHRKO mice under fed conditions. This provides further evidence that longevity-conferring diets cause major metabolic changes in normal mice, but not in GHRKO mice.

Metabolic adaptations to short-term every-other-day feeding in long-living Ames dwarf mice

Restrictive dietary interventions exert significant beneficial physiological effects in terms of aging and age-related disease in many species. Every other day feeding (EOD) has been utilized in aging research and shown to mimic many of the positive outcomes consequent with dietary restriction. This study employed long living Ames dwarf mice subjected to EOD feeding to examine the adaptations of the oxidative phosphorylation (OXPHOS) and antioxidative defense systems to this feeding regimen.

Every other day feeding lowered liver glutathione (GSH) concentrations in dwarf and wild type (WT) mice but altered GSH biosynthesis and degradation in WT mice only. The activities of liver OXPHOS enzymes and corresponding proteins declined in WT mice fed EOD while in dwarf animals, the levels were maintained or increased with this feeding regimen. Antioxidative enzymes were differentially affected depending on the tissue, whether proliferative or post-mitotic. Gene expression of components of liver methionine metabolism remained elevated in dwarf mice when compared to WT mice as previously reported however, enzymes responsible for recycling homocysteine to methionine were elevated in both genotypes in response to EOD feeding.

The data suggest that the differences in anabolic hormone levels likely affect the sensitivity of long living and control mice to this dietary regimen, with dwarf mice exhibiting fewer responses in comparison to WT mice. These results provide further evidence that dwarf mice may be better protected against metabolic and environmental perturbations which may in turn, contribute to their extended longevity.


Not so long ago a reader asked me about cell fusion in relation to repairing age-damaged cells, and I noted that while some work on cell fusion is taking place it seems far less researched as a basis for regenerative therapies than, say, straightforward stem cell transplants. I certainly don't see much on this topic in the course of my browsing.

Still, fusion of transplanted stem cells with local cells shows up in the recent work linked below, in which researchers demonstrates partial functional regeneration of damaged retinal tissue in mice - which is a pretty big deal as an outcome, and I can't imagine that the authors will have any trouble finding additional funds to move ahead with their work. It seems that the fusion process can effectively be used as a form of cell reprogramming, and fused cells go on to take useful actions that repair surrounding tissues to a degree that would otherwise not occur. Press materials on this research are doing the rounds:

A Step Forward in Neuronal Regeneration

Researchers from the Centre for Genomic Regulation (CRG) in Barcelona have managed to regenerate the retina thanks to neuronal reprogramming. There are currently several lines of research that explore the possibility of tissue regeneration through cell reprogramming. One of the mechanisms being studied is reprogramming through cell fusion. [Researchers] have used the cell fusion mechanism to reprogramme the neurones in the retina. This mechanism consists of introducing bone marrow stem cells into the damaged retina. The new undifferentiated cells fuse with the retinal neurones and these acquire the ability to regenerate the tissue.

Here is the open access paper for those who want to dig in deeper to the mechanisms involved and discussion of the work by the researchers:

Wnt/β-Catenin Signaling Triggers Neuron Reprogramming and Regeneration in the Mouse Retina

Cell-fusion-mediated somatic-cell reprogramming can be induced in culture; however, whether this process occurs in mammalian tissues remains enigmatic. Here, we show that upon activation of Wnt/β-catenin signaling, mouse retinal neurons can be transiently reprogrammed in vivo back to a precursor stage. This occurs after their spontaneous fusion with transplanted hematopoietic stem and progenitor cells (HSPCs). Moreover, we demonstrate that retinal damage is essential for cell-hybrid formation in vivo.

Newly formed hybrids can proliferate, commit to differentiation toward a neuroectodermal lineage, and finally develop into terminally differentiated neurons. This results in partial regeneration of the damaged retinal tissue, with functional rescue. We show that upon [induced] retinal damage, transplanted stem and progenitor cells (SPCs), such as mouse hematopoietic stem and progenitor cells (mHSPCs), human (h)HSPCs, retinal (R)SPCs, and embryonic stem cells, can fuse with retinal neurons in vivo with high efficiency. Importantly, we show that the fate of these hybrids is to embark upon apoptosis unless Wnt/β-catenin signaling is activated in the transplanted cells.

Indeed, the activation of the Wnt pathway induces reprogramming of retinal neurons back to precursor or embryonic stages after HSPC or ESC fusion, respectively. HSPC-derived reprogrammed hybrids can proliferate and in turn differentiate into ganglion and amacrine neurons, thereby contributing to retinal regeneration. Remarkably, multielectrode recordings of retinal explants showed functional rescue of ganglion neurons to light response in the regenerated retinas.

The next stage in this research is to improve the quality of the result, and demonstrate that the signs of restored function observed here translate into restored sight. We shall see how long that takes to arrive.


Monday, July 8, 2013

Growth hormone receptor knockout (GHRKO) mice are smaller, age more slowly, and live considerably longer than their unaltered peers. Researchers have yet to create a longer-lived mouse lineage. Interestingly, and perhaps unfortunately for the prospects of slowing aging in our species, similar human mutants do not appear to live longer than the rest of us. Much the same is true of the practice of calorie restriction: long-lived mice, tremendous health benefits in both mice and humans, but no signs of greatly extended life in humans.

Aging more slowly, either through disruption of growth hormone metabolism or through calorie restriction, means that all measures of degeneration are impacted - such as the frailty and muscular weakness examined by these researchers:

Neuromusculoskeletal (physical) frailty is an aging-attributable biomedical issue of extremely high import, from both public health and individual perspectives. Yet, it is rarely studied in nonhuman research subjects and very rarely studied in animals with extended longevity. In an effort to address this relatively neglected area, we have conducted a longitudinal investigation of the neuromusculoskeletal healthspan in mice with two senescence-slowing interventions: growth hormone (GH) resistance, produced by GH receptor "knockout" (GHR-KO), and caloric restriction (CR).

We report marked improvements in the retention of strength, balance, and motor coordination by the longevity-conferring GHR/BP gene disruption, CR regimen, or a combination of the two. Specifically, GHR-KO mice exhibit superior grip strength, balance, and motor coordination at middle age, and CR mice display superior grip strength at middle age. The advantageous effects established by middle-age are more pronounced in old-age, and these robust alterations are, generally, not gender-specific. Thus, we show that genetic and/or dietary interventions that engender longevity are also beneficial for the retention of neuromusculoskeletal health and functionality. The translational knowledge to be gained from subsequent molecular or histological investigations of these models of preserved functionality and decelerated senescence is potentially relevant to the efforts to reduce the specter of fear, falls, fracture, and frailty in the elderly.

Tuesday, July 9, 2013

Researchers are making progress on the construction of cell structures that look very much like naturally formed nerve tissue, and may thus be useful substitutes for the current practice of nerve grafting:

Regeneration of nerves is challenging when the damaged area is extensive, and surgeons currently have to take a nerve graft from elsewhere in the body, leaving a second site of damage. Nerve grafts contain aligned tissue structures and Schwann cells that support and guide neuron growth through the damaged area, encouraging function to be restored.

[Researchers have now] reported a way to manufacture artificial nerve tissue with the potential to be used as an alternative to nerve grafts. Pieces of Engineered Neural Tissue (EngNT) are formed by controlling natural Schwann cell behaviour in a three-dimensional collagen gel so that the cells elongate and align, then a stabilisation process removes excess fluid to leave robust artificial tissues. These living biomaterials contain aligned Schwann cells in an aligned collagen environment, recreating key features of normal nerve tissue.

Building the artificial tissue from natural proteins and directing the cellular alignment using normal cell-material interactions means the EngNT can integrate effectively at the repair site. "We previously reported how self-alignment of Schwann cells could be achieved by using a tethered collagen hydrogel, which exploited cells' natural ability to orientate in the appropriate direction by using their internal contraction forces. Our current research shows that cell-alignment in the hydrogel can be stabilised using plastic compression. The compression removes fluid from the gels, leaving a strong and stable aligned structure that has many features in common with nerve tissue."

Tuesday, July 9, 2013

Reliability theory can be used to model aging in terms of progressive failure of component subsystem, just as occurs in electronic equipment and other systems prone to complex forms of decay. One of the predictions that results from this method is that we are born with a preexisting level of damage, and so we should expect to see correlations between aspects of newborn biology and later aging.

On a similar note it has been determined in recent years that at least some species adjust the metabolism of their descendants in reaction to environmental factors such as availability of food. Calorie restriction, for example, doesn't just change the metabolism of the individuals that are living on fewer calories, but also results in different patterns of gene expression that show up in their offspring.

Here is an example of a correlation between early life metabolism and later life progression of aging in humans, which might be considered in the context provided by the above points:

Scientists have found that key metabolites in blood - chemical 'fingerprints' left behind as a result of early molecular changes before birth or in infancy - could provide clues to a person's long-term overall health and rate of ageing in later life.

One particular metabolite - C-glyTrp - is associated with a range of age-related traits such as lung function, bone mineral density, cholesterol and blood pressure. Its role in ageing is completely novel. Crucially, researchers found it was also associated with lower weight at birth when they compared the birth weights of identical twins. This finding suggests that levels of this novel metabolite, which may be determined in the womb and affected by nutrition during development, could reflect accelerated ageing in later adult life.

Scientists have known for a long time that a person's weight at the time of birth is an important determinant of health in middle and old age, and that people with low birth weight are more susceptible to age related diseases. So far the molecular mechanisms that link low birthweight to health or disease in old age had remained elusive, but this discovery has revealed one of the molecular pathways involved. "This unique metabolite, which is related to age and age related diseases, was different in genetically identical twins that had very different weight at birth. This shows us that birth weight affects a molecular mechanism that alters this metabolite. This may help us understand how lower nutrition in the womb alters molecular pathways that result in faster ageing and a higher risk of age-related diseases fifty years later."

Wednesday, July 10, 2013

Enhanced longevity associated with changes in the insulin/IGF-1 pathway is one of the most studied areas of the genetics of longevity in laboratory animals. Metabolism is complex enough that researchers are still building the picture of how alterations like this work to extend life. The open access research quoted below suggests that broad reductions in rate of creation of proteins from DNA blueprints are involved, and thus a related boost in the level of autophagy as the body seeks to recycle more proteins.

This shows up elsewhere in processes related to longevity - for example in dietary methionine restriction, as methionine is required for the assembly of all proteins. Increased levels of the housekeeping processes of autophagy appear in many forms of metabolic alteration that extend life, and most likely work by consistently reducing the levels of cellular damage that contribute to degenerative aging over the long term.

To date, the biological processes underlying Insulin/IGF-1-mediated longevity remain studied predominantly at the gene level. However, organismal phenotypes are far more dependent on protein function. An initial quantitative proteomics study of Insulin/IGF-1 pathway confirmed the role of stress-protective pathways during longevity signalling. Additionally, it uncovered several compensatory pathways involved in longevity, underscoring the potential of this approach to identify novel longevity pathways. However, this analysis was restricted to a subset of the nematode proteome, involving mainly cytoplasmic and non-membrane bound proteins.

In this study, a more stringent and non-biased proteomics approach of the whole nematode using TMT proteomics was employed. This recently developed quantification method was used to identify novel processes and pathways involved in Insulin/IGF-1-mediated longevity. The obtained results confirmed the previously reported alteration of several proteins in daf-2(e1370) nematodes, including an increased representation of stress-resistance enzymes and a decrease in chaperone proteins. However, our results go on to reveal a severe and previously overlooked reduction in ribosomal proteins and concomitant translational activity. In addition, reduced expression of proteins involved in mRNA processing, translation, and the ubiquitin-proteasome system (UPS) was observed. Functional assays confirmed reduced mRNA levels and 20S proteasomal activity while at the same time total protein content of the mutants compared with wild-type nematodes remained unchanged. Moreover, the importance of these processes for lifespan extension is demonstrated using RNA interference (RNAi)-mediated knockdown of identified candidates.

All together, we propose a model for Insulin/IGF-1-mediated longevity that, in addition to an enhanced stress response, relies on protein metabolism coupled to the reduction in de novo protein synthesis and a shift from the UPS of degradation to recycling of proteins via autophagy.

Wednesday, July 10, 2013

Being sedentary has a cost: your health will most likely be worse, and your life expectancy shorter. One of the metabolic dysfunctions that arises with increasing age is a reduction in insulin sensitivity, most often associated with excess fat tissue and the descent into type 2 diabetes, but lack of exercise is also an important contributing factor. Here researchers look into some of the low-level biological mechanisms involved in the relationship between exercise and insulin metabolism:

Both aging and physical inactivity are associated with increased development of insulin resistance whereas physical activity has been shown to promote increased insulin sensitivity. Here we investigated the effects of physical activity level on aging-associated insulin resistance in myotubes derived from human skeletal muscle satellite cells. Satellite cells were obtained from young (22 yrs) normally active or middle-aged (56.6 yrs) individuals who were either lifelong sedentary or lifelong active.

Human myotubes in culture obtained from middle-aged sedentary individuals have differences in insulin stimulated glucose metabolism that would be expected to be seen due to secondary aging in vivo, including impaired insulin-stimulated glucose uptake. Interestingly, physical activity throughout life seems to protect myotubes from these aspects of secondary aging potentially through adaptations including increased expression of GLUT4 and MYH2.

Additionally, lifelong physical activity exerts positive effects on muscle metabolism (including enhanced GSK3 phosphorylation and GLUT4 expression) when compared to the same parameters in myotubes from young, recreationally active, healthy controls. Life-long physical activity, such as seen in elite athletes, has shown that 60 year old athletes have the same glucose and insulin levels during an oral glucose tolerance test as 26 year olds. It is therefore unlikely that deterioration in insulin sensitivity is an inevitable consequence of aging and is maintained by regular physical activity.

Thursday, July 11, 2013

A machine-translated interview with Aubrey de Grey, cofounder of the SENS Research Foundation and author of the SENS proposals for developing biotechnologies to repair and reverse the root causes of aging:

Interviewer: Why should we stop aging?

de Grey: The fundamental reason why we should develop a drug against aging is that aging is bad for you. It makes people sick. There are many views on how people should live, but there is really no debate about the fact that people do not like being sick. That's the main reason. It is also important to emphasize that the human body is just a machine. It is a very complicated machine, but a machine after all, which means that if you can stop people becoming sick, then you're also avoiding the increased risk of death that comes with being sick. A person has a very low probability of dying anytime soon if he avoids becoming ill. There will be a side effect of increased longevity that comes with the medical defeat of aging, but it is only a secondary effect. I do not work on longevity, I work so that people will not become sick.

Interviewer: Who are the supporters of aging, the opponents of longevity research?

de Grey: Most people, I think, is little concerned when talking about the defeat of aging. The fear of the unknown overwhelms them. They forget that we have a problem today, and prefer not to think about the tremendous costs of Alzheimer's disease or heart problems and the like. They instead remain concerned about the kinds of hypothetical disadvantages envisaged for a post-aging world such as overcrowding, dictators living forever or inability to pay pensions, or whatever it might be. I find this extremely frustrating because it is a complete abandonment of any sense of proportion. I find it extraordinary that people are willing to enjoy this kind of denial. But it is not extraordinary from a psychological point of view because until recently - until I came along - it was perfectly reasonable to consider that the defeat of aging was a long way distant because many people had tried and failed.

Interviewer: What question would you like to be asked more often?

de Grey: "How big do you want the check to be?" What I do is work on the science behind the development of anti-aging treatments. This requires three things. The first is that it requires a solid scientific basis. So the reason why we can make predictions about the future, although speculative, is that we can describe in detail what already exists and where we go from there. So a good level of precursor technology must exist. The second is that people who are better placed to further develop this technology should be excited about it. They must be aware of the potential applicability of the work of others for the defeat of old age. The third is that you have to have the resources to make this happen.

I realized about fifteen years ago that we now have the technological foundations in place, and it was then when I developed the SENS concept. The second case is something I've been working on, meeting with the world's scientific leaders in the relevant fields. We do not lack people who know what they are doing. So the only missing link is the number three, the financial resources to do the job.

Thursday, July 11, 2013

It would be a good thing to have a brain that is a robust collection of artificial machinery when such a thing becomes possible, as the present evolved biological human brain is short-lived and frail in comparison to what could be achieved with a mature nanorobotics industry, capable of producing robust nanomachines that replicate cell functions. But how do you move from a biological to a machine brain without destroying or merely copying yourself? All of the obvious, easily envisaged methodologies are variations on the theme of destructive copying, in which you die and a copy of you continues.

This continuity of the self through an upgrade of the physical structure hosting your mind is a popular topic in the longevity advocacy community. Pretty much everyone has written on the subject at some point in time, despite the fact that it's definitely not the next thing up on deck in the march of technology - the first order of business is to develop the means to repair aging in our biology, to give us enough time to live into a future in which things like brain upgrades are possible.

Later in the piece quoted below the half-brain methodology is discussed. This is one of the earliest attempts to produce a physically realistic method of progressive brain replacement that is at least one step less fatal than all-in-one-go destructive copying. But I think that it is still undesirable: hauling out and replacing large chunks of the brain at a time is still functionally destructive to the self if the chunks are large enough. The safest approach is to scale down the replacement to the level of individual cells, proceeding at a pace similar to the natural processes of cell replacement in the brain.

I love life. And so the prospect of indefinite life extension is very attractive, IMO. Then again, seeing as how I wish to live much longer than my biologically-fixed clock dictates, to simply make a copy of myself to live forever, but not actually myself, just doesn't cut it. I would never destroy my brain and let someone else be me for me. If I'm to achieve indefinite life extension, then I want to do so with both my physical and functional continuity still in complete operation. Without one, the other is completely irrelevant.

What is physical and functional continuity? Functional continuity is basically the stream of consciousness which makes "Destroying" functional continuity wouldn't necessarily do anything to you, nor would it remain destroyed, per se. When we're going through REM sleep every night, our functional continuity fluctuates on and off, only to be completely restored the next morning. Yes, your consciousness before sleep was different from the consciousness you now acquire after sleep, but you remain yourself - you're still self-aware.

So what about physical continuity? Physical continuity is very important - much more important than functional continuity. Physical continuity - using as simple an understanding as possible - is essentially the brain and all of its synaptic operations. To destroy physical continuity would be to destroy the brain. Thus destroying everything, including the functional continuity which comes along with it. You can destroy your functional continuity and still have the chance to regain it so long physical continuity remains intact. The contrary, however, would be the end of yourself in its entirety.

Thus bringing us to our current dilemma of mind uploading. How are we to achieve mind uploading without destroying physical continuity in the process? To simply "download" everything within your brain and upload it into an artificial brain, while functional continuity is being streamed, physical continuity is being replicated, not maintained. Essentially you'd be partaking in a really cool process of cloning. That's it.

Thursday, July 11, 2013

The effort to understand how exactly metabolic processes determine longevity is a frustrating business. Researchers are at the stage in the game where they can increase or reduce longevity in many different ways through various genetic and epigenetic manipulations in mice, worms, flies, and other laboratory species. They can obtain mountains of data from these longer-lived or shorter-lived animals: gene expression patterns and any number of different measures of metabolism and the operation of organs and cells. Making sense out of all this data is the challenge.

For example, some interventions boost the free radical output of mitochondria and extend life. Others raise that free radical output and reduce life span. The interplay of different systems in the body is far too complicated for simple models of "more of X is bad" to survive for long. Extra damaging free radicals might a bad thing in one context, but in another they happen to trigger enough of an extra effort from cell maintenance processes to cause a net gain in robustness and longevity in the organism. More of a specific regulatory protein in circulation might be beneficial in one amount, harmful in a slightly greater amount, and those threshold levels will change depending on the levels of four or five other proteins. It's a complicated business.

Here is an example of a life-extending and memory-improving genetic alteration in mice that reduces mitochondrial function (generally thought to be a bad thing) and increases the output of damaging free radicals from the mitochondria (also generally thought to be a bad thing):

Decreased in vitro mitochondrial function is associated with enhanced brain metabolism, blood flow, and memory in Surf1-deficient mice

Recent studies have challenged the prevailing view that reduced mitochondrial function and increased oxidative stress are correlated with reduced longevity. Mice carrying a homozygous knockout (KO) of the Surf1 gene showed a significant decrease in mitochondrial electron transport chain Complex IV activity, yet displayed increased lifespan and reduced brain damage after excitotoxic insults.

In the present study, we examined brain metabolism, brain hemodynamics, and memory of Surf1 KO mice using in vitro measures of mitochondrial function, in vivo neuroimaging, and behavioral testing. We show that decreased respiration and increased generation of hydrogen peroxide in isolated Surf1 KO brain mitochondria are associated with increased brain glucose metabolism, cerebral blood flow, and lactate levels, and with enhanced memory in Surf1 KO mice. These metabolic and functional changes in Surf1 KO brains were accompanied by higher levels of hypoxia-inducible factor 1 alpha, and by increases in the activated form of cyclic AMP response element-binding factor, which is integral to memory formation.

Friday, July 12, 2013

Scientists demonstrate the ability to make stem cells assemble into small inner ear structures in this research. This is a long way from building tissue masses that are easy to see with the naked eye, but it is progress nonetheless:

[Researchers] reported that by using a three-dimensional cell culture method, they were able to coax stem cells to develop into inner-ear sensory epithelia - containing hair cells, supporting cells and neurons - that detect sound, head movements and gravity. Previous attempts to "grow" inner-ear hair cells in standard cell culture systems have worked poorly in part because necessary cues to develop hair bundles - a hallmark of sensory hair cells and a structure critically important for detecting auditory or vestibular signals - are lacking in the flat cell-culture dish.

The team determined that the cells needed to be suspended as aggregates in a specialized culture medium, which provided an environment more like that found in the body during early development. The team mimicked the early development process with a precisely timed use of several small molecules that prompted the stem cells to differentiate, from one stage to the next, into precursors of the inner ear. But the three-dimensional suspension also provided important mechanical cues, such as the tension from the pull of cells on each other. "We were surprised to see that once stem cells are guided to become inner-ear precursors and placed in 3-D culture, these cells behave as if they knew not only how to become different cell types in the inner ear, but also how to self-organize into a pattern remarkably similar to the native inner ear."

Friday, July 12, 2013

If asked yesterday, I'd have guessed that there wasn't a great deal of difference in the majority of the life history of people born ten years apart in the early 1900s in Europe: a small incremental improvement in adult life expectancy for those born later and a larger improvement in life expectancy at birth due to lowered infant mortality. Advances in medicine are weighted towards the recent past: progress is speeding up and practical improvements in medical technology - and patient outcomes - are presently arriving far more rapidly than, say, fifty or a hundred years ago. So the study noted below may be largely measuring improvements in medical care for the elderly that have taken place across the past few decades rather than anything that happened prior to that.

We compared the cognitive and physical functioning of two cohorts of Danish nonagenarians, born 10 years apart. People in the first cohort were born in 1905 and assessed at age 93 years (n=2262); those in the second cohort were born in 1915 and assessed at age 95 years (n=1584). Both cohorts were assessed by surveys that used the same design and assessment instrument, and had almost identical response rates (63%). Cognitive functioning was assessed by mini-mental state examination and a composite of five cognitive tests that are sensitive to age-related changes. Physical functioning was assessed by an activities of daily living score and by physical performance tests (grip strength, chair stand, and gait speed).

The chance of surviving from birth to age 93 years was 28% higher in the 1915 cohort than in the 1905 cohort (6.50% vs 5.06%), and the chance of reaching 95 years was 32% higher in 1915 cohort (3.93% vs 2.98%). The 1915 cohort scored significantly better on the mini-mental state examination than did the 1905 cohort, with a substantially higher proportion of participants obtaining maximum scores. Similarly, the cognitive composite score was significantly better in the 1915 than in the 1905 cohort. The cohorts did not differ consistently in the physical performance tests, but the 1915 cohort had significantly better activities of daily living scores than did the 1905 cohort. [These results suggest] that more people are living to older ages with better overall functioning.


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