Fight Aging! Newsletter, June 9th 2014

June 9th 2014

The Fight Aging! Newsletter is a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: both the road to future rejuvenation and the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the longevity science community, advocacy and fundraising initiatives to help advance rejuvenation biotechnology, links to online resources, and much more.

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  • A Look at a Different Paradigm of Thought on Aging Research
  • A Review of Work on Scaffolds for Tissue Engineered Cartilage
  • Another View of Aging Science: That We Don't Know Enough
  • Fasting Can Be Used to Restore Some Loss of Immune System Function
  • The Liver is a Singular Organ
  • Latest Headlines from Fight Aging!
    • Methuselah Foundation Announces Award to Dr. Huber Warner
    • Researchers Demonstrate Erasure and Restoration of Memory
    • A Method of Destroying Only Damaged Mitochondrial DNA
    • Never Too Late to Exercise
    • Liver Cancer Vaccine Demonstrated in Mice
    • The Abysmal State of Data on Causes of Death in Old Age
    • High Blood Pressure Leads to Greater Damage to the Brain
    • Contact Inhibition, Cancer, and Cellular Senescence
    • Arguing that Metformin Extends Life via Hormesis
    • Small Steps Towards Exercise Mimetics


There are many, many people who think of fighting aging only in terms of exercise, diet, and supplements. As hobbies go, there are certainly innumerable far worse ways to spend your time and energy, but bear in mind that the expected outcome of being fanatically conscious of your health and aging is only a marginally longer life expectancy of perhaps 5 to 10 years, all of which emerges from either exercise or calorie restriction, and all of which can be captured by very laid back arrangements of regular aerobic exercise and a sane calorie restricted diet. All that fuss over advanced and ornate supplement plans and lifestyle engineering produces essentially nothing: the best scientific evidence suggests that effects are negative if they exist at all.

The modern health and supplements view on aging has evolved with the times, reaching out to encompass and follow research that aims to produce drugs and other interventions that marginally slow aging. This is a very understandable, logical progression. If you are interested in supplement research in the context of health and aging, then it is a short step from there to be interested in sirtuins, rapamycin, and other attempts to extend life by artificially altering metabolism that are presently underway. A person can be rigorous and sensible in following this research, throwing out all that is speculative, and decrying the hype, confusion, and outright lies that make up the "anti-aging" industry.

Today I'll point out a good example of this sort of viewpoint to contrast with my own views on science and aging. A recent post from the site Aging Sciences - Anti-Aging Firewalls provides an excellent insight into the mindset of those who are far more enthusiastic about the development of drugs to slow aging than I am, and who see the present as a time of palpable progress towards near term goals in this arena:

Five-Year Progress Report on Major Trends Impacting on Longevity

This is a progress report on the changing state of human longevity during the five-year lifespan of this blog. From the broadest perspective, a combination of better scientific knowledge, social trends and initiatives, industry and engineering developments are already propelling the general populations in our country and in other advanced societies towards greater health and enhanced longevity. It is not just that science will do this in the future; it is already happening by the interaction of science, social and commercial developments and engineering developments. Extending human lifespans is not just something that is going to be in the future. It is something very much with us in the fabric of what is happening right now.

From a personal perspective, I believe that the swelling stream of scientific knowledge about health and longevity is increasingly enabling earlier adapters to live lives that are longer, healthier, and more productive than the lives experienced in the general population. Enhanced life extension is increasingly available for those willing to learn about how to pursue it and who are willing to modify their lifestyles and habits to bring it about.

Starting now, every seven years will see the emergence of practical age-extension interventions (ones that have a potential of leading to extraordinary longevity) that double the power of the interventions available at the start of the 7 year period. That is, on an average basis, the practical anti-aging interventions available at the end of a seven-year period will enable twice the number of years of life extension than did the interventions available at the start of the period. Life extension is measured in years of life expectancy beyond those actuarially predicted for a given population starting in a certain base year.

I've cut out the references in favor of the summary in the quote above, so you should scan the whole thing; a lot of work went into it. Fundamentally the view is that progress is taking place now, and this progress is the most interesting aspect of aging research: we should be watching excitedly for studies that show new ways to use pharmaceuticals or the like to slow aging in mice, and consider how rapidly they could be brought into human trials. The expectation is that for the bigger picture of all potential treatments considered as a whole there is a sliding scale of improvement, and that improvement has been happening, is still happening, and will continue to happen on quite a short time frame.

This is all far removed from my view of aging research and present progress. With no great offense intended to those who spend so much time and effort on this aspect of research, I have to say that it is very clearly a road to nowhere, one that is not in any way producing steady gains at this time. Yes, there is an increasing portfolio of methods to increase life span in mice by 10-30% via metabolic alteration, usually the low end of that range, but little to show that these methods stack. At base most are turning out to be simply different ways of manipulating the same few core mechanisms. The outer limit of mouse life extension has not been rising to approach the record of over 60% set more than decade ago by the discovery of growth hormone receptor knockout mutants.

Further, consider that those methods of life extension with dramatic effects in mice that have existing, measurable analogs in humans, such as calorie restriction and growth hormone receptor knockout mutants, do not extend life by anywhere near the same degree in our species. We'd have certainly noticed by now if human life span could be extended 40% by eating less, for example. There is no reason to expect this current portfolio of ways to slow aging in mice to have wondrous results in people, and for most there is no evidence whatsoever to support anything other than ethereal hope. There is still no such thing as a solid, proven method of measuring biomarkers of aging in humans over short periods of time and using that to make confident predictions on the effects of a treatment on mortality and aging. It doesn't exist yet, and until it does you can't talk about effects on life span due to methods of metabolic manipulation emerging from the labs now in anything but a very speculative way.

What do I see when I look at aging research today? Where the quoted folk above see a gradual upward slope, I see a low, flat swamp of muddy humps that leads to a soaring cliff in the distance. Near all of present day aging and longevity research is a matter of people slogging to the top of one of these muddy humps, and is of very little benefit other than to better map the swamp. But if the research community works instead on making it to the cliffs, through programs such as the development of SENS repair biotechnologies, then at some point in the decades ahead there will be a sudden take-off as means of reversing aging emerge. Not just slowing, but reversing: making the old physically younger, preventing the occurrence of age-related disease, and extending healthy life by decades initially and indefinitely later.

To my eyes the evidence for the foundation technologies of SENS to produce large benefits to health and longevity, based on the identification of the causes of degenerative aging, is far better than that supporting any branch of metabolic manipulation, most of which is still a matter of exploration rather than tackling clear and known line items.

The chief problem today is that most people who might support meaningful work on treatments for degenerative aging are focused on the swamp, which in this analogy is work on slowing aging through drugs and genetic engineering of metabolism. They don't see the cliffs ahead as a viable goal, or don't understand that the clifftops exist as a possibility. But the only way we are going to obtain significant extension of life in our lifetimes is by reaching for the greater goal: the development of rejuvenation treatments that repair the known root causes of aging. Tinkering with metabolism can do no more than slow down the damage: it can't prevent it or remove it. It is useless to the old, and of only marginal benefit to the young. It won't greatly extend our lives, and focusing on it is thus a waste and a lost opportunity.


Regrowth and replacement of age-damaged cartilage is one of the obvious candidates for early applications of tissue engineering. It tends to be most in need of treatment in non-vital parts of the body, such as joints, and is not as evidently complicated to work with from a surgical point of as, say, a major organ such as the heart or liver. Which is all a way of saying that it should cost less to get underway, while failures should be nowhere near as likely to cause enormous harm to patients in trials or undergoing eventual treatments. It is not a terrible approach to start at the shallow end of the difficulty pool and work into deeper waters once that is going well.

Unfortunately cartilage is tremendously complicated at the small-scale level of proteins and tissue structure. If you throw a bunch of cartilage cells into even a sophisticated bioreactor and grow them, then the result is a pseudo-tissue that bears little resemblance to real cartilage. The most important aspects of cartilage are its mechanical properties, such as the ability to bear load, for example. These arise from the fine structure of cartilage extracellular matrix (ECM), arrangements of cells, and relationships between proteins, and getting that right has proven to be a challenge. It is only recently that some researchers claim to have produced cartilage tissue that does begin to measure up.

This open access review paper covers attempts in past years to build nanoscale-featured scaffold materials to guide cartilage regrowth. Such a scaffold is a partial replacement for the extracellular matrix in living tissue, and in an ideal situation would be digested and replaced with real extracellular matrix by the cells that colonize it. This approach has shown considerable promise for the engineering of other tissues, such as bone, skin, and muscle. Efforts to make it work for cartilage have so far met with limited success, however, and for the reasons noted above.

Nanotechnology Biomimetic Cartilage Regenerative Scaffolds

There are three different forms of cartilage in the body: hyaline, elastic and fibrous cartilage. Each can be found in specific sites and with different properties and functions. Hyaline cartilage can be found in the joints, nose, trachea and ribs. To date, detailed cartilage regeneration studies of human hyaline cartilage have been predominantly focused on articular cartilage. This has been driven by the volume of demand related to degenerative osteoarthritis. Articular cartilage samples have been more widely available to science due to the prevalence of joint replacement surgery. Nonetheless, the fundamental principles and advances of cartilage regeneration derived from articular cartilage studies provide a template for the engineering of head and neck cartilage.

Tissue engineering has advanced over the past two decades and continues to evolve in search of optimal tissue replacements alongside nanotechnology. The concept and results of mimicking the structure and function of the natural ECM form the current direction of travel for the fabrication of an optimal tissue regenerative scaffold.

Although the results of current studies have been encouraging, further refinements need to be made. As active growth factors used in current studies are inevitably subjected to contact with organic solvents or time-consuming procedures during processing and scaffold fabrication, it is likely that the majority of the growth factors are denatured. Uncompromised delivery of any growth factor at an optimal concentration with precise release kinetics is ideally required to translate growth factor delivery from an in vitro to in vivo level for tissue regeneration. A system of cell-mediated activation of available bioactive molecules may provide a breakthrough. This might be achieved by incorporating the latent form of the desired protein into the scaffold design. The incorporation of nanotechnology and bioactive cues into tissue scaffold design should prove increasingly promising in cartilage engineering.

Many research studies in cartilage tissue engineering often focus on specific areas of interest with encouraging results, but these studies often lack the holistic requirements to produce a successful tissue replacement. Thus, a multidisciplinary collaborative approach which includes specialised stem cell culture, nanotechnology and bioactive cues, materials science, environmental and mechanical stimulation, and bioreactor culture as well as vascular tissue engineering may offer a breakthrough in functional cartilage regeneration.


A few days ago I pointed out an example of the viewpoint on aging research that focuses on drugs, lifestyle, and metabolic manipulation and sees present work in that area to be a matter of significant and ongoing process. I disagree, for reasons that were explained in that post. Today, I'll take a glance at a different view of the science of aging and longevity, one that is far more popular in the mainstream research community, and with which I also vehemently disagree.

Researchers in this field might be loosely divided into three camps, which are as follows ordered from largest to smallest: (a) those who study aging as a phenomenon without seeking to produce treatments, (b) those who see to slow aging through development of means to alter the operation of metabolism, such as calorie restriction mimetic drugs, and (c) those who aim to produce rejuvenation biotechnology capable of reversing aging. The vast majority of the aging research community at present consider that too little is known of the details of the progression of aging to make significant inroads in the design of treatments, and that the way forward is fundamental research with little hope of meaningful application for the foreseeable future. This attitude is captured here:

Let me ask you this: 'Why can't we cure death yet?'

We can't 'cure death' because biology is extremely complicated. Without a fundamental understanding of how biological organisms work on a molecular level, we're left to educated guesses on how to fix things that are breaking in the human body. Trying to cure disease without a full understanding of the underlying principles is like trying to travel to the moon without using Newton's laws of motion.

The reason we haven't cured death is because we don't really understand life.

This is only half true, however. It is true if your goal is to slow down aging by engineering metabolism into a new state of safe operation in which the damage of aging accumulates more slowly. This is an enormous project. It is harder than anything that has been accomplished by humanity to date, measured on any reasonable scale of complexity. The community has only a few footholds in the vast sea of interactions that make up the progression of metabolism and damage through the course of aging, and this is despite the fact that there exists an easily obtained, very well studied altered state of metabolism that does in fact slow aging and extend life. Calorie restriction can be investigated in almost all laboratory species, and has been the subject of intense scrutiny for more than a decade now. Yet that barely constitutes a start on the long road of figuring out how to replicate the effects of calorie restriction on metabolism, let alone how to set off into the unknown to build an even better metabolic state of operation.

Listing these concerns is not even to start in on the fact that even if clinicians could perfectly replicate the benefits of calorie restriction, these effects are still modest in the grand scheme of things. It probably won't add more than ten years to your life, and it won't rejuvenate the old, nor restore any of their lost functionality. It is a way of slowing down remaining harm, not repairing the harm that has happened. All in all it seems like a poor use of resources.

People who argue that we don't understand enough of aging to treat it are conveniently omitting the fact that the research community does in fact have a proven, time-tested consensus list of the causes of aging. These are the fundamental differences between old tissue and young tissue, the list of changes that are not in and of themselves caused by any other process of aging. This is the damage that is the root of aging. There are certainly fierce arguments over which of these are more important and how in detail they actually interact with one another and metabolism to cause frailty, disease, and death. I've already said as much: researchers are still in the early days of producing the complete map of how aging progresses at the detail level. The actual list of damage and change is not much debated, however: that is settled science.

Thus if all you want to do is produce good treatments that reverse the effects of aging, you don't need to know every detail of the progression of aging. You just need to remove the root causes. It doesn't matter which of them are more or less important, just remove them all, and you'll find out which were more or less important in the course of doing so - and probably faster than those who are taking the slow and stead scholarly route of investigation. If results are what we want to see then instead of studying ever more esoteric little corners of our biology, researchers might change focus on ways to repair the known forms of damage that cause aging. In this way treatments can be produced that actually rejuvenate patients, and unlike methods of slowing aging will benefit the old by reversing and preventing age-related disease.

This is exactly analogous to the long history of building good bridges prior to the modern age of computer simulation and materials science. With the advent of these tools engineers can now build superb bridges, of a quality and size that would once have been impossible. But the engineers of ancient Rome built good bridges: bridges that allowed people to cross rivers and chasms and some of which still stand today. Victorian engineers built better bridges to facilitate commerce that have stood the test of time, and they worked with little more than did the Romans in comparison to today's technologies. So the aging research community could begin to build their bridges now, we don't have to wait for better science. Given that we are talking about aging, and the cost of aging is measured in tens of millions of lives lost and hundreds of millions more left suffering each and every year, it is amazing to me that there are not more initiatives focused on taking what is already known and settled about the causes of aging and using that knowledge to build rejuvenation treatments.

What we see instead is a field largely focused on doing nothing but gathering data, and where there are researchers interesting in producing treatments, they are almost all focused on metabolic engineering to slow aging. The long, hard road to nowhere helpful. Yet repairing the known damage of aging is so very obviously the better course for research and development when compared to the prospect of an endless exploration and cataloging of metabolism. If we want the chance of significant progress towards means of treating aging in our lifetime, only SENS and other repair-based approaches have a shot at delivering. Attempts to slow aging are only a distraction: they will provide a growing flow of new knowledge of our biochemistry and the details of aging, but that knowledge isn't needed in order to work towards effective treatments for aging today.


Regular intermittent fasting practices such as alternate day fasting are not as well studied as calorie restriction, but do seem to have similar effects with regard to improved health and extended healthy life spans. In some studies this is absolutely because intermittent fasting is reducing overall calorie intake. But even in studies where the calorie intake is controlled, so that fasting individuals consume the same amount as non-fasting controls, lesser benefits to health and longevity in rodents are still observed. So as is usually the case in the life sciences the underlying biology must be a complex mess of overlapping mechanisms.

We're probably going to be hearing a lot more about these overlapping mechanisms of intermittent fasting in the next few years as at least one group is working towards clinical trials based on human studies, and the folk involved have in mind starting up a company to market some sort of related products based on their data.

The latest work from the group looks at the details of the relationship between fasting and immune function, which turns out to be of interest to the cancer research community, among others. Ways to better recover from treatments like chemotherapy that greatly impact the immune system by thinning the ranks of white blood cells are high on the priority list. Since there is already a fair amount of work underway on generating better outcomes for cancer patients by combining calorie restriction with chemotherapy, it shouldn't be surprising to find that there is funding for work on intermittent fasting as well.

Fasting triggers stem cell regeneration of damaged, old immune system

Cycles of prolonged fasting not only protect against immune system damage - a major side effect of chemotherapy - but also induce immune system regeneration, shifting stem cells from a dormant state to a state of self-renewal. In both mice and a Phase 1 human clinical trial, long periods of not eating significantly lowered white blood cell counts. In mice, fasting cycles then "flipped a regenerative switch": changing the signaling pathways for hematopoietic stem cells, which are responsible for the generation of blood and immune systems, the research showed.

The study has major implications for healthier aging, in which immune system decline contributes to increased susceptibility to disease as we age. By outlining how prolonged fasting cycles - periods of no food for two to four days at a time over the course of six months - kill older and damaged immune cells and generate new ones, the research also has implications for chemotherapy tolerance and for those with a wide range of immune system deficiencies, including autoimmunity disorders.

Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

Because during prolonged fasting (PF) mammalian organisms minimize energy expenditure in part by rapidly reducing the size of a wide range of tissues, organs, and cellular populations including blood cells, the reversal of this effect during refeeding represents one of the most potent strategies to regenerate the hematopoietic and possibly other systems and organs in a coordinated manner.

Here, we show that PF causes a major reduction in white blood cell (WBC) number, followed, during refeeding, by a coordinated process able to regenerate this immune system deficiency by changes beginning during the fasting period, which include a major increase in [stem cell activity and lineage balancing]. In fact, we show that PF alone causes a 28% decrease WBC number, which is fully reversed after refeeding. Even after WBCs are severely suppressed or damaged as a consequence of chemotherapy or aging, cycles of PF are able to restore the normal WBC number and lineage balance, suggesting that the organism may be able to exploit its ability to regenerate the hematopoietic system after periods of starvation, independently of the cause of the deficiency.

To begin to determine whether PF cycles can potentially promote a similar effect in humans, we also analyzed the hematological profiles of cancer patients from a phase I clinical trial for the feasibility and safety of a 24 - 72 hr PF period in combination with chemotherapy. Although three different platinum-based drug combinations were used, the results from a phase I clinical trial indicate that 72 but not 24 hr of PF in combination with chemotherapy were associated with normal lymphocyte counts and maintenance of a normal lineage balance in WBCs. These encouraging preliminary results will need to be expanded and confirmed in the ongoing phase II randomized phase of the clinical trial.

As modern research results go, this ranks highly if scored in terms of cost and difficulty to implement for any given individual (near zero) versus benefits derived (greater than zero). That is true of anything relating to calorie restriction or fasting, however. Anyone can do it, though in this case the cautious late adopter would wait a few years for more human data that uses relatively healthy old people rather than cancer patients undergoing chemotherapy as a baseline. It may well be that this doesn't in fact do much for the aged immune system in people, while still being a helpful enough approach to use in conjunction with cancer treatments. Trying this in old people would be a comparatively low cost study to set up, so I imagine we won't have to wait too long for that data to emerge.


The mammalian liver is an odd organ, all things told. It has the greatest natural capacity for regeneration among our internal organs, which makes it a prime target for research into regenerative medicine. On the one hand we want to know exactly why the liver has this ability to regrow large sections of lost tissue in mammals, something that none of our other organs can manage, while on the other hand the fact that it can do this suggests that achieving greater results with either stem cell treatments or growing an entire new liver from a patient's own cells should be easier than is the case for other organs. However, the more time that researchers spend digging into the mechanisms of liver regrowth, the more they find that the biological details are quite different from those of other organs. Thus in fact the liver might not be the best place to look for ways to create a general platform for enhanced regeneration throughout the body. It is entirely possible that ways to manipulate liver biochemistry to enhance regeneration may have only limited application elsewhere.

This news of recent research well illustrates these points. In comparison to other organs, the liver may be far more reliant on a widespread as-needed transformation of normal cells, rather than a small population of empowered stem cells, when it comes to regrowth and regeneration. This has echoes in it of what is known of the way in which lower animals such as salamanders regenerate organs and limbs, which makes sense in this context:

A new model of liver regeneration: Switch causes mature liver cells to revert back to stem cell-like state

Switching off the Hippo-signaling pathway in mature liver cells generates very high rates of dedifferentiation. This means the cells turn back the clock to become stem-cell like again, thus allowing them to give rise to functional progenitor cells that can regenerate a diseased liver. The liver has been a model of regeneration for decades, and it's well known that mature liver cells can duplicate in response to injury. Even if three-quarters of a liver is surgically removed, duplication alone could return the organ to its normal functioning mass. This new research indicates that there is a second mode of regeneration that may be repairing less radical, but more constant liver damage, and chips away at a long-held theory that there's a pool of stem cells in the liver waiting to be activated.

"I think this study highlights the tremendous plasticity of mature liver cells. It's not that you have a very small population of cells that can be recruited to an injury; almost 80 percent of hepatocytes [liver cells] can undergo this cell fate change. "I think that maybe it is something that people have overlooked because the field has been so stem cell centric. But I think the bottom line is that the cells that we have in our body are plastic, and understanding pathways that underlie that plasticity could be another way of potentially manipulating regeneration or expanding some kind of cell type for regenerative medicine."

Hippo Pathway Activity Influences Liver Cell Fate

The Hippo-signaling pathway is an important regulator of cellular proliferation and organ size. However, little is known about the role of this cascade in the control of cell fate. [We] demonstrate that Hippo pathway activity is essential for the maintenance of the differentiated hepatocyte state. Remarkably, acute inactivation of Hippo pathway signaling in vivo is sufficient to dedifferentiate, at very high efficiencies, adult hepatocytes into cells bearing progenitor characteristics. These hepatocyte-derived progenitor cells demonstrate self-renewal and engraftment capacity at the single-cell level.

As the researchers note, this is a promising set of results from the point of view of generating supplies of liver cells for research and regenerative therapies - which is no small thing. It is probably of little application for anything other than liver tissue, however.


Monday, June 2, 2014

The Methuselah Foundation occasionally makes awards to researchers who are doing more than others to advance aging research. In this case it is the Interventions Testing Program that is being rewarded, a rigorous effort that is serving to remove the uncertainty over which of the existing ways thought to slow aging in mice actually work. Many past studies were flawed, or didn't use enough mice for statistical certainty, or were compromised by inadvertent calorie restriction.

This is all quite important for gaining a better understanding of the details as to how aging progresses, and for researchers who are trying to build treatments that alter metabolism to slow aging, but it is probably of less scientific relevance to rejuvenation research based on repair of cellular and molecular damage. The whole point of the latter field is that it doesn't require a full understanding of the progression of aging or alteration of the operation of metabolism in order to achieve significant reversal of aging and age-related disease. But beyond the science there is the ever illogical world of politics and funding, where success in carrying out an initiative like the ITP can translate into more attention and a better fundraising environment for all efforts relating to enhancing human longevity.

Methuselah Foundation, a medical charity focused on advancing the field of regenerative medicine to extend healthy life, is pleased to announce the Award of the Methuselah Prize to Dr. Huber Warner at the 43rd Annual Meeting of the American Aging Association. This $10,000 award is being given to recognize Dr. Warner's founding of the National Institute on Aging's Intervention Testing Program (ITP), a "multi-institutional study investigating treatments with the potential to extend lifespan and delay disease and dysfunction in mice."

According to Kevin Perrott, Executive Director of the Methuselah Prize, "The vision Dr. Warner showed, and his persistence over years of resistance to establish the ITP, is truly worthy of recognition. This program is going to provide not only potential near-term interventions in the aging process, but hard data to support claims of health benefits in a statistically significant manner. Science needs solid foundations on which to base further investigations, and the ITP provides the highest level of confidence yet established."

"I saw lots of papers from grantees of the NIA about slowing down aging and extending lifespan, but they were rarely backed up and given credibility through testing," said Dr. Warner. "Research over the last 25 years has been characterized by great success in identifying genes that play some role in extending the late-life health and longevity of several useful animal models of aging, such as yeast, fruit flies, and mice. The next challenging step is to demonstrate how this information might be used to increase the health of older members of our human populations around the world as they age."

The Intervention Testing Program also seeks to demonstrate the legitimacy of utilizing scarce government funding for life extension research. The program has already achieved an early success in proving that the immunosuppressant drug, Rapamycin, extends maximum lifespan in mice.

Monday, June 2, 2014

For at least the earlier stages of some forms of dementia it has been shown that lost memories are still there, just inaccessible. The storage is not destroyed, but rather the process of retrieval is impacted. Here researchers demonstrate that they can block and restore interaction with memory in rats, but it isn't yet clear that the restoration portion of their work can be applied to age-related loss of memory. The underlying cellular mechanisms look similar, but may or may not turn out to be similar enough, and there is also the case that the actual demonstration is quite specific to one portion of the nervous system. So a confirmation of utility for human medicine is something to look for in the years ahead:

Scientists optically stimulated a group of nerves in a rat's brain that had been genetically modified to make them sensitive to light, and simultaneously delivered an electrical shock to the animal's foot. The rats soon learned to associate the optical nerve stimulation with pain and displayed fear behaviors when these nerves were stimulated. Analyses showed chemical changes within the optically stimulated nerve synapses, indicative of synaptic strengthening.

In the next stage of the experiment, the research team demonstrated the ability to weaken this circuitry by stimulating the same nerves with a memory-erasing, low-frequency train of optical pulses. These rats subsequently no longer responded to the original nerve stimulation with fear, suggesting the pain-association memory had been erased. In what may be the study's most startlingly discovery, scientists found they could re-activate the lost memory by re-stimulating the same nerves with a memory-forming, high-frequency train of optical pulses. These re-conditioned rats once again responded to the original stimulation with fear, even though they had not had their feet re-shocked.

In terms of potential clinical applications [researchers] noted that the beta amyloid peptide that accumulates in the brains of people with Alzheimer's disease weakens synaptic connections in much the same way that low-frequency stimulation erased memories in the rats. "Since our work shows we can reverse the processes that weaken synapses, we could potentially counteract some of the beta amyloid's effects in Alzheimer's patients."

Tuesday, June 3, 2014

Mitochondrial DNA (mtDNA) damage is an important cause of degenerative aging. Via a complicated chain of events it leads to a small population of malfunctioning cells overtaken by malfunctioning mitochondria that export harmful reactive compounds into surrounding tissue.

There are a number of possible approaches to fix this issue, reversing its contribution to aging and age-related disease. One of them is to deliver undamaged, replacement mitochondrial DNA to all cells in the body, such as via protofection. The issue with this approach is that mitochondria are essentially like bacteria in the way they reproduce. Certain types of damage to their DNA produce mitochondria that evade cellular quality control mechanisms and outcompete their undamaged peers despite the fact that they are dysfunctional. Delivering fresh undamaged mitochondrial DNA into that cell doesn't get rid of the damaged copies, and the damaged copies have already demonstrated an ability to thrive. The suspicion is that the benefits of such a treatment would be temporary at best.

But what if this delivery of new mitochondrial DNA could be paired up with a means to selectively remove the damaged mitochondrial DNA? Given such a technology it might even be possible to skip the delivery entirely and just remove damaged DNA. This would sacrifice a small number of cells, those in a state of dysfunction that lack any remaining undamaged mitochondrial DNA to recreate a population of working mitochondria. Here is an example of such research; like most work on mitochondrial repair it is focused on inherited mitochondrial disease rather than aging, but could produce a technology platform applicable to aging:

Delivery and selection of mtDNA in mitochondria in a heritable manner is yet to be achieved, so alternative approaches to genetic therapy of primary mitochondrial diseases are being sought. One of these approaches is based on pathogenic mtDNA mutations being generally heteroplasmic, with observable pathology only present when the ratio of mutated mtDNA exceeds a certain threshold. The selective elimination of mutated mtDNA allows a cell to repopulate with wild-type mtDNA molecules by a yet uncharacterized mechanism of mtDNA copy number maintenance, alleviating the defective mitochondrial function that underlies mtDNA disease.

We designed and engineered mitochondrially targeted obligate heterodimeric zinc finger nucleases (mtZFNs) for site-specific elimination of pathogenic human mitochondrial DNA (mtDNA). Expression of mtZFNs led to a reduction in mutant mtDNA haplotype load, and subsequent repopulation of wild-type mtDNA restored mitochondrial respiratory function in a [cell model of mtDNA damage]. This study constitutes proof-of-principle that, through heteroplasmy manipulation, delivery of site-specific nuclease activity to mitochondria can alleviate a severe biochemical phenotype in primary mitochondrial disease arising from deleted mtDNA species.

Tuesday, June 3, 2014

Moderate regular exercise correlates with better health and life expectancy in human epidemiological studies, and is shown in animal studies to be the cause of better health and life expectancy. Here is one of many studies to show that the benefits of exercise continue all the way into old age:

The majority of adults aged 65 and older remains inactive and fails to meet recommended physical activity guidelines, previous research has shown. However, these studies have not represented elders living in retirement communities who may have more access to recreational activities and exercise equipment. Now, [researchers] found that older adults in retirement communities who reported more exercise experienced less physical decline than their peers who reported less exercise, although many adults - even those who exercised - did not complete muscle-strengthening exercises, which are another defense against physical decline.

"Physical decline is natural in this age group, but we found that people who exercised more declined less. The most popular physical activities the residents of the retirement community reported doing were light housework and walking, both of which are easily integrated into individuals' daily lives, but these exercises are not the best choices for maintaining muscle strength."

[Researchers] studied the physical activity of 38 residents at TigerPlace, an independent-living community in Columbia, four times in one year. The researchers tested the residents' walking speed, balance and their ability to stand up after sitting in a chair. Then, researchers compared the results of the tests to the residents' self-reported participation in exercise. [Residents] who reported doing more exercise had more success maintaining their physical abilities over time.

Wednesday, June 4, 2014

These days, the term "vaccine" covers a very broad range of immune system manipulations, especially when it comes to prospective treatments for cancer. The high level plan is to guide the immune system to aggressively destroy cancer cells without causing it to attack ordinary cells, but there are many different approaches that can achieve this goal. Here is one example:

Alpha-fetoprotein, or AFP - normally expressed during development and by liver cancer cells as well - has escaped attack in previous vaccine iterations because the body recognizes it as "self." AFP is expressed by about 80 percent of most common liver cancer cells but not typically by healthy adults. For cancer to flourish, cells must revert to an immature state, called dedifferentiation, which is why liver cancer cells express a protein during development and why the immune system can recognize AFP as "self."

In a process called antigen engineering, [researchers] tweaked AFP just enough to get the immune system to recognize it but still keep the AFP expressed by liver cancer cells in the bull's eye. [The] modified AFP was delivered in a vehicle with a proven record for getting into cells. The lentivector is the backbone of the human immunodeficiency virus, or HIV, minus most of its genes. It is particularly good at targeting dendritic cells, whose job is to show the immune system antigens then activate T cells to attack.

In a proven model where mice are exposed to chemicals known to induce liver cancer, the vaccine blocked cancer about 90 percent of the time. Mice receiving the vaccine had more T cells generally and more that targeted AFP, which could keep an eye out for re-emerging liver cancer. Recurring tumor cells is an unfortunately realistic scenario for liver cancer patients, who have a 70 percent recurrence rate in five years. Patients typically have surgery to remove the diseased portion of the liver, but there are currently no effective adjuvant therapies, such as chemotherapy, to reduce recurrence. Ideally, some version of [this] vaccine will one day provide that key missing piece and dramatically improve patient survival.

Wednesday, June 4, 2014

When you look at official statistics on the causes of death in old age and how they have changed over time, it is worth remembering that the underlying records are of terrible quality for more advanced ages, even in wealthier regions of the world. A great deal of work must take place to make anything of them, and all sorts of varying assumptions are baked into that work. In some cases the data simply isn't there, obscured by the tradition of marking the cause of death as 'old age' rather than any more specific item if known.

The researchers extracted information about the place and cause of death of centenarians in England between 2001 and 2010 from the ONS death registration database, linked these data with area level information on deprivation and care-home bed capacity, and analyzed the data statistically. Over the 10-year study period, 35,867 centenarians (mainly women, average age 101 years) died in England. The annual number of centenarian deaths increased from 2,823 in 2001 to 4,393 in 2010.

[The] findings suggest that many centenarians have outlived death from the chronic diseases that are the common causes of death among younger groups of elderly people and that dying in the hospital is often associated with pneumonia. Overall, these findings suggest that centenarians are a group of people living with a risk of death from increasing frailty that is exacerbated by acute lung infection. The accuracy of these findings is likely to be affected by the quality of UK death certification data. Although this is generally high, the strength of some of the reported associations may be affected, for example, by the tendency of clinicians to record the cause of death in the very elderly as "old age" to provide some comfort to surviving relatives.

'Old age' was the most common cause of certifying death (28%), followed by pneumonia (18%) and other respiratory diseases (6%); stroke (10%); heart disease (9%) and other circulatory diseases (10%); dementia and Alzheimer's disease (6%); and cancer (4%). Pneumonia accounted for the largest group of hospital deaths, while across non-hospital settings 'old age' formed the largest category followed by pneumonia. Overall, three-quarters of centenarian death certificates stated 'old age' as either an underlying cause (28%) or contributing cause (47%). The main causes of death changed with increasing age. In the group aged 80-85 years, heart disease was stated on 19% of death certificates, with 'old age' on only one per cent of certificates.

Thursday, June 5, 2014

There are many good reasons to better manage your general health in earlier life. As researchers produce more data on the workings of our biology over the course of aging they uncover specific causal links between the earlier consequences of poor lifestyle choices and later damage to vital organs. Here the link is between high blood pressure, one of the many expected results of living a sedentary, overweight lifestyle, and the integrity of the brain and its blood vessels:

For the study, 4,057 older participants free of dementia had their blood pressure measured in middle-age, (average age of 50). In late life (an average age of 76) their blood pressure was remeasured and participants underwent MRIs that looked at structure and damage to the small vessels in the brain. They also took tests that measured their memory and thinking ability.

The study found that the association of blood pressure in old age to brain measures depended on a history of blood pressure in middle age. Higher systolic (the top number on the measure of blood pressure) and diastolic (the bottom number on the measure of blood pressure) blood pressure were associated with increased risk of brain lesions and tiny brain bleeds. This was most noticeable in people without a history of high blood pressure in middle age. For example, people with no history of high blood pressure in middle age who had high diastolic blood pressure in old age were 50 percent more likely to have severe brain lesions than people with low diastolic blood pressure in old age.

However, in people with a history of high blood pressure in middle age, lower diastolic blood pressure in older age was associated with smaller total brain and gray matter volumes. This finding was reflected in memory and thinking performance measures as well. In people with high blood pressure in middle age, lower diastolic blood pressure was associated with 10 percent lower memory scores.

"Older people without a history of high blood pressure but who currently have high blood pressure are at an increased risk for brain lesions, suggesting that lowering of blood pressure in these participants might be beneficial. On the other hand, older people with a history of high blood pressure but who currently have lower blood pressure might have more extensive organ damage and are at risk of brain shrinkage and memory and thinking problems."

Thursday, June 5, 2014

The phenomenon of contact inhibition is of importance in resisting cancer, and also appears to influence cellular senescence. Both of these topics are of considerable interest to researchers working on in aging and longevity, and the more so since it seems that naked mole rat cancer immunity appears to be based on more effective contact inhibition. One has to wonder whether this also contributes to their considerable longevity as well, perhaps via suppression of cellular senescence.

During cell cycle arrest caused by contact inhibition (CI), cells do not undergo senescence, thus resuming proliferation after replating. The mechanism of senescence avoidance during CI is unknown. Recently, it was demonstrated that the senescence program, namely conversion from cell cycle arrest to senescence (i.e., geroconversion), requires mammalian target of rapamycin (mTOR). Geroconversion can be suppressed by serum starvation, rapamycin, and hypoxia, which all inhibit mTOR.

Here we demonstrate that CI, as evidenced by p27 induction in normal cells, was associated with inhibition of the mTOR pathway. Furthermore, CI antagonized senescence caused by CDK inhibitors. Stimulation of mTOR in contact-inhibited cells favored senescence. In cancer cells lacking p27 induction and CI, mTOR was still inhibited in confluent culture as a result of conditioning of the medium. This inhibition of mTOR suppressed p21-induced senescence. Also, trapping of malignant cells among contact-inhibited normal cells antagonized p21-induced senescence.

Thus, we identified two nonmutually exclusive mechanisms of mTOR inhibition in high cell density: (i) CI associated with p27 induction in normal cells and (ii) conditioning of the medium, especially in cancer cells. Both mechanisms can coincide in various proportions in various cells. Our work explains why CI is reversible and, most importantly, why cells avoid senescence in vivo, given that cells are contact-inhibited in the organism.

Friday, June 6, 2014

The evidence for metformin to modestly slow aging and extend life in mammals is very mixed, with study results falling all over the map. This is worth bearing in mind when reading any new paper claiming metformin to extend life in other species, as this is just one more item in a distribution of results that does not show clear, compelling, easily replicated evidence of life extension. So that said, here researchers are suggesting that metformin extends life via hormetic effects. Since they are proposing a mechanism, this should lead to ways to better test and replicate the claim without involving metformin itself:

Recently it has been suggested that metformin, the most commonly used antidiabetic drug, might also possess general health-promoting properties. Elucidating metformin's mode of action will vastly increase its application range and will contribute to healthy aging.

Via a quantitative proteomics approach using the model organism Caenorhabditis elegans, we gained molecular understanding of the physiological changes elicited by metformin exposure, including changes in branched-chain amino acid catabolism and cuticle maintenance.

We show that metformin extends lifespan through the process of mitohormesis and propose a signaling cascade in which metformin-induced production of reactive oxygen species increases overall life expectancy. We further address an important issue in aging research, wherein so far, the key molecular link that translates the reactive oxygen species signal into a prolongevity cue remained elusive. We show that this beneficial signal of the mitohormetic pathway is propagated by the peroxiredoxin PRDX-2. Because of its evolutionary conservation, peroxiredoxin signaling might underlie a general principle of prolongevity signaling.

Friday, June 6, 2014

Just as scientists are attempting to build calorie restriction mimetics to recapture the well-studied benefits of eating fewer calories, so too some research groups are in search of ways to replicate the benefits of exercise. These efforts are nowhere near as far along as calorie restriction mimetic studies, but I expect that the field will grow in the years ahead. Here is an example of present work, which is still very much at the stage of discovering important mechanisms that might later be manipulated:

In the last few years, the benefits of short, intense workouts have been extolled by both researchers and exercise fans as something of a metabolic panacea. In a new study, [scientists] confirm that there is something molecularly unique about intense exercise: the activation of a single protein. The study revealed the effects of a protein known as CRTC2. The scientists were able to show that following high-intensity exercise, which enlists the sympathetic nervous system's "fight or flight" response, CRTC2 integrates signals from two different pathways - the adrenaline pathway and the calcium pathway, to direct muscle adaptation and growth only in the contracting muscle.

Using mice genetically modified to conditionally express CRTC2, the scientists showed that molecular changes occurred that emulated exercised muscles in the absence of exercise. "The sympathetic nervous system gets turned on during intense exercise, but many had believed it wasn't specific enough to drive specific adaptations in exercised muscle. Our findings show that not only does it target those specific muscles, but it improves them - the long-term benefits correlate with the intensity of the workout."

In the genetically altered animal models, this resulted in a muscle size increase of approximately 15 percent. Metabolic parameters, indicating the amount of fuel available to the muscles, also increased substantially - triglycerides went up 48 percent, while glycogen supplies rose by a startling 121 percent. In an exercise stress test, the genetically altered animals improved 103 percent after the gene was activated, compared to an 8.5-percent improvement in normal animals.


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