Fight Aging! Newsletter, January 13th 2014

January 13th 2014

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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  • 700 For Science, Whole Organ, and Solving Organ Shortage
  • Extremely Low Frequency Electromagnetic Fields Enhance Neurogenesis
  • Cryonics in the UK
  • Further Confirmation that AGE-Breaker Alagebrium Has No Significant Effect in Humans
  • Estimating the Global Cost of Heart Failure
  • Latest Headlines from Fight Aging!
    • A Profile of Valter Longo
    • What Might Telomerase Do Besides Lengthening Telomeres?
    • Human Longevity Not Due to Always-On Calorie Restriction Responses
    • A Motivating Fear of Stagnation
    • Even the Longest Known and Most Studied Longevity Mutations are Poorly Understood
    • Enough is Enough: An Editorial on Supplements
    • Targeting p62 as a Cancer Therapy
    • Growing Numbers of Centenarians
    • Comparing Fitness and Leanness in Lowering Heart Disease Risk
    • An Example of Peripheral Nerve Regeneration


A reader pointed me to the 700 for Science site a few days back. This is a vetted social network of research advocates and scientists with a medical and biotechnology focus, defining its own place on the spectrum that includes research crowdfunding, non-profit advocacy, and scientific fundraising for specific projects. The current project focus is similar to that of the Methuselah Foundation and New Organ initiative: driving the research and development community towards faster realization of tissue engineered, patient-matched organs. These organs will be created as needed and transplanted with minimal risk of rejection, as they are grown from the patient's own cells.

700 for Science FAQ

We are an international nonprofit organization comprised of research scientists, business and industry leaders, entrepreneurs and investors in early-stage technologies. Collectively, we are creating a community of experts willing to support novel biotech and clean technologies with real social value.

Early-stage technologies no longer qualify for research funds and because they generally still need to demonstrate proof-of-concept, they are often too risky to attract downstream money. As a result many technologies with significant social value are languishing. Our network of experienced commercialization experts can often help startups with small contributions of time and talent and, occasionally, funding from angel investors.

Our members select a core group of technologies from those submitted throughout the year. The annual Portfolio700 is announced in January. Throughout the rest of that calendar year, we identify and execute key activities that will help advance these technologies. Once selected, a technology remains a part of Portfolio700 - receiving support from the organization and our members - for three years.

The organization has set up separate web sites for the two collaborative projects currently published, both of which are worth a look. The current state of progress is that a summit will occur later this year and a research consortium is forming: the hard work of raising funds and coordinating research is to follow.

It is interesting that both 700 for Science and New Organ choose to focus on the liver as the first target for organ engineering: this most likely reflects the state of thought in the field as to which goals will be easiest or are presently closest to realization. The liver is the human organ with the greatest natural ability to regenerate itself, which might prove to be a head start, or it might not - we shall see.

Whole Organ

Great technical challenges must be resolved if we are to engineer whole organs. On April 30, 2014, the world's recognized experts are gathering to form a transdisciplinary international scientific consortium. Our goal? To create a transdisciplinary, science-driven effort to engineer a human liver.

We're at a watershed moment in medical history. The world's top research teams are ready to focus on the goal of engineering a replacement liver for human transplantation. Now it's time to come together and forge partnerships to overcome daunting technical challenges. And since hard math is a part of any bold endeavor, we'll also determine the best strategy for leveraging grant-supported research.

Solving Organ Shortage

We've conceived an ambitious agenda of research and policy-making initiatives aimed at solving the organ shortage. Now we're ready to begin. Research over the past decade yielded a flurry of information about the nature of adult stem cells, progenitor cells and their differentiated cell types. Then came the breakthrough discovery of induced pluripotent stem cells and progress has been breathtaking ever since. Now the research community is ready to use these cells to address the growing organ shortage and improve the quality of life for transplant recipients.

Advocating for replacement organs is the exciting part. Aligning with a broad-based constituency of organizations to create a comprehensive strategy to address the organ shortage will require a new level of resourcefulness. The mission of SOS is to anticipate needs, overcome roadblocks, augment the work of likeminded organizations and enlist allies who share our vision. Our work has just begun.


It is interesting to theorize that a range of treatments as effective as some drugs might emerge from the use of electromagnetic fields in medicine. Researchers are still in the very early stages of establishing the boundaries of the possible, however - you might look at work involving transcranial magnetic stimulation as an example of present explorations. Clearly it is possible to influence biology with electromagnetism, but what types of influence are plausible and controllable? It doesn't seem completely out of the question that some forms of electromagnetic field could change the behavior of cells in ways that are similar to that achieved with specific types of globally applied drug compounds, but it remains an open question as to how useful or limited this might prove to be.

Here researchers provide evidence for one desirable outcome that can be attained via suitable magnetic fields. They demonstrate an effective boost to rates of neurogenesis, the creation of new neurons in the brain. Higher rates of neurogenesis imply greater neuroplasticity, the ability of the brain to adapt, repair, and resist minor damage - which overall seems to be a good thing to aim for. In this work the scientists are not increasing the pace at which new neurons are created, as is the case in some other approaches, but are instead enhancing the survival of those cells.

Extremely low-frequency electromagnetic fields enhance the survival of newborn neurons in the mouse hippocampus

In recent years, much effort has been devoted to identifying stimuli capable of enhancing adult neurogenesis, a process that generates new neurons throughout life, and that appears to be dysfunctional in the senescent brain and in several neuropsychiatric and neurodegenerative diseases. We previously reported that in vivo exposure to extremely low-frequency electromagnetic fields (ELFEFs) promotes the proliferation and neuronal differentiation of hippocampal neural stem cells (NSCs) that functionally integrate in the dentate gyrus.

Here, we extended our studies to specifically assess the influence of ELFEFs on hippocampal newborn cell survival, which is a very critical issue in adult neurogenesis regulation. Mice were injected with 5-bromo-2′-deoxyuridine (BrdU) to label newborn cells, and were exposed to ELFEFs 9 days later, when the most dramatic decrease in the number of newly generated neurons occurs. The results showed that ELFEF exposure (3.5 h/day for 6 days) enhanced newborn neuron survival.

The effects of ELFEFs were associated with enhanced spatial learning and memory. In an in vitro model of hippocampal NSCs, ELFEFs exerted their pro-survival action by rescuing differentiating neurons from apoptotic cell death. Western immunoblot assay revealed reduced expression of the pro-apoptotic protein Bax, and increased levels of the anti-apoptotic protein Bcl-2, in the hippocampi of ELFEF-exposed mice as well as in ELFEF-exposed NSC cultures, as compared with their sham-exposed counterparts. Our results may have clinical implications for the treatment of impaired neurogenesis associated with brain aging and neurodegenerative diseases.


The cryonics industry offers the means to store your body and brain immediately following death. This involves vitrification rather than freezing (to avoid ice crystal formation) and then indefinite low temperature preservation: for so long as the fine structure of the brain is preserved the possibility remains for future restoration to life in an age with more advanced capabilities in medicine and nanotechnology. Cryonics is the only plausible presently available stopgap measure to prevent the vast ongoing loss of life due to aging, and it is a great horror that so far it has remained a niche industry, even as tens of millions of lives are lost to oblivion with each passing year. In a better world they could all have been saved, preserved for a wealthier technological future capable of rebuilding bodies and reversing vitrification.

A number of countries outside the US have cryonics organizations of one form or another, although the only providers offering low-temperature storage are in the US and Russia at this time. Australia might also see a provider launch in the near future, but in general people in other parts of the world should plan on moving as a part of any end of life organization. The alternative is probably going to be expensive and much less certain; moving trained staff to where they are needed and then transporting the cryopreserved patient afterwards is a good deal more complicated. Moving closer to the provider is generally advised as the most optimal course in any case, regardless of where you live: it will increase the chances of a good outcome.

The UK, like Australia, is home to organized cryonics supporters whose numbers have not yet expanded to the degree needed to launch a local provider and storage center. Given the level of regulation in the UK that would probably be more of a challenge than it is in Russia, home to KrioRus. What they can do is to form their own volunteer associations and companies to provide standby services: the early stages in the process of preparation for vitritication, or actual vitrification itself. Here is a good press piece that manages to avoid slipping into most of the lazy modes of coverage that attend any non-mainstream activity:

Why this big freeze could take us back to the future

"My wife thinks it's weird," says Tim Gibson, whose house we're in. "But I tell her it's weird not to at least try."

The group are cryonicists. They are among the 100 or so Brits who have paid to have their bodies frozen when they die so, one day, they might be brought back to life. They have arranged for their brains to be pumped with anti-freeze and their bodies to be stored in liquid nitrogen until science has advanced to a point where they can be resurrected. And today - in this pleasant Meadowhead family home - they are learning how to do the preserving.

Around 1982 Sussex care home owner Alan Sinclair set up Cryonics UK - a volunteer group where members take a pledge that when one dies the others will be on hand to immediately preserve the body and then have it shipped to America for permanent storage. Only a handful have so far made that ultimate journey. Tim, a 42-year-old father-of-two, joined the group around 1992 and took over in 2009. His Meadowhead home is now the HQ. Members meet there every three months.

Aren't members - who are charged £10-15 a month - simply throwing their money away on a one-in-a-million chance? "Could be," nods Tim. "We certainly don't promise anything. You could die in such a way that we can't preserve your body in the first place and then it's over before it starts. All we say is we will do whatever we can to preserve your body and then what happens in the future happens."

"I look at it like buying a lottery ticket," he says. "I'm pretty certain I won't win and nothing will come of it. But I'm still going to keep buying it on the off chance. What have I got to lose?"

It is, indeed, weird not to try. It is a strange thing to live in a world in which near everyone is determinedly trudging towards oblivion with no intent to do anything about it.


Alagebrium (or ALT-711) was an early and ultimately unsuccessful foray into the development of an AGE-breaker drug: a treatment intended to safely break down the build up of advanced glycation end-products (AGEs) that characterize aged tissue. These are chemical cross-links that form as a byproduct of the normal operation of metabolism, and which glue together proteins to cause various forms of harm, such as destroying the elasticity of skin and blood vessels. Eventually this process contributes significantly to age-related disease and death, meaning that any attempt to treat and reverse aging by attacking the causes must include proficient AGE-breakers.

The attempted clinical development of alagebrium followed initially promising studies in rats, but as it turns out the types of AGE important in human tissue are not the same at all, and as a consequence alagebrium had no meaningful effect in human trials. This was sufficiently well determined that you can color me surprised to see that anyone is continuing with the thankless but important work of confirming past negative results for this line of research. But here we have it:

The effect of an advanced glycation end-product crosslink breaker and exercise training on vascular function in older individuals: a randomized factorial design trial.

Aging leads to accumulation of irreversible advanced glycation end-products (AGEs), contributing to vascular stiffening and endothelial dysfunction. When combined with the AGE-crosslink breaker Alagebrium, exercise training reverses cardiovascular aging in experimental animals. This study is the first to examine the effect of Alagebrium, with and without exercise training, on endothelial function, arterial stiffness and cardiovascular risk in older individuals.

Forty-eight non-exercising individuals (mean age 70 ± 4 years) without manifest diseases or use of medication were allocated into 4 groups for a 1-year intervention: Exercise training and Alagebrium (200 mg/day); exercise training and placebo; no exercise training and Alagebrium (200 mg/day); and no exercise training and placebo. We performed a maximal exercise test (VO2max) and measured endothelial function. Arterial stiffness was measured using pulse wave velocity. Cardiovascular risk was calculated using the Lifetime Risk Score (LRS).

In the exercise training groups, LRS and VO2max improved significantly (23.9 ± 4.5 to 27.2 ± 4.6 mLO2/min/kg). Endothelial response to the vasoactive substances did not change, nor did arterial stiffness in any of the four groups. In conclusion, one year of exercise training significantly improved physical fitness and lifetime risk for cardiovascular disease without affecting endothelial function or arterial stiffness. The use of the AGE-crosslink breaker Alagebrium had no independent effect on vascular function, nor did it potentiate the effect of exercise training. Despite the clinical benefits of exercise training for older individuals, neither exercise training nor Alagebrium (alone or in combination) was able to reverse the vascular effects of decades of sedentary aging.

Present work on AGE-breaker development is very limited indeed. At the present time it is known that one type of AGE - glucosepane - makes up the overwhelming majority of AGEs present in human tissue, so in theory finding ways to treat and reverse AGE build up in our species is in fact a comparatively simple research and development undertaking. Unfortunately the drug development community has little infrastructure in place for working with this sort of compound, and little interest in building that infrastructure: groups with funding tend to find other things to work on, where there is a shorter and more certain path to producing a useful end result.

This is where the SENS Research Foundation comes into the picture. The Foundation is presently funding research to produce the tools needed to work with glucosepane and thereafter produce technology demonstrations to show that it can be cleared from tissues. Hopefully work on AGE-breakers will pick up again over the next few years as a result of this intervention. This whole situation might not be the best candidate for an example of clearly useful near-term medical research and development that should yield enormous benefits, but yet just isn't happening - but it is certainly up there in the charts. From a distance we might see constant progress, but down in the weeds every field is beset with this sort of problem.


The financial costs of degenerative aging are vast. Each year hundreds and possibly thousands of times what it would cost to fully develop a demonstration of first generation SENS rejuvenation biotechnologies is spent or lost due to aging and age-related disease. This is depressing but fairly standard for any field of research and development: the funds allocated towards finding ways to improve the situation are usually minuscule in comparison to the funds that go towards running, coping with, or propping up the status quo. It's amazing that anything ever improves when you look at that split of investment.

You can look back into the Fight Aging! archives to find various estimates from the research community on the ongoing cost of specific diseases. The costs incurred by stroke patients in the US alone are thought to be in the vicinity of $50 billion each year, for example. Various forms of skeletal and muscular degeneration may add another $20 billion, and some researchers suggests that dementia costs more than $150 billion each year. Grand totals in the US from mainstream data providers approach $300 billion in direct costs, with much more in lost productivity every year.

Here researchers run worldwide numbers on heart failure, another of the major causes of age-related death. The total given in the abstract is surprisingly low, considering per-condition cost estimates I've seen elsewhere, such as those mentioned above:

The annual global economic burden of heart failure

We estimated the overall cost of heart failure in 2012, in both direct and indirect terms, across the globe. Existing country-specific heart failure costs analyses were expressed as a proportion of gross domestic product and total healthcare spend. Using World Bank data, these proportional values were used to interpolate the economic cost of HF for countries of the world where no published data exists. Countries were categorized according to their level of economic development to investigate global patterns of spending.

197 countries were included in the analysis, covering 98.7% of the world's population. The overall economic cost of HF in 2012 was estimated at $108 billion per annum. Direct costs accounted for ~60% ($65 billion) and indirect costs accounted for ~40% ($43 billion) of the overall spend. Heart failure spending varied widely between high-income and middle and low-income countries. High-income countries spend a greater proportion on direct costs: a pattern reversed for middle and low-income countries.

The indirect costs that include lost productivity are more usually several times the size of the direct costs, but that all depends on methodology and definitions. The total for direct costs globally is a small multiple of US-only direct costs in other conditions, so perhaps these scientists are defining heart failure very narrowly, excluding the costs of the chronic conditions and events such as heart attacks that lead to heart failure.

Either way, these are the costs that might be avoided through the development of rejuvenation therapies. Some people are persuaded by finances rather than human costs of suffering and death: the numbers have long been very persuasive. The cost of even fully funded development is small compared to the costs of aging as they stand today.


Monday, January 6, 2014

Following on from last week's post on intermittent fasting research, here is a profile of the scientist coordinating that study and other, related work:

[Valter Longo worked] in the UCLA lab of Roy Walford, a renowned practitioner of calorie restriction for longevity. For part of that time, Longo used a video conferencing system to communicate with Walford, who was sealed inside a self-contained glass structure called Biosphere 2 in the Arizona desert from 1991 to 1993. After a couple of years, Longo decided that he wanted to bring a more molecular approach to questions of aging. Looking at yeast, a very simple unicellular organism, he discovered a group of genes that promote the aging process in response to glucose. By knocking out these genes, he could mimic a calorie- and glucose-restricted diet and extend the life span of yeast.

First as a postdoctoral fellow and then as a faculty member and director of the Longevity Institute at USC, Longo has continued this research into the genes that control aging. In 2001, he discovered another important group of yeast genes that control both aging and overall growth in response to amino acids. He later found a population of humans in Ecuador that had a mutation in the equivalent genes. As a result, they lacked a growth-hormone receptor, and this made them both small in stature and long-lived, with very little susceptibility to diabetes or cancer.

By inhibiting these same groups of genes either by mutations or starvation, Longo has found evidence that healthy cells might receive protection not only from the stresses of aging, but also from the effects of chemotherapy, and that cancer cells might become more sensitive to chemotherapy. Clinical trials are currently underway [to] explore whether fasting can improve outcomes in patients receiving chemotherapy for lymphoma as well as breast, prostate and colorectal cancers.

Monday, January 6, 2014

Telomerase is of primary interest to the research community for its role in lengthening telomeres, the protective caps on the ends of chromosomes. This is an important function in cell dynamics: telomeres shorten with each cell division, forming a crude clock that limits the number of times cells divide in populations without significant telomerase activity. Age tends to reduce average telomere length in tissues, but this seems most likely a measure of damage and changes rather than a form of damage in and of itself - a consequence, not a cause of aging. Nonethless, using genetic engineering to boost levels of telomerase in mice leads to extension of life. In past years there has been some suggestion that telomerase might help maintain mitochondrial integrity against oxidative damage, and this could be why it can be used to extend life. But this is still an open question.

Most cancers abuse telomerase to keep their cells dividing to form tumors, and the SENS anti-cancer strategy of WILT would involve suppressing telomerase as a part of the way to strike at the root commonality shared by all cancer. But what else might telomerase do? There is no shortage of proteins in the body that have multiple important roles: evolution clearly often leads to reuse of existing components. If telomerase has other roles, this would complicate WILT. Here is a recent paper that looks into the evidence for other activities on the part of telomerase:

For more than a decade, diverse telomerase mouse models have provided us with precious opportunities for evaluating the patho-physiological significance of telomerase in genetically defined environments and at an organismal level. With an emphasis on defective telomeres, these mouse models have considerably contributed to understanding a broad spectrum of phenomena associated with cancer and ageing. Furthermore, growing evidence has indicated that defective telomerase functions are involved in distinct diseases other than human cancers including dyskeratosis congenita, atherosclerosis, and renal diseases.

Despite the evident roles in telomeres, currently emerging extra-telomeric functions of telomerase are completely changing the scope of this enzyme. Notably, the direct roles of TERT in transcriptional regulation provide good rationale for several phenotypes that cannot be explained by telomere dysfunction, and their physiological significance has been also confirmed using telomerase mouse models. As might be expected, these lines of evidence make us consider that diverse observations supporting extra-telomeric roles of telomerase should be scrutinized and validated in vivo by generating novel mouse models.

For example, in addition to the effect of short telomeres on mitochondria, mitochondrial targeting of telomerase upon certain stressful conditions, and the recently identified RNA-dependent RNA polymerase activity of TERT indicates that telomerase has direct roles in mitochondria. Furthermore, considering the important roles of telomerase in cellular homeostasis, telomerase may be a critical factor for regulating the subcellular organelle homeostasis. Undoubtedly, we believe that these extra-telomeric functions of telomerase should be intimately associated with life span regulation, and that some regions of TERT, other than the RT domain, will be required for mediating protein-protein interactions with known functions in controlling the life span of an organism.

Tuesday, January 7, 2014

Humans are long-lived in comparison to other primates, as well as in comparison to other mammal species of a similar size. Given that we don't experience the same degree of enhanced longevity in response to calorie restriction as occurs in shorter-lived species, some researchers have hypothesized that in the course of evolving greater longevity - perhaps due to the grandmother effect - some of the changes that occur in metabolism under calorie restriction in those shorter-lived species become permanently turned on in humans.

If this is in fact true, then we would expect only limited benefits to result from the development of calorie restriction mimetic drugs: anything that looked promising in mice and even primates would not work as well in people. We might think, however, based on the degree to which calorie restriction is demonstrated to improve health in humans, that this hypothesis of always-on calorie restriction responses is not the case. The research here adds some supporting evidence to this view, but leaves standing the question of how calorie restriction can produce similar sweeping changes in health and metabolism in both humans and mice, and yet only the mice have a large extension of life span:

Caloric restriction (CR) and chemical agents, such as resveratrol and rapamycin that partially mimic the CR effect, can delay morbidity and mortality across a broad range of species. In humans, however, the effects of CR or other life-extending agents have not yet been investigated systematically. Human maximal lifespan is already substantially greater compared to that of closely related primate species. It is therefore possible that humans have acquired genetic mutations that mimic the CR effect.

Here, we tested this notion by comparing transcriptome differences between humans and other primates, with the transcriptome changes observed in mice subjected to CR. We show that the human transcriptome state, relative to other primate transcriptomes, does not match that of the CR mice or mice treated with resveratrol, but resembles the transcriptome state of ad libitum fed mice. At the same time, the transcriptome changes induced by CR in mice are enriched among genes showing age-related changes in primates, concentrated in specific expression patterns, and can be linked with specific functional pathways, including insulin signalling, cancer, and the immune response.

These findings indicate that the evolution of human longevity was likely independent of CR-induced lifespan extension mechanisms. Consequently, application of CR or CR-mimicking agents may yet offer a promising direction for the extension of healthy human lifespan.

Tuesday, January 7, 2014

Will the same thing happen to the promise of extended longevity as happened to the space program in the past half century - an early push, and then lack of interest and stagnation? I don't think that this is a likely model, due to the very different institutions and costs. It is comparatively cheap to contribute to progress in medicine, and many groups have the ability to do so usefully at this time.

Nonetheless, this is one of the nagging fears that motivates us to action - that present public disinterest in enhanced longevity will spread to the medical community, rather than giving way in the face of clear signs of progress and benefits emerging from the lab. That no new groups will arise to carry forward the torch of progress.

Again, I don't think that this is as plausible as a future of continued progress. But will that progress be fast enough to help us? That depends on what we do - progress only happens when it is made to happen. We build the future. If you want something done, you have to work on it:

My greatest fear about the future is not of technology running out of control or posing existential risks to humankind. Rather, my greatest fear is that, in the year 2045, I will be 58 years old and already marked by notable signs of senescence, sitting at the kitchen table, drinking my morning coffee, and wondering, "What happened to that Singularity we were promised by now? Why did it not come to pass? Why does the world of 2045 look pretty much like the world of 2013, with only a few cosmetic differences?" My greatest fear is that, as I stare into that mug of coffee, I would recognize that it will all be downhill from there, especially as "kids these days" would pay no more attention to technological progress and life-extension possibilities than their predecessors did.

My greatest fear is that they would consider me a quixotic old man, fantasizing about a future that never was, while they struggle to make ends meet in an ever-more hostile economy (which would look much like our own, except farther along in the sequence of gradual decay, because nobody cares), strangled by labyrinthine restrictions arising out of Luddism and change-aversion within the widespread society. In short, my greatest fear is that our present will be our future, except that I and the present generation of longevity activists will lose our youthful vitality and will ourselves be rapidly approaching the abyss of oblivion.

Wednesday, January 8, 2014

One of the arguments for focusing on repair strategies for reversing aging rather than manipulation of metabolism to slow aging is that metabolism is fantastically complex. Researchers don't have anywhere near enough understanding to safely alter metabolic operation in desired ways, and even simply trying to replicate aspects of the known and easily studied altered state of calorie restriction has proven to be very challenging. So there is no comprehensive plan on how to slow aging in this way. We can compare that absence to the existence of the comprehensive SENS plan on how to repair damage to reverse aging - and in that case we don't need to know anywhere near as much about how metabolism works. We just need to identify the damage and determine how to produce means of repair, and this goal has already been achieved.

An example of the complexity of metabolism and its interaction with the processes of aging is provided by this research, which illustrates that there is still much to be cataloged and understood in one of the longest known longevity mutations:

Twenty years ago it was discovered that loss of insulin/IGF-1-like signaling (IIS) - such as occurs in daf-2(-) mutants - dramatically extends longevity in the nematode C. elegans via the FOXO transcription factor DAF-16. Under favorable conditions, DAF-16 remains cytosolic and transcriptionally inactive; under stress, it is driven into the nucleus, leading to both up-regulation and down-regulation of large sets of genes, referred to as Class I and II, respectively. Identifying these genes and their functions is key to understanding the molecular and biochemical determinants of aging and longevity. While several studies have been performed to determine the genes regulated by DAF-16, agreement on the identity of targets has been limited to a relatively small number of top responders. Moreover, recent results have made it clear that while DAF-16 is responsible for the activation of Class I genes through the DAF-16 binding element (DBE), it does not interact directly with the upstream promoter regions of Class II genes, leaving the down-regulation of the latter in IIS mutants unexplained.

To address these issues, we first performed a careful meta-analysis of all available genomewide expression profiles with DAF-16 active (nuclear) vs. inactive (cytosolic or null). We reprocessed relevant raw data from various laboratories, and used a voting algorithm developed specifically for this purpose to construct a consensus ranking of all C. elegans genes in terms of their responsiveness to DAF-16. This allowed us to redefine Class I and Class II targets with unprecedented sensitivity and specificity. Next, using a combination of computational and experimental methods, we discovered that the little-studied transcription factor PQM-1 regulates Class II genes (and Class I to a lesser extent), via the DAF-16 associated element (DAE). [PQM-1] binding is strongly associated with both proximal upstream DAE occurrence and responsiveness to DAF-16. Indeed, a reporter gene assay confirmed that PQM-1 activates transcription in a DAE-dependent manner.

Next, we investigated whether and how PQM-1 subcellular localization depends on IIS status. [We] found that the nuclear presence of PQM-1 and DAF-16 is controlled by IIS in opposite ways. A model emerged in which both the DBE and the DAE contribute to the expression of Class I genes, while Class II genes are exclusively controlled through the DAE. Under normal conditions, the DAE-dependent transcriptional activation of Class II genes by nuclear PQM-1 enables growth and development. Upon acute stress, PQM-1 leaves the nucleus while DAF-16 enters. The nuclear exit of PQM-1 causes expression of Class II genes to fall in response to loss of activation through the DAE; at the same time, DAF-16 moves into the nucleus, where its binding to the DBE in the upstream promoter region of Class I genes activates a stress response in the cell.

Wednesday, January 8, 2014

I'd missed this journal editorial from last month on the topic of the current scientific consensus on the utility (or rather lack of utility) of dietary supplements. The evidence presently strongly favors the view that for people who have no vitamin deficiencies adding more dietary supplements does nothing or may even harm long term health - such as when dietary antioxidants block the hormetic processes necessary to benefit from exercise. The supplement industry is somewhat louder than the scientific community, however.

Reviews and guidelines that have appraised the role of vitamin and mineral supplements in primary or secondary prevention of chronic disease have consistently found null results or possible harms. Evidence involving tens of thousands of people randomly assigned in many clinical trials shows that β-carotene, vitamin E, and possibly high doses of vitamin A supplements increase mortality and that other antioxidants, folic acid and B vitamins, and multivitamin supplements have no clear benefit.

The large body of accumulated evidence has important public health and clinical implications. Evidence is sufficient to advise against routine supplementation, and we should translate null and negative findings into action. The message is simple: Most supplements do not prevent chronic disease or death, their use is not justified, and they should be avoided. This message is especially true for the general population with no clear evidence of micronutrient deficiencies, who represent most supplement users in the United States and in other countries.

The evidence also has implications for research. Antioxidants, folic acid, and B vitamins are harmful or ineffective for chronic disease prevention, and further large prevention trials are no longer justified. Vitamin D supplementation, however, is an open area of investigation, particularly in deficient persons. Clinical trials have been equivocal and sometimes contradictory.

With respect to multivitamins, [studies] and previous trials indicate no substantial health benefit. This evidence, combined with biological considerations, suggests that any effect, either beneficial or harmful, is probably small. As we learned from voluminous trial data on vitamin E, however, clinical trials are not well-suited to identify very small effects, and future trials of multivitamins for chronic disease prevention in well-nourished populations are likely to be futile. Although available evidence does not rule out small benefits or harms or large benefits or harms in a small subgroup of the population, we believe that the case is closed - supplementing the diet of well-nourished adults with (most) mineral or vitamin supplements has no clear benefit and might even be harmful. These vitamins should not be used for chronic disease prevention. Enough is enough.

Thursday, January 9, 2014

Effective development of treatments for cancer will involve finding actionable commonalities that exist in as many cancers as possible. Focusing on targets that only exist in a few cancers will necessarily be a much longer and more expensive process. Here researchers demonstrate the ability to direct the immune system to attack cancer cells expressing the protein p62 / sequestosome 1:

Autophagy plays an important role in neoplastic transformation of cells and in resistance of cancer cells to radio- and chemotherapy. p62 (SQSTM1) is a key component of autophagic machinery which is also involved in signal transduction. Although recent empirical observations demonstrated that p62 is overexpressed in variety of human tumors, a mechanism of p62 overexpression is not known. Here we report that the transformation of normal human mammary epithelial cells with diverse oncogenes (RAS, PIK3CA and Her2) causes marked accumulation of p62.

Based on this result, we hypothesized that p62 may be a feasible candidate to be an anti-cancer DNA vaccine. Here we performed a preclinical study of a novel DNA vaccine encoding p62. Intramuscularly administered p62-encoding plasmid induced anti-p62 antibodies and exhibited strong antitumor activity in four models of allogeneic mouse tumors - B16 melanoma, Lewis lung carcinoma (LLC), S37 sarcoma, and Ca755 breast carcinoma.

In mice challenged with Ca755 cells, p62 treatment had dual effect: inhibited tumor growth in some mice and prolonged life in those mice which developed tumor size similar to control. P62-encoding plasmid has demonstrated its potency both as a preventive and therapeutic vaccine. Importantly, p62 vaccination drastically suppressed metastasis formation: in B16 melanoma where tumor cells were injected intravenously, and in LLC and S37 sarcoma with spontaneous metastasis. Overall, we conclude that a p62-encoding vector(s) constitute(s) a novel, effective broad-spectrum antitumor and anti-metastatic vaccine feasible for further development and clinical trials.

Thursday, January 9, 2014

This study shows that in Ontario the number of centenarians in the population has been rising at about twice the rate of the population as a whole over the past twenty years. This is most likely representative of most wealthier regions of the world, where life expectancy for adults is climbing at around a year every decade as an incidental result of general improvements in medical technologies. This pace should pick up considerably as the research community becomes more interested in targeting aging deliberately, but note that your personal odds of reaching the age of 100 under present levels of medical technology are still very poor. The only way to improve these odds significantly is to support research into human rejuvenation such as that carried out by the SENS Research Foundation.

All individuals living in Ontario aged 65 and older on April 1 of each year between 1995 and 2010 were identified and divided into three age groups (65-84, 85-99, ≥100). A detailed description was obtained on 1,842 centenarians who were alive on April 1, 2010.

The number of centenarians increased from 1,069 in 1995 to 1,842 in 2010 (72.3%); 6.7% were aged 105 and older. Over the same period, the number of individuals aged 85 to 99 grew from 119,955 to 227,703 (89.8%). Women represented 85.3% of all centenarians and 89.4% of those aged 105 and older. Almost half of centenarians lived in the community (20.0% independently, 25.3% with publicly funded home care). Preventive drug therapies (bisphosphonates and statins) were frequently dispensed. In the preceding year, 18.2% were hospitalized and 26.6% were seen in an emergency department. More than 95% saw a primary care provider, and 5.3% saw a geriatrician.

The number of centenarians in Ontario increased by more than 70% over the last 15 years, with even greater growth among older people who could soon become centenarians. Almost half of centenarians live in the community, most are women, and almost all receive care from a primary care physician.

Friday, January 10, 2014

This study shows that avoiding an accumulation of excess fat tissue is more beneficial than physical fitness when it comes to long term health, as measured by reduced risk of suffering heart disease. This seems plausible based on a survey of data gathered in various mouse studies on fat, exercise, and life span. Calorie restriction and even surgical removal of visceral fat extend maximum life span while exercise only improves healthspan. The best bet is to be both fit and lean, of course:

[Researchers] analysed data from 743,498 Swedish men who received a medical examination at the age of 18 when they were conscripted into national service from 1969 to 1984. The men's fitness level was measured with a bicycle test in which the resistance was gradually increased until they were too exhausted to continue. The men were monitored for an average of 34 years until they suffered a heart attack or died or until 1 January 2011, whichever came first.

The study shows that being physically fit in your teenage years reduces the risk of a heart attack later in life. Fit but overweight or obese men also ran a significantly higher risk of suffering a heart attack than unfit, lean men. "While being physically fit at the end of your teens can reduce the risk of heart attack, fitness alone does not appear to fully compensate for the risks with being overweight or obese. In other words, having a normal weight is more important than being in good physical shape, but it is even better to be both fit and have a normal weight."

The study shows that with every 15% increase in physical fitness, the risk of suffering a heart attack 30 years later is reduced by around 18 percent after factoring in different variables such as socioeconomic background and Body Mass Index, BMI. The results also indicate that regular fitness training late in your teenage years is consistent with a 35% lower risk of a premature heart attack.

Friday, January 10, 2014

Regenerative medicine is progressing towards the ability to reliably repair nerve damage. As for the growth of blood vessels, this is challenging and a work in progress, with some demonstrated successes but still a way to go yet towards the realization of a comprehensive technology platform for nerve regeneration:

We previously developed a collagen tube filled with autologous skin‐derived stem cells (SDSCs) for bridging long rat sciatic nerve gaps. Here we present a case report describing a compassionate use of this graft for repairing poly‐injured motor and sensory nerves of upper arms of a patient. Preclinical assessment was performed with collagen‐SDSCs implantation in rats after sectioning sciatic nerve. For the patient, during the 3‐year follow‐up period, functional recovery of injured median and ulnar nerves was assessed by pinch gauge test and static two‐point discrimination and touch test with monofilaments, along with electrophysiological and MRI examinations.

Preclinical experiments in rats revealed rescue of sciatic nerve and no side effects of patient‐derived SDSCs transplantation (30 and 180 days of treatment). In the patient treatment, motor and sensory functions of the median nerve demonstrated ongoing recovery post‐implantation during the follow‐up period. The results indicate that the collagen/SDSCs artificial nerve graft could be used for surgical repair of larger defects in major lesions of peripheral nerves, increasing patient quality of life by saving the upper arms from amputation.


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