Fight Aging! Newsletter, December 1st 2014

December 1st 2014

Herein find a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress on the road to bringing aging under medical control, the prevention of age-related disease, and present understanding of what works and what doesn't when it comes to extending healthy life. Expect to see summaries of recent advances in medicine, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Giving Tuesday Arrives on December 2nd
  • Experimentation in Regenerative Reprogramming
  • Not Everyone Likes Mitochondrial DNA Damage as a Theory of Aging
  • An Interview with Bob Hariri of Human Longevity, Inc.
  • The Ridiculous Cost of Medical Research Regulation
  • Mitochondrial Function and Cellular Senescence
  • Latest Headlines from Fight Aging!
    • Restoring Function to Old Pancreatic Islets
    • Investigating Nail Stem Cells
    • Lysosomal Dysfunction in Atherosclerosis
    • Initial Evidence for Glycogen Buildup in the Brain to Contribute to Aging
    • Atherosclerosis Correlates with Cognitive Impairment
    • An Update on Reprogramming Glial Cells into Neurons
    • Inhibiting IFN-1 to Partially Restore Lost Cognitive Function
    • Exercise Improves Cognitive Function in Older People
    • Just Like All Aspects of our Biology, Age-Related Damage in the Brain is Complicated
    • Suppressing a Stroke Damage Mechanism


Giving Tuesday is just a couple of days away, an annual reminder to reach out and help charitable causes to make a real difference in the world. We are raising funds for SENS rejuvenation research to speed progress towards and end to pain and frailty in aging - and we need your help to hit our 2014 fundraising target. For every $1 you give to the SENS Research Foundation before the end of December, we will match it with $2 from the challenge fund set up by our generous donors. So this Giving Tuesday, tell someone you know about the prospects for ending the suffering and disease caused by aging: with more support for the cause, we can create faster progress towards therapies for degenerative aging.

Remember that if you work for even a moderately sized company, your employer most likely matches employee donations to charitable causes such as SENS research. It makes a real difference to your contributions, so don't forget to look into it.


Salamanders and zebrafish are among the species that can regenerate limbs and even large portions of vital organs after injury, and the regrown portions of their anatomy are just the same as the original. We mammals cannot do this: we can manage fingernails, occasionally fingertips at a very early age, and portions of the liver, but that is about it. One line of modern regenerative research asks whether it is possible to somehow induce the regenerative biochemistry of salamanders and zebrafish in mammals. Is mammalian incompetence in healing a matter of lost capabilities that originally evolved in a distant shared ancestor species, and thus the necessary biochemistry still exists, but is in some way dormant? The answer to that question, and the more important questions regarding whether or not it will be very hard to make use of anything learned about regeneration in species like salamanders, are only going to be revealed by more research. The present state of knowledge leaves a lot of room for speculation.

In recent years research has pointed to the importance of the immune system in enhanced regeneration: immune cell activity seems key to regeneration in both salamanders and zebrafish, and if suppressed injuries scar rather than regrowing lost tissues. Also some inroads have been made into finding protein machinery such as the ERK pathway that is vital to salamander-like regeneration, but different and less active in mammals. These are all still starting points for later research rather than answers in and of themselves, guideposts that may help focus other scientific groups on the right paths. All in all this is largely a matter of preliminary research aimed at understanding exactly how regeneration works in these species, and trying to do anything with this knowledge is still a fairly remote possibility for much of this work.

That isn't always the case, however. This research group has taken a more aggressive approach, cataloging microRNAs in heart tissue that are shared by zebrafish and mice, finding those that differ in amount between species after heart injury, and then artificially altering mouse microRNA levels to be more like those of the zebrafish. The result is positive, which suggests that this research is a step in the right direction. In particular it adds weight to the idea that at least some shared regenerative mechanisms from the deep evolutionary past remain dormant in mammals rather than lost entirely:

Salk scientists discover a key to mending broken hearts

[Researchers] have healed injured hearts of living mice by reactivating long dormant molecular machinery found in the animals' cells, a finding that could help pave the way to new therapies for heart disorders in humans. The new results suggest that although adult mammals don't normally regenerate damaged tissue, they may retain a latent ability as a holdover, like their distant ancestors on the evolutionary tree.

In a [2010 paper], the researchers described how regeneration occurred in the zebrafish. Rather than stem cells invading injured heart tissue, the cardiac cells themselves were reverting to a precursor-like state (a process called 'dedifferentiation'), which, in turn, allowed them to proliferate in tissue. Although in theory it might have seemed like the next logical step to ask whether mammals had evolutionarily conserved any of the right molecular players for this kind of regenerative reprogramming, in practice it was a scientific risk. "When you speak about these things, the first thing that comes to peoples' minds is that you're crazy. It's a strange sounding idea, since we associate regeneration with salamanders and fish, but not mammals."

The team decided to focus on microRNAs, in part because these short strings of RNA control the expression of many genes. They performed a comprehensive screen for microRNAs that were changing in their expression levels during the healing of the zebrafish heart and that were also conserved in the mammalian genome. Their studies uncovered four molecules in particular - MiR-99, MiR-100, Let-7a and Let-7c - that fit their criteria. All were heavily repressed during heart injury in zebrafish and they were also present in rats, mice and humans. However, in studies of mammalian cells in a culture dish and studies of living mice with heart damage, the group saw that the levels of these molecules were high in adults and did not decline with injury. So the team used adeno-associated viruses specific for the heart to target each of those four microRNAs, suppressing their levels experimentally.

Injecting the inhibitors into the hearts of mice that had suffered a heart attack triggered the regeneration of cardiac cells, improving numerous physical and functional aspects of the heart, such as the thickness of its walls and its ability to pump blood. The scarring caused by the heart attack was much reduced with treatment compared to controls, the researchers found. The improvements were still obvious three and six months after treatment - a long time in a mouse's life.

In Vivo Activation of a Conserved MicroRNA Program Induces Mammalian Heart Regeneration

Heart failure is a leading cause of mortality and morbidity in the developed world, partly because mammals lack the ability to regenerate heart tissue. Whether this is due to evolutionary loss of regenerative mechanisms present in other organisms or to an inability to activate such mechanisms is currently unclear. Here we decipher mechanisms underlying heart regeneration in adult zebrafish and show that the molecular regulators of this response are conserved in mammals. We identified miR-99/100 and Let-7a/c and their protein targets smarca5 and fntb as critical regulators of cardiomyocyte dedifferentiation and heart regeneration in zebrafish. Although human and murine adult cardiomyocytes fail to elicit an endogenous regenerative response after myocardial infarction, we show that in vivo manipulation of this molecular machinery in mice results in cardiomyocyte dedifferentiation and improved heart functionality after injury. These data provide a proof of concept for identifying and activating conserved molecular programs to regenerate the damaged heart.


There are factions within the research community who argue against mitochondrial DNA damage as an important cause of aging. That said, I think I could pick any present hypothesis on the biochemistry of aging and find a faction whose members don't think much of it. For all that the mountains of data cataloging the differences between old tissues and young tissues are largely agreed upon, the field as a whole is a battleground of interpretations over the processes involved in moving from young to old. There are those who think damage akin to wear and tear at a cellular level causes change in metabolism, and those who think that evolved programs of changes in metabolism cause damage. Within the damage-as-root-cause school there are any number of debates over which forms of damage are more important, and which are primary causes of aging versus secondary consequences of other forms of damage.

After a decade following research I more or less agree with the SENS vision of aging and the approach of damage repair. But agreeing with the approach isn't the only reason to back a strategy that aims to repair identified forms of damage that differentiate old tissues from young tissues. The other good reason is that building the various clearly envisaged repair treatments is the fastest way to settle most of the arguments in the field. The past two decades of aging research have demonstrated that it is enormously expensive and very slow to try to figure out what is going on at a cellular and metabolic level in aging. Billions of dollars and thousands of researcher years have not produced any great advance in the big picture consensus: researchers still argue over quite fundamental matters of interpretation despite vast vaults of new data.

So I think it is past time to cut to the chase: implement some of the SENS repair biotechnologies, a task that could be accomplished for a fraction of what has been spent on investigations of calorie restriction alone in the past twenty years. So removal of senescent cells, clearance of metabolic waste, restoration of stem cell populations, destruction of misbehaving immune cells, repair of mitochondrial DNA, and so forth. Try out these technologies in mice: whether or not each type of treatment works, that effort will go a long way towards settling the debate over one particular form of age-related damage. In particular think of arguments over the relevance of mitochondrial DNA damage in aging; if we had a means to repair mitochondrial DNA, and any one of three or four such means is really only a few years distant given a sizable project fund, then there would be no real debate. Either removing the damage works, in the sense of meaningful improvement in measures of health, or it doesn't. There would be far less ambiguity possible after running that experiment a few times.

In any case, here is an open access paper whose authors are not hot on mitochondrial DNA damage in aging. While the mitochondrial theory of aging as originally envisaged is indeed becoming an outmoded viewpoint and is halfway overthrown, rejecting an important role for mitochondrial DNA damage seems like throwing out the baby with the bathwater. It is not hard to argue in opposition to some parts of their position, and I think there's a little of seeing what they want to see going on here. For every paper they could produce to support their points, there are others that undermine them. Mitochondrial dynamics are exceedingly complex, and there is a lot of subtlety in the relationship between mitochondria, generation of oxidative damage, and the possible means by which mitochondrial DNA might become damaged - of which oxidative reactions are but one mechanism. This is why I'd say focus on repair technologies as one of the primary methods of investigation at this time, and cut this Gordian knot - something that these authors would probably agree with, though they envisage an exploration conducted via better ways to induce defined levels and types of mitochondrial DNA damage.

Aging: A mitochondrial DNA perspective, critical analysis and an update

The mitochondrial theory of aging (MTA), a mainstream theory of aging which once included accumulation of mitochondrial DNA (mtDNA) damage by reactive oxygen species (ROS) as its cornerstone, has been increasingly losing ground and is undergoing extensive revision due to its inability to explain a growing body of emerging data. This, in turn, has resulted in both a growing skepticism towards the role of mtDNA mutations in aging, and in the transformation of some of our views on mtDNA, ROS, and aging.

Thus, the increased susceptibility of mtDNA to ROS-induced strand breaks (but not to oxidative base damage) is now viewed as a component of the mitochondria-specific mechanism for the maintenance of mtDNA integrity through abandonment and degradation of severely damaged mtDNA molecules, rather than as a mechanism for accelerated mtDNA mutagenesis. Also, we have begun to appreciate that increased ROS production in aging may represent evidence for adaptive signaling aimed at mitigating detrimental changes, rather than constituting an unwanted but unavoidable byproduct of respiration.

Even though its current status is controversial, it is the MTA that stimulated the research that advanced our understanding of aging and clarified the place of mtDNA in this process. While it is no longer plausible that mtDNA is either the sole or the main determinant of aging, epidemiological studies do still suggest a contribution of mtDNA variation to longevity. Also, it is becoming increasingly obvious that maternally transmitted low levels of germline mtDNA mutations can have a significant impact on health and lifespan. The random genetic drift theory has the potential to reconcile the observed mitochondrial dysfunction in aged organs with the low average levels of mtDNA mutations in some tissues. These and other findings demonstrate that despite dramatic advances, our understanding of the role of mtDNA in aging remains incomplete. This incomplete understanding persists in large part due to our limited ability to manipulate mitochondria in a meaningful way. The lack of approaches to introduce defined base lesions into mtDNA impedes our progress in understanding the specifics of mitochondrial processing of oxidative DNA damage. This, in turn, limits our ability to deconvolute and interpret the spectrum of mtDNA mutations observed in aging.


Bob Hariri is a cofounder of Human Longevity, Inc., the present exemplar of the mainstream focus on genetics when it comes to aging and longevity. I've had my say as to why I think this sort of effort is likely only to incrementally improve the present state of medicine rather than actually deliver meaningful extension of healthy life. It is much the same argument as I've made for initiatives aimed at slowing aging through altering the operation of metabolism: that research is slow, expensive, the primary output is knowledge of the detailed operation of metabolism rather than useful therapies, and even if successful beyond the expectations of those involved, it will still result in treatments that are near useless for old people. What good does it do to slightly slow the pace at which damage accumulates in your tissues if you are already very old and damaged? What good does it do to change some of your epigenetic patterns to those of a longer-lived human, when the difference in outcome is only a few years of extra health, and probably not even that if you are already old?

The only way to effectively add decades to healthy life spans and help the old is to produce rejuvenation treatments. From where I stand, the only viable way forward, a path likely to produce useful results within a short enough span of time to matter for those in middle age today, is to repair the various forms of damage that cause aging. The catalog of fundamental differences between old tissues and young tissues is well known, and detailed proposals exist on how to build repair treatments for each of these types of damage. But that work is for the most part very poorly funded, excepting those portions relating to stem cells and cancer. Genetics on the other hand is the flavor of the decade and it is comparatively easy to raise funds for any work in that field, regardless of its relative merits in the bigger picture.

So genetics is what we get. On the one hand this is work that is necessary for the future of medicine as a whole and should indeed be accomplished, and the sooner the better. On the other hand there seems to be an ambition to move the needle on aging and longevity that is simply unrealistic given the tools to hand in this field. Adding decades to healthy human life spans within the next few decades is not a plausible outcome of genetic research over that time scale, but it is for the less acknowledged and far less well funded work on rejuvenation treatments carried out by groups like the SENS Research Foundation. If SENS-like repair research had the funding and attention of the genetics field, I'd feel a lot more confident about the timeline for future rejuvenation treatments.

So all that said - again - what are the founders of Human Longevity, Inc. going to do with the vast mountain of genetic data they plan to accumulate? How do they tie the data gathering to their vision of improving human longevity and intervening in the aging process? Below are some interesting snippets from a recent interview with cofounder Bob Hariri, and as you can see there is a lot of emphasis placed on stem cell therapies as the treatment mode:

The Regeneration Generation: A Conversation With Bob Hariri, Vice-Chairman and Co-Founder of Human Longevity Inc.

RS: How did you get together with Craig Venter and Peter Diamandis?

BH: The three of us realized that we shared many common passions, among which was a desire to impact human health and society by exploring aging as a targetable disease. All of us have ventured, failed and succeeded by seeking to answer scientific questions based in real-world experience and offering solutions. We all took paths that were challenged, in some cases ridiculed and rejected, by established scientific institutions. In part that's because invention without relevance or context has less impact than true innovation. We all saw aging as an opportunity to innovate, not as an obstacle to human progress and prosperity.

RS: Can stem cells prevent aging and even turn back the clock?

BH: We believe that stem cells that are functioning well can play an important role in extending health and improving physical and cognitive performance and cosmetic vitality. Our work in stem cells has shown that if you can identify and measure individual variation for specific markers of disease at particular ages, you can identify the factors that predict the variability in how cells change over the lifespan. Then, using the information derived by interrogation of the genomics, proteomics and metabolomics, we can tailor treatments to how individuals get sick and improve their health.

RS: What is the game plan for the years ahead?

BH: Our goal is to sequence over 1 million full human genomes, microbiomes, MRI body-image scans, metabolomes, etc. We will commercialize therapies for diseases that are associated with the biological and molecular breakdown associated with aging. And we will develop a preventive healthcare model that will take baseline measures of stem-cell function, monitor that in real time and correct any drift from optimal activity with stem-cell therapy.

RS: How do you feel about Google's Calico venture? Are they competition for you?

BH: We are thrilled and excited that a remarkable company like Google has invested so actively in biomedicine and see Calico as part of what will be a rapidly expanding enterprise of age management or wellness. I hope there are many more companies who participate in helping people live longer, healthier lives.

RS: What do you think the field looks like 20 years from now?

BH: I believe stem-cell innovations will have a quantum impact on the kind of people we can be. Throughout our short history on this planet, our progress can be measured by our ability to thrive. By this, I don't just mean the fact that we will live longer and live better or that, as a result, we will spend less on health care. Rather, I believe the technological and physical evolution of our species will increase the capacity to share, and to be more flexible, inventive and determined in the face of uncertainty. Living longer at a time when the supply of ideas and inventions increase more quickly will exponentially increase the opportunity to pursue many more possibilities.


The much-touted ballpark estimate of a billion dollars to produce a modern pharmaceutical from start to finish is about a decade old now - that figure is adjusted for today's diminished dollar value, eroded by inflation. You can replace "pharmaceutical" with any medical technology that is going to require a fair amount of original research and further tinkering in the laboratory to obtain the first working prototypes and the result is much the same. This large round number is the kitchen sink cost across a decade of work, including failed attempts and the opportunity cost of investment. The lion's share of the direct expenditures are imposed by regulatory requirements: trials, data, and more trials.

It has long been my position that almost all of the work carried out in the US at the behest of the FDA to prove safety is unnecessary. In fact it is counter-productive, as the immense imposed costs on development shut out a great deal of the experimentation and small-scale initiatives needed for rapid progress. Much of what the FDA demands is not demanded by similar regulatory bodies in other parts of the world, and even their requirements are very onerous in comparison to the standards in place fifty years past, a time when medical development seems to me to have worked just fine. It is a question of balances and choice: it is better to err in favor of faster progress and informed patient choice, but that is very far from the present state of affairs.

The result of an excessive and growing regulatory burden is that many potential medical technologies languish, are rejected outright, or are never developed at all, and patients suffer as a result. Our future health is determined by the pace of progress, and a slowdown across the board harms all of us considerably. Unfortunately that cost is invisible to the public at large and thus bureaucrats suffer very little as a result of the harms they cause by blocking progress. Meanwhile even comparatively small harms caused by an approved treatment that turns out to be overwhelmingly beneficial save for some negative effects for some people can snowball in the media to cause great damage to a career in the FDA bureaucracy. So you can see that the incentives are very much aligned with ever greater demands for proof and ever greater costs imposed on medical research and development. This is in fact what has happened over the past few decades, with the present result that in an age of radical progress and plummeting costs in the laboratory it is nonetheless the case that medicine is ever more expensive and the introduction of new applications of medical research has slowed down. This is well known and widely commented on, but so entrenched that this detrimental trend shows no signs of slowing.

So, to return to the cost of developing a modern pharmaceutical product: estimated at a billion dollars (in today's dollars) ten years ago, the same approach results in an estimated $2.5 to $2.8 billion dollars now. Interestingly the bulk of that is apparently not due to the increased time required to run the regulatory gauntlet, but rather largely due to other increases in the demands of regulators: much larger trials and more data. Via In the Pipeline, here are a couple of items on this topic. The second includes a very educational model and cost breakdown - you might take a look at that to see that initial research to the prototype stage, many failures included, is a fraction of the full cost of development and approval. That is something to think about as we raise money to help fund SENS research into the foundations of near future rejuvenation treatments.

Cost to Develop and Win Marketing Approval for a New Drug Is $2.6 Billion

Developing a new prescription medicine that gains marketing approval, a process often lasting longer than a decade, is estimated to cost $2,558 million, according to a new study by the Tufts Center for the Study of Drug Development. The $2,558 million figure per approved compound is based on estimated: 1) Average out-of-pocket cost of $1,395 million. 2) Time costs (expected returns that investors forego while a drug is in development) of $1,163 million. Estimated average cost of post-approval R&D - studies to test new indications, new formulations, new dosage strengths and regimens, and to monitor safety and long-term side effects in patients required by the U.S. Food and Drug Administration as a condition of approval - of $312 million boosts the full product lifecycle cost per approved drug to $2,870 million. All figures are expressed in 2013 dollars.

In a study published in 2003, Tufts CSDD estimated the cost per approved new drug to be $802 million (in 2000 dollars) for drugs first tested in human subjects from 1983 to 1994, based on average out-of-pocket costs of $403 million and capital costs of $401 million. The $802 million, equal to $1,044 million in 2013 dollars, indicates that the cost to develop and win marketing approval for a new drug has increased by 145% between the two study periods, or at a compound annual growth rate of 8.5%.

A Billion Here, A Billion There: The Cost Of Making A Drug Revisited

At first principles, there are several items that need to be factored in: direct costs of moving a drug forward, paying for failures along the way, and the time value of money (forgoing other investments). Since they haven't shared their model, I've built a quick-and-dirty version using their public assumptions to recreate in a ballpark fashion their $2.5B drug cost estimate. The distribution of costs (30-33% of spending into pre-clinical phases) is similar to their report. Here is my "estimated" model that you can download and play with.

The silver lining in all of this is that the greater the demands of the regulators, the more that development will move to much less costly regions of the world. We've seen this in the initial growth of the stem cell field, with proficient clinical industries established in Asia and elsewhere years prior to the first therapies eventually obtaining approval in the US - and we'd likely still be waiting on that approval if not for the fact that the existence of establish clinical networks and research groups elsewhere in the world puts increasing public pressure on US regulators to speed things up. Travel halfway around the world is cheap in comparison to the initial cost of most new medical technologies, which ultimately means that regulators set on ever-increasing demands will paint themselves out of the picture. Given yet more regulatory costs, the US research community will only thrive in the years ahead to the extent that it forges bridges to developers and clinics in other parts of the world - but that will definitely become the new normal if the trend continues.


The myriad mechanisms of cellular biology are a seething pool of feedback loops and interactions. Every protein that plays a role has half a dozen other roles on the side: evolution produces promiscuous reuse of every new component that arises. Thus little if anything happens in isolation in our cells, and changes produce reactions. So when we say that degeneration in aging is produced by the accumulation of a variety of forms of damage, we refer to a very complicated progress that spirals out from comparatively simple beginnings. Consider the SENS model for the causes of aging, for example. Broadly, the operation of metabolism produces waste byproducts that are not always entirely cleaned up or recycled. Separately, some important cellular components can become damaged in the course of normal operation in ways that resist the otherwise highly efficient recycling machinery. Further, evolution has adapted certain quiescent cell states used in embryonic development into a way to resist cancer. These senescent cells behave in ways that may well suppress cancer risk in the short term, but are not good at all for tissues over the long term. Separately again, some larger and more complex structures, such as the thymus or the immune system considered as a whole, become misconfigured or less useful over the course of time as an inevitable consequence of their structure and modes of operation. Even if all of their cellular components continued to work perfectly in and of themselves, some of our biological systems cannot operate well indefinitely.

These are all discrete sources of damage and gradual failure, distinct processes and harms that must be addressed separately by any suite of rejuvenation treatments. Damage doesn't accumulate in isolation, however. The harms interact. Persistent metabolic waste products degrade the effectiveness of cellular recycling systems, for example, and that probably exacerbates other sources of damage that arise from damaged cell components, misfolded proteins, and the like. There are many other examples of the way in which forms of damage might interact with one other, but there is also a lot of room for theory and speculation, since a complete map is lacked of the detailed progression of aging from its root causes through to age-related disease and death. Researchers have a catalog of the simple forms of damage at the beginning of the road, a catalog of complex diseases at the end of the picture, and only the first sketches of the story in between. Fortunately, if you have the catalog of damage you don't need the full picture in order to build treatments based on repair. Unfortunately the majority of the scientific community is more interested in filling in the gaps in the picture than in producing treatments.

As to speculation: given the list of forms of damage outlined in the SENS vision of aging, it is interesting to consider which of them are working in concert. If mitochondrial DNA damage was repaired throughout the body, would it result in diminished levels of misbehaving senescent cells, for example? Generally cells become senescent in response to a tissue environment that appears more damaged, or in response to the presence of toxins that might have that effect. Does the presently partially understood set of influences include the state of mitochondrial damage in a straightforward way? That is hard to tell in absence of good ways to control that damage experimentally. The fastest approach to answering this sort of question at the present point in time is probably to implement mitochondrial repair treatments in mice and see what happens.

Mitochondrial effectors of cellular senescence: beyond the free radical theory of aging

Cellular senescence is a process that results from a variety of stresses, leading to a state of irreversible growth arrest. Senescent cells accumulate during aging and have been implicated in promoting a variety of age-related diseases. Mitochondrial stress is an effective inducer of cellular senescence, but the mechanisms by which mitochondria regulate permanent cell growth arrest are largely unexplored.

The free radical theory of aging has been adapted to the study of cellular senescence. Many studies show that reactive oxygen species (ROS) can induce cellular senescence. Indeed, hydrogen peroxide (H2O2), which is considered as the major ROS within the cell, is a potent inducer of cellular senescence in many cell types. While exogenous treatment with H2O2 can promote cellular senescence, endogenous ROS (such as superoxides and hydroxyl radicals) is also implicated in the establishment and maintenance of the irreversible growth arrest.

While several studies implicate the role of ROS during cellular senescence, others also suggest that mitochondrial ROS generation may not necessarily be the primary cause of cellular senescence. One [study] suggests that increased mitochondrial ROS production in replicative senescent cells is a consequence of the senescence phenotype rather than the reverse. Because mitochondria influence many cellular processes, accumulation of mitochondrial oxidative damage, as proposed in the free radical theory of aging, may be an oversimplification of the signaling mechanisms involved in the establishment of cellular senescence. It is also possible that mitochondrial ROS can act as signaling molecules to trigger cellular senescence, independent of mitochondrial oxidative damage, although this hypothesis still needs to be proven.

It is then necessary to go beyond the free radical theory and examine other mitochondrial effectors that may be involved in the irreversible cell growth arrest. Multiple mitochondrial factors, such as excessive mitochondrial ROS production, aberrant mitochondrial dynamics, defective electron transport chain, imbalanced bioenergetics, activated AMPK, decreased NAD+ levels, altered metabolism, and dysregulated mitochondrial calcium homeostasis, contribute to the establishment of irreversible growth arrest. All of these different mitochondrial signaling pathways can regulate each other, but how these factors cooperate to promote cellular senescence, and whether these pathways are conserved in all senescent cells still remains unclear.

As you can probably tell, this is one of those "look at all these things we don't know yet!" papers. I see a lot of these day in and day out. There is indeed a great deal that is still a big blank space on the map of how exactly we age, and that is exactly why more of a focus should be placed on the development of repair technologies based on what is presently well known.


Monday, November 24, 2014

Researchers here transplant pancreatic islets from old to young mice and see restored function. They conclude that replacing the microvasculature that supplies blood to the tissue is the important change in this process, but I suspect that being in a young tissue environment brings many more significant alterations in the form of different levels of signal proteins in the blood. A number of research teams have demonstrated restoration of stem cell function in old tissues through altered levels of signal proteins, for example. So this is an interesting result that needs further investigation to determine whether or not it is just blood vessel declines producing this effect:

Islets, which contain the beta cells responsible for secreting the blood-glucose-regulating hormones insulin and glucagon, typically decrease in function with age. The researchers hypothesized that the decrease in function might not be due solely to a decrease in glucose-sensing or hormone-secreting capacity, but also to a decrease in blood supply caused by inflammation and scarring of the vessels. Replacing the islet vasculature in grafts transplanted into young mice restored the islets to full function, even at an advanced age. The study finding is significant because it suggests that targeting inflammation and fibrosis in the small blood vessels of the islet may offer new treatment options for diabetes.

To determine how revascularization might affect islet function, the researchers transplanted pancreatic islets from 18-month-old mice into the eyes of 2-month-old diabetic mice. [This is the equivalent to ages 65 and 18 in humans.] The transplanted islets, which had been revascularized with healthy blood vessels, exhibited strong beta cell proliferation and regained control of blood glucose levels within three months of transplantation. "This is an unexpected but highly important finding that we predict will have a significant impact on diabetes research in the future. The results indicate that beta cell function does not decline with age, and instead suggest that islet function is threatened by an age-dependent impairment in islet vascular function."

Monday, November 24, 2014

Nails are one of the few parts of the human body that can regenerate completely after loss in adults. So why not dig deeper into the biology of the stem cells involved? Perhaps it will teach us something more about why only a few types of mammalian tissue are capable of such complete regeneration. This initial investigation is only the starting point for such a research program, but we'll no doubt hear more in the years ahead:

There are plenty of body parts that don't grow back when you lose them. Nails are an exception. [Researchers have] identified a new population of nail stem cells, which have the ability to either self-renew or undergo specialization or differentiation into multiple tissues. To find these elusive stem cells, the team used a sophisticated system to attach fluorescent proteins and other visible "labels" to mouse nail cells. Many of these cells repeatedly divided, diluting the fluorescence and labels among their increasingly dim progeny. However, a few cells located in the soft tissue attached to the base of the nail retained strong fluorescence and labels because they either did not divide or divided slowly - a known property of many stem cells.

The researchers then discovered that these slow-dividing stem cells have the flexibility to perform dual roles. Under normal circumstances, the stem cells contribute to the growth of both the nails and the adjacent skin. However, if the nail is injured or lost, a protein called "Bone Morphogenic Protein," or BMP, signals to the stem cells to shift their function exclusively to nail repair. The researchers are now wondering whether or not the right signals or environmental cues could induce these nail stem cells to generate additional types of tissue - potentially aiding in the repair of everything from nail and finger defects to severe skin injuries and amputations.

Tuesday, November 25, 2014

Atherosclerosis is the build up of fatty plaques known as atheromas in blood vessel walls, leading to death or injury when blood vessels suffer structural failure or part of a plaque breaks loose to block a blood vessel elsewhere. Plaques start because damaged lipids cause a reaction in blood vessel walls, drawing in the immune cells called macrophages that ingest the lipids to remove them. Sometimes this doesn't work well enough, and the immune cells become stressed by intake of too many lipids and die. Plaques are comprised of the remnants of cells, and the presence of all this waste material causes further inflammation, producing a vicious cycle in which the plaques grow by attracting ever more immune cells.

This is a process that can be sped up by a number of factors, such as greater chronic inflammation or more lipids damaged by oxidation due to higher levels of oxidative stress in tissues. Both of these occur with aging and as a result of conditions such as obesity known to raise the risk of suffering atherosclerosis. Another item to consider is the degree to which immune cells are capable of digesting lipids. These molecules should be broken down in the cells' lysosomes, but lysosomal function is another aspect of cell biology that deteriorates with age.

Here, researchers show that spurring macrophages to generate more new lysosomes in reaction to the stress of ingesting lipids slows the development of atherosclerosis, which is much as expected. Even if they lysosomes are dysfunctional, more of them should still improve this particular situation:

Recent reports of a proatherogenic phenotype in mice with macrophage-specific autophagy deficiency have renewed interest in the role of the autophagy-lysosomal system in atherosclerosis. Lysosomes have the unique ability to process both exogenous material, including lipids and autophagy-derived cargo such as dysfunctional proteins/organelles. We aimed to understand the effects of an atherogenic lipid environment on macrophage lysosomes and to evaluate novel ways to modulate this system.

Using a variety of complementary techniques, we show that oxidized low-density lipoproteins and cholesterol crystals, commonly encountered lipid species in atherosclerosis, lead to profound lysosomal dysfunction in cultured macrophages. We find that macrophages isolated from atherosclerotic plaques also display features of lysosome dysfunction. We then investigated whether enhancing lysosomal function can be beneficial. Transcription factor EB (TFEB) is the only known transcription factor that is a master regulator of lysosomal biogenesis although its role in macrophages has not been studied. Lysosomal stress [leads] to TFEB nuclear translocation and activation of lysosomal and autophagy genes. TFEB overexpression in macrophages further augments this prodegradative response and rescues several deleterious effects seen with atherogenic lipid loading.

Taken together, these data demonstrate that lysosomal function is markedly impaired in atherosclerosis and suggest that induction of a lysosomal biogenesis program in macrophages has antiatherogenic effects.

Tuesday, November 25, 2014

This research suggests another type of metabolic waste should be added to those already known to contribute to degenerative aging. Given where the researchers presently stand, one logical next step might be to run mouse life span studies to augment the data already gathered in flies, but those are quite expensive in comparison to other choices:

Glycogen is a branched polymer of glucose and the carbohydrate energy store for animal cells. In the brain, it is essentially found in glial cells, although it is also present in minute amounts in neurons. In humans, loss-of-function mutations in laforin and malin, proteins involved in suppressing glycogen synthesis, induce the presence of high numbers of insoluble polyglucosan bodies in neuronal cells. Known as Lafora bodies (LBs), these deposits result in the aggressive neurodegeneration seen in Lafora's disease. Polysaccharide-based aggregates, called corpora amylacea (CA), are also present in the neurons of aged human brains. Despite the similarity of CA to LBs, the mechanisms and functional consequences of CA formation are yet unknown.

Here, we show that wild-type laboratory mice also accumulate glycogen-based aggregates in the brain as they age. These structures are immunopositive for an array of metabolic and stress-response proteins, some of which were previously shown to aggregate in correlation with age in the human brain and are also present in LBs. Remarkably, these structures and their associated protein aggregates are not present in the aged mouse brain upon genetic ablation of glycogen synthase. Similar genetic intervention in Drosophila prevents the accumulation of glycogen clusters in the neuronal processes of aged flies. Most interestingly, targeted reduction of Drosophila glycogen synthase in neurons improves neurological function with age and extends lifespan. These results demonstrate that neuronal glycogen accumulation contributes to physiological aging and may therefore constitute a key factor regulating age-related neurological decline in humans.

Wednesday, November 26, 2014

Aging is a global phenomenon of damage accumulation throughout the body. Different people age at modestly different rates due to their lifestyle choices and environment, so correlations between different manifestations of the aging process are easy to pull from the data even if there is no obvious way in which the known causative processes are linked. Yet since many bodily systems do in fact influence one another, that aging is global doesn't necessarily mean that any given set of age-related conditions are independent - so a correlation may be meaningful.

Atherosclerosis is a condition in which fat, cholesterol and other substances collect in the arteries, forming a substance called plaque that can build up, limiting blood flow. It can occur in any artery of the body, including the carotid, which supplies blood to the brain, coronary arteries and the aorta, which carries oxygenated blood from the heart through the abdomen to the rest of body. In a study of nearly 2,000 adults, researchers found that a buildup of plaque in the body's major arteries was associated with mild cognitive impairment. "It is well established that plaque buildup in the arteries is a predictor of heart disease, but the relationship between atherosclerosis and brain health is less clear. Our findings suggest that atherosclerosis not only affects the heart but also brain health."

In the study, researchers analyzed the test results of 1,903 participants (mean age, 44 years) in the Dallas Heart Study. The participants included both men and women who had no symptoms of cardiovascular disease. Study participants completed the Montreal Cognitive Assessment (MoCA), a 30-point standardized test for detecting mild cognitive impairment, and underwent magnetic resonance imaging (MRI) of the brain to identify white matter hyperintensity (WMH) volume. Bright white spots known as high signal intensity areas on a brain MR images indicate abnormal changes within the white matter.

Study participants also underwent imaging exams to measure the buildup of plaque in the arteries in three distinct vascular areas of the body: MRI to measure wall thickness in the carotid arteries and the abdominal aorta, and computed tomography (CT) to measure coronary artery calcium, or the amount of calcified plaque in the arteries of the heart. Using the results, researchers performed a statistical regression to correlate the incidence of atherosclerosis and mild cognitive impairment.

Wednesday, November 26, 2014

Neuroglia are a variety of of types of support cell in the brain and nervous system. They perform all sorts of necessary tasks, some of which are still being uncovered, such as the recent discovery that recycling of damaged mitochondria in long axons is delegated to astrocyte glial cells rather than being performed by the nerve cell owning the axon. One of the possibilities opened up by the growing ability to reprogram cell state is to change some of these supporting glial cells into functional neurons, thus creating an increased supply of new cells to repair brain injuries and the damage of aging. Some inroads have already been made in animal studies, and basic proof of concept work has demonstrated that this is a potentially practical approach. Here is a more recent update:

The portion of the adult brain responsible for complex thought, known as the cerebral cortex, lacks the ability to replace neurons that die as a result of Alzheimer's disease, stroke, and other devastating diseases. A [study] shows that a Sox2 protein, alone or in combination with another protein, Ascl1, can cause nonneuronal cells, called NG2 glia, to turn into neurons in the injured cerebral cortex of adult mice. The findings reveal that NG2 glia represent a promising target for neuronal cell replacement strategies to treat traumatic brain injury.

[Researchers] have previously shown that Sox2, Ascl1, and other transcription factors - proteins that bind to specific DNA sequences to control the activity of genes - can induce the nonneuronal "support cells" known as glia to turn into neurons. It has been difficult, however, to convert glia into neurons after brain injuries such as stroke in the adult cerebral cortex of living animals. To test potential brain repair strategies, [the researchers] delivered transcription factors into the cerebral cortex of adult mice three days after traumatic injury. Surprisingly, they found that Sox2 alone or in combination with Ascl1 was sufficient to trigger the emergence of neurons, contrary to the widely accepted view that Sox2 prevents stem cells from turning into more mature cells such as neurons. Notably, the majority of cells that converted into neurons were NG2 glia. These glial cells have received relatively little attention in the past, even though they represent a promising cellular source for brain repair strategies because of their abundance and life-long capacity for proliferation.

Thursday, November 27, 2014

Researchers are expanding their exploration of signal molecules in the blood that differ in abundance between old and young individuals. Changing the levels in an old individual can somewhat restore stem cell function and partly turn back some other measurable declines that occur with aging, possibly through enhanced stem cell activities, possibly through other mechanisms. In considering aging as an accumulation of damage, these environmental changes are a reaction to that damage, a part of the evolved loss of stem cell activity with age that likely exists because it suppresses the risk of increasingly damaged cells spawning a cancer. The present human life span is a balance between diminished tissue maintenance on the one hand and cancer on the other. So it remains to be seen as to how to manage potential risks if this and other similar research is to produce useful treatments in the near term, though the benefits demonstrated in recent studies are large enough to make it well worth the effort:

Brain function declines in aging mammals. Recent work has identified dysregulation of key blood-borne factors whose altered expression during aging diminishes brain function in mice. Increased chemokine CCL11 expression with aging is detrimental to brain function. On the other hand, plasma levels of trophic factor GDF11 decrease with aging. Restoration of youthful levels of GDF11 by injection partially restores brain function and neurogenesis by improving endothelial cell function and vasculature. Moreover, GDF11 has a rejuvenative effect on cardiac and skeletal muscle.

Decreased IFN-II and increased IFN-I signaling during aging at the choroid plexus (CP), which constitutes the brain-cerebrospinal fluid barrier (B-CPF-B), negatively effects brain function. Blood from young mice contains factors that restore IFN-II levels. IFN-II is required for maintenance of the CP and low IFN-II levels are associated with decreased cognitive abilities.

IFN-1 levels appear to drive increased CCL11 expression through the cerebrospinal fluid (CSF). Blood from young animals does not restore IFN-1 levels. However, injecting anti-IFNAR antibodies into the CSF inhibits downstream IFN-I gene and protein expression, and decreases expression of CCL11, partially restoring neurogenesis and cognitive function. These results suggest that IFN-1 plays a critical role to increase CCL11 during aging of brain. An emerging theme is that aging-associated loss of function in mammals may involve a set of defined, potentially reversible changes in many tissues and organs, including the brain, permitting development of potential rejuvenative therapies.

Thursday, November 27, 2014

Here is a little more evidence to suggest that regular moderate exercise is worth the effort at any age, and even if you are already quite far advanced along the path of age-related degeneration:

A decline in cognitive ability commonly occurs among older individuals. This study sought to explore the restorative effects of exercise in older patients with existing cognitive disabilities. Ninety-six patients with mild cognitive impairment were placed in an exercise program for six months. Following completion of the program, participants were assessed via the Chinese Mini Mental Status Examination (MMSE), Activity of Daily Living (ADL) assessment, and body movement testing and compared to a control group of patients with mild cognitive impairment who did not participate in the exercise program (N = 102).

Compared with the control group, patients who exercised showed improved cognitive function in immediate memory and delayed recall function. In addition, activities associated with daily living showed improvement, as did body movement, arm stability, and the appearance of rotation. Based on these results, we conclude that participation in an exercise program can improve patients' cognitive function, physical abilities, and body movement capacity.

Friday, November 28, 2014

There are many ways in which age-related damage emerges in the brain, and the details of any one individual's cognitive function decline with age is a result of the interactions between all of the processes and specific dysfunctions involved. It is very complicated, which is what you get as the result of simple degenerative mechanisms operating in a complex machine. Think of rust in an intricate metal structure: the complexity of the many possible failure modes is a function of the structure, not the rust. Rust is simple. Aging research aimed at producing therapies should focus on manipulating and fixing the simple things, in other words work on ways to periodically repair the causative damage. If the focus is on the complex things, such as trying to fully understand and manipulate the operation of the brain in a damaged state, then progress will be slow, expensive, and produce only marginal benefits.

Owing to increased life expectancy, understanding the pathogenesis of age-associated cognitive decline is becoming more and more important. There are many causes of dementia, but neurodegenerative diseases are thought to be one of the most prevalent in the aging population. Indeed, during the last century neuropathological examinations, based mostly on silver stainings, have demonstrated that the brains of the majority of the individuals with cognitive decline show Alzheimer's disease (AD)-related pathologies, including neurofibrillary tangles and senile plaques.

The spectrum of mixed brain pathologies expands beyond accompanying vascular pathology in brains with Alzheimer's disease-related pathology. Co-occurrence of neurodegenerative non-Alzheimer's disease-type proteinopathies is increasingly recognized to be a frequent event in the brains of symptomatic and asymptomatic patients, particularly in older people. Owing to the evolving concept of neurodegenerative diseases, clinical and neuropathological diagnostic criteria have changed during the last decades. Autopsy-based studies differ in the selection criteria and also in the applied staining methods used.

The present review summarizes the prevalence of mixed brain pathologies reported in recent community-based studies. In these cohorts, irrespective of the clinical symptoms, the frequency of Alzheimer's disease-related pathology is between 19 and 67%, of Lewy body pathology is between 6 and 39%, of vascular pathologies is between 28 and 70%, of TDP-43 proteinopathy is between 13 and 46%, of hippocampal sclerosis is between 3 and 13% and, finally, of mixed pathologies is between 10 and 74%. Some studies also mention tauopathies. White-matter pathologies are not discussed specifically in all studies, although these lesions may be present in more than 80% of the aging brains.

In summary, community-based neuropathology studies have shown that complex constellations of underlying pathologies may lead to cognitive decline, and that the number of possible combinations increases in the aging brain. These observations have implications for the prediction of the prognosis, for the development of biomarkers or therapy targets, or for the stratification of patient cohorts for genome-wide studies or, eventually, for therapy trials.

Friday, November 28, 2014

Researchers have found a way to make neurons more resistant to the oxidative damage that occurs in the restoration of blood flow following a stroke. An effective way to resist this particular form of damage may have broader applications than just the treatment of stroke:

Researchers have discovered a mechanism linked to the brain damage often suffered by stroke victims - and are now searching for drugs to block it. Strokes happen when the blood supply to part of the brain is cut off but much of the harm to survivors' memory and other cognitive function is often actually caused by "oxidative stress" in the hours and days after the blood supply resumes. "Until now, much of the drug research has been focusing on the direct damage caused by the loss of blood flow, but this phase can be hard to target. The patient may not even be in the ambulance when it is happening. We have found a mechanism that is linked to the next phase of damage that will often be underway after patients have been admitted to hospital."

[The researchers] looked at the damage caused by the excessive production of chemicals called "reactive oxygen species" in brain tissues immediately after blood supply is re-established. In a healthy brain, there are very low levels of reactive oxygen species, but the quantity dramatically increases after a stroke to levels that are harmful to neurons. "We identified an 'ion channel' in the membranes of neurons, called TRPM2, which is switched on in the presence of the reactive oxygen species. Basically, an ion channel is a door in the membrane of a cell that allows it to communicate with the outside world - TRPM2 opens when the harmful levels of reactive oxygen species are present and we found that removing it significantly reduced neuronal cell damage."

The researchers compared the effects of strokes on mice with TRPM2 with a transgenic strain without it. "In the mice in which the TRPM2 channel does not function, the reactive oxygen species are still produced but the neurons are very much protected. The neuronal death is significantly reduced. More importantly, we observed a significant difference in brain function, with the protected mice demonstrating significantly superior memory in lab tests. This study has pinpointed a very promising drug target. We are now screening a large chemical library to find ways of effectively inhibiting this channel."


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