FIGHT AGING! NEWSLETTER
December 29th 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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- Investigation of a Role for Progerin in Normal Aging
- Considering Microbial Contributions to the Evolution of Aging
- A Malfunction of Homeostatic Control Theory of Aging
- Meeting in the Middle Between Aging as a Genetic Program and Aging as Accumulated Damage
- There is Still Not Enough Use of Research Prizes in Medicine
- Latest Headlines from Fight Aging!
- Preliminary Evidence Suggesting Long Term Memory is Not Stored in Synapses
- A Review of the Endocrinology of Aging
- Updates on the Biodemography of Aging and Longevity
- Cellular Senescence is Complicated
- A Role for Hydrogen Sulfide in Calorie Restriction
- Hair Regrowth as a Pointer to the Role of Immune System Activity in Tissue Regeneration
- Towards a Signature of Age in Blood Plasma
- Falling Mitochondrial DNA Copy Number in Type 2 Diabetes
- Are Advanced Glycation End-Products Protective as Well as Harmful?
- Mitochondrial DNA Damage in Atherosclerosis
INVESTIGATION OF A ROLE FOR PROGERIN IN NORMAL AGING
Progerin is a malformed variant of lamin A, a protein vital in the nuclear lamina. These are structures that provide mechanical support for the cell, but are also involved in a variety of fundamental and important processes in the cell cycle. The genetic disorder Hutchinson-Gilford progeria syndrome, HGPS or progeria for short, is caused by a rare spontaneous mutation that leads to progerin being created in place of lamin A. Cells are malformed and dysfunctional as a result, and patients rarely live past their early teens. Progeria has the appearance of accelerated aging, characterized by poor tissue maintenance and the development of normally age-related diseases such as atherosclerosis, but at root it is a specific dysfunction in cellular metabolism that is thought to play little to no role in aging.
As an aside there are all sorts of ways to break important aspects of cellular biology to produce results that look at least somewhat like accelerating aging at the high level. The class of DNA repair deficiencies fall into this category, but pretty much anything that causes a significant reduction in stem cell activity will do it. At root aging is damage, but it is a particular balance of various forms of damage. It can be argued either way as to whether we should in fact refer to any of these conditions as accelerating aging, given that they involve forms of cellular damage that do not occur to a significant degree in normal aging.
Over the years since the identification of the cause of progeria there has been some investigation into the degree to which progerin exists and causes harm in old people subject to normal aging. Is it in fact the case that the consensus on this as an insignificant effect is correct? That malformed lamin A is present in small amounts in old tissues seems fairly settled, but this is probably to be expected given the rise in random DNA mutations with age. Are these small amounts sufficient to make it a significant cause of degeneration in comparison to all of the other issues that occur in cellular biochemistry with age? These researchers suggest that at least some stem cell populations are accumulating enough progerin over a human life span to make an impact on their function and thus on their ability to maintain tissues. That in turn would indicate that some mechanism other than random mutation is involved. By the sound of it this group should move on to a proof of concept in an animal model at this point, so as to link the observations made in cell cultures to a meaningful effect on health or stem cell activity - or rule it out, as the case may be:
Progerin expression disrupts critical adult stem cell functions involved in tissue repair
The vascular system is under constant mechanical and inflammatory stress. Fluid pressure and sheer stress combined with inflammatory cytokines lead to damage of the arterial compartment primarily, resulting in injury and death of endothelial, vascular smooth muscle cells and pericytes in the arterial and arteriole walls. In order to repair injured arteries and maintain vascular integrity, damaged or dying cells need to be replaced in a rapid and efficient manner. This is achieved by progenitor or stem cells sensing the damage, migrating to the injured area, differentiating into the needed cell phenotype, and modulating the inflammatory milieu at the injury site. Furthermore, sufficient numbers of these cells are needed in order to maintain a vascular reparative capacity throughout adult life. Thus, these stem/progenitor cells need to self-renew and proliferate in order to maintain a suitable pool of cells available for repair.
The arterial compartment is extremely sensitive to progerin expression, demonstrated by the robust atherosclerosis and vascular diseases exhibited by HGPS patients. Progerin is also expressed in atherosclerotic vascular tissues collected from aged, non-HGPS individuals. Both cases indicate a mechanistic role for progerin expression in interfering with general vascular tissue homeostasis. Efficient vascular repair that is unimpaired by disease or aging requires an adult stem cell population that can maintain their immature status (self-renewal), proliferate, detect damaged tissue and migrate toward it, and contribute to tissue repair by decreasing inflammation and differentiating into necessary cell lineages. We have shown that Marrow Isolated Adult Multilineage Inducible (MIAMI) cells, an immature subpopulation of mesenchymal stem cells, can perform all these described functions and participate in the repair of the arterial compartment both in vivo and in vitro. Interrupting any of these key stem cell functions could decrease vascular repair, increase persistent vascular damage, and result in atherosclerosis and eventual vascular accidents.
The results presented here demonstrate that progerin protein interferes with basic, critical stem cell functions that play an essential role during vascular repair. Endogenous progerin expression observed in MIAMI cells collected from a non-HGPS older donor suggest that MIAMI cells can accumulate progerin in vivo, and therefore are likely subject to the effects of progerin expression. One remarkable observation is that progerin mRNA in MIAMI cells from an aged (65-year old) donor appears to be expressed at similar levels when compared to transduced GFP-progerin MIAMI cells. Because it is likely that cells from aged individuals express progerin at lower levels than cells from HGPS patients, we consider our transduced GFP-Progerin MIAMI cells provide a suitable model to assess the effects of progerin expression in the context of physiological aging in a defined stem/progenitor cell population, with implications to age-related disorders during organismal aging.
CONSIDERING MICROBIAL CONTRIBUTIONS TO THE EVOLUTION OF AGING
Two more or less opposing ways to think about the evolution of aging are as follows (a) aging is actively selected for because it provides some benefit to species survival, such as increased adaptability to environmental change, or (b) aging occurs in a post-reproductive part of life that is not under selection pressure, and is thus a side-effect of mechanisms that are selected for because they provide benefits during the earlier period of reproductive life span, but which systematically fail over time. To a certain extent the former viewpoint is associated with the minority position that aging is a genetic program of deterioration while the latter viewpoint is associated with the majority position that aging is caused by an accumulation of cellular and molecular damage.
That sweeping generalization obscures a lot of important subtlety, however. The evolution of aging is a fairly dynamic field of theory, and probably won't settle down until the progression of aging from young to old in individuals is cataloged and understood to a far greater level of detail than is presently the case. That will probably post-date the first rejuvenation treatments, however, as that full understanding isn't necessary in order to construct treatments that repair age-related damage. Or at least it is not necessary provided that aging is caused by damage, as I think to be the case, rather than being a very complicated program of genetic changes that cause damage. If aging is a genetic program, then we are in for a very long and expensive road to any meaningful extension of healthy life.
I ran across an open access paper today that presents a novel view of the evolution of aging, one with a focus on our microbial fellow travelers. It is clear that gut bacteria have a modest degree of influence on aging, but is this large enough for microbial populations to be significant in the evolution of aging? This paper takes more of a programmed aging position in arguing that microbial species that help to wear down and kill the host in later life - that promote faster aging through mechanisms such as chronic inflammation, in other words - are selected for because of this outcome, and not just due to an ability to provide benefits in early life.
Does any of this theorizing matter in a practical sense? Yes in the long term: evolution has proven to be a powerful tool in many fields of medicine. Yes for researchers working on understanding the detailed progression of aging. No if we are focused on repair of the cellular and molecular damage that causes aging, as this repair approach enables us to sidestep a full understanding of how aging progresses. The research community has a robust list of the differences between old and young tissues, so we should be working now to fix them all regardless of how they come about or what exactly their role might be or why they evolved in the first place. Still, this is an interesting enough paper and point of view for me to point it out, and you can probably see why the title caught my eye:
Host Demise as a Beneficial Function of Indigenous Microbiota in Human Hosts
The age structure of human populations is exceptional among animal species. Unlike with most species, human juvenility is extremely extended, and death is not coincident with the end of the reproductive period. We examine the age structure of early humans with models that reveal an extraordinary balance of human fertility and mortality. We hypothesize that the age structure of early humans was maintained by mechanisms incorporating the programmed death of senescent individuals, including by means of interactions with their indigenous microorganisms.
First, before and during reproductive life, there was selection for microbes that preserve host function through regulation of energy homeostasis, promotion of fecundity, and defense against competing high-grade pathogens. Second, we hypothesize that after reproductive life, there was selection for organisms that contribute to host demise. While deleterious to the individual, the presence of such interplay may be salutary for the overall host population in terms of resource utilization, resistance to periodic diminutions in the food supply, and epidemics due to high-grade pathogens.
We provide deterministic mathematical models based on age-structured populations that illustrate the dynamics of such relationships and explore the relevant parameter values within which population viability is maintained. We argue that the age structure of early humans was robust in its balance of the juvenile, reproductive-age, and senescent classes. We hypothesize that the human microbiome evolved mechanisms specific to the mortality of senescent individuals among early humans because their mortality contributed to the stability of the general population. The hypothesis that we present provides new bases for modern medical problems, such as inflammation-induced neoplasia and degenerative diseases of the elderly. We postulate that these mechanisms evolved because they contributed to the stability of early human populations, but their legacy is now a burden on human longevity in the changed modern world.
A MALFUNCTION OF HOMEOSTATIC CONTROL THEORY OF AGING
There are many theories of aging, and we should expect more of them arise in the years ahead. On the one hand there is a growing interest in the science of aging as a place where careers can be made and on the other hand there is a great gulf of missing knowledge when it comes to a full and detailed catalog of exactly how aging actually progresses at the very detailed level of cells and cellular mechanisms. That is very much the type of environment that will lead to more theorizing. The research community has a very defensible list of fundamental differences between old and young tissues, changes that result directly from the ordinary operation of metabolism. There is, however, endless debate over which of these forms of damage are important, how they interact, and how they cause other changes and dysfunction. There is even a higher level debate over whether accumulated damage is in fact the cause of aging, or whether damages instead results from the operation of an epigenetic program that is itself the root cause of aging.
Mountains of data are being gathered on an ongoing basis to feed into this mill. As a process that is actually fairly typical for modern fields wherein the researchers study very complex systems but are collectively nowhere near attaining a full understanding of those systems. We live in an age in which obtaining and managing data in massive volumes is now feasible, and the all too human researchers are often playing catch up in the analysis. So there is a lot of back and forth, many conflicting study results, and everyone of note has their own pet hypotheses when it comes to poorly understood areas of the field. Aging research is far from the only area of scientific study that looks this way at present, and this is how science is done at the cutting edge.
As an aside, the primary and most important conceptual innovation contained in the Strategies for Engineered Negligible Senescence (SENS) is to note that since there exists a defensible list of fundamental differences between old and young tissues, we can skip the full understanding that will likely require decades further to arrive and use that list to work directly on repair biotechnologies now. The majority of the as yet unknown details of how and why simply don't matter all that much from a practical engineering perspective of producing rejuvenation treatments. In this, SENS is firmly in the aging as damage accumulation camp.
Over at the Russian end of the research community there tends to be more support for programmed aging theories. In their most common manifestation these theories suggest that aging is driven by epigenetic changes, and evolutionary processes select for aging to exist in this form. This might be because specific mechanisms are beneficial in youth and are thus selected for despite the fact that they run awry after reproductive life span is ended, a concept known as antagonist pleiotropy. It may be because aging allows for more successful adaptation of the species in the face of environmental change. There are many other evolutionary theories of aging, and there is some overlap between those used to explain programmed aging versus those used to explain aging as an accumulation of damage. The evolutionary explanations for aging are "why" and the mechanisms by which we age are "how", and those two questions can be considered separately from one another.
Just as there is a lot of debate among researchers who see aging as damage accumulation, there is similarly a lot of debate among researchers who theorize on programmed aging. This is an interesting if fairly dense paper from Russian researchers. If I'm reading it correctly, they are suggesting that aging is caused by a drift of set points in the biological mechanisms collectively responsible for maintaining homeostasis, keeping everything roughly the same and in place throughout an organism. That seems to me a layer of explanation on top of the more general idea that epigenetic changes happen in aging and they are the fundamental cause of damage rather than being responses to damage, though the researchers here declare their theory a third way, neither programmed nor damage-based:
Aging Is a Simple Deprivation Syndrome Driven by a Quasi-programmed Preventable and Reversible Drift of Control System Set Points Due to Inappropriate Organism - Environment Interaction
There are two well-known but opposing concepts of the reason for aging. The first supposes that senescence is programmed similarly to the genetic program of development from a zygote up to a mature organism. Genetically determined senile wasting is thought to be associated with the necessity to renovate the population to ensure its adaptation and survival. According to the concept of the stochastic aging (due to accumulation of occasional error and damage), there is no built-in program of aging. There is only a program of development up to the state of maturity, and then the organism should be able to maintain itself limitlessly. However, although the efficiency of repair systems is assumed to be rather high, it is less than 100%. Just this has to result in aging because of accumulation of various errors.
We have continued and developed another approach that considers both programmed and stochastic concepts to be incorrect. Aging is a simple deprivation syndrome driven by preventable and even reversible drifts of control systems set points because of an inappropriate "organism-environment" interaction.
Reading the whole thing, which isn't long enough to fully outline the thinking here, it seems pretty easy to pick holes in this. But the core idea of a set point drift is an interesting one in the context of present debates over the details of aging. That said it is probably not very relevant to the type of research strategy that I support. Fix the damage first, move as rapidly as possible towards saving lives, and then figure out how young turns to old in as much detail as you like - you'll have the time for it.
MEETING IN THE MIDDLE BETWEEN AGING AS A GENETIC PROGRAM AND AGING AS ACCUMULATED DAMAGE
As noted in a prior post, a great deal of theorizing on aging takes place in the research community. We should expect this as the natural outcome of the study of a very complex and still only partially understood system, which is to say the operation of biology and how that changes over time in any given individual, how it differs between species, and why near universal processes such as aging or the calorie restriction response exist. It is a vast field of study into which scientists have made some inroads: the mountains of data and toil of thousands of researchers today is but the foothills of what is to come in the decades ahead. Coming to a full accounting of our biochemistry is the Great Work for this century, but fortunately we could choose to strike out directly for rejuvenation treatments without needing that complete understanding of aging at a detailed level. As outlined by the SENS research proposals, the scientific community does in fact have a well defined and defensible list of the fundamental forms of damage that cause aging, and can envisage in some detail the therapies needed to repair them - and thus reverse the course of aging. All that needs to happen is for more funding and attention to be directed to that path, away from the natural scientific inclination to dismiss applications of their work and focus instead on completing the grand catalog of metabolism and aging, the aforementioned Great Work.
There is some debate in the aging research community over whether cellular and molecular damage is in fact the root cause of aging, essentially a complex form of wear and tear by stages in a self-repairing system of many interacting parts, or whether damage accumulates with age because of the operation of an evolved genetic program. The former is very much the majority position, and baked into the repair approach to rejuvenation, but the latter is a large enough minority to be generating all sorts of internal schisms and hybrid theories in and of itself. This ties back into ongoing investigations into why aging evolved at all, which has become an especially interesting question over time given the growing list of species wherein individuals do not seem to deteriorate with age as we do, even though they fail at the end, such as naked mole-rats, and a very few species whose members might not age to death at all, such as hydras.
This very readable paper from the Russian research community, where programmed aging theories are much more popular than is the case in the English speaking world, meanders through a range of topics with no particular central thesis: what is known of naked mole-rats and their peculiarly age- and cancer-resistant biology; reconciling differences between scientific factions favoring programmed aging versus aging as damage accumulation; thoughts on how aging may accelerate evolutionary change and thus be beneficial for species survival; oxidative mechanisms in aging; and more. It is all interesting, and much of it still relevant insofar as it considers data on biological mechanisms rather than their causes, a useful insight into the thinking of the programmed aging side of the research community. A few snippets are quoted below:
Review: New Data on Programmed Aging - Slow Phenoptosis
The concept of aging as a special biological program provides an alternative to the hypothesis of random errors. According to this concept, aging is a particular case of the phenomenon of programmed death of an organism, phenoptosis. Aging is assumed to accelerate evolution since over the years the organism weakened by aging is subjected to increasing pressure of natural selection. For example, a fox is hardly a factor of natural selection for young hares, which run much faster than the predator. As noted by Aesop, a hare will always run away from the fox because for the hare it is a matter of life and death, and for the fox - of a dinner. However, age-related sarcopenia reduces the hare's running speed, so the fox gets a chance to win the race. As sarcopenia is one of the early signs of aging in mammals, developing well before senile infertility, foxes could accelerate the evolution of hares by eliminating the slowest and least clever individuals.
The biological literature contains many examples of phenoptosis enhancing the organism's ability to evolve (their "evolvability"). Along with aging, they include different mechanisms providing, on one hand, increase in offspring diversity (which is beneficial for the search for new properties) and, on the other hand, the conservatism of inheriting of already acquired useful traits. These mechanisms, while being undoubtedly useful for evolution, are often counterproductive for the individual, as in the case of aging.
The great physicist Leo Szilard believed the reduction of tissue and organ cellularity to be the main cause of aging. According to Szilard, the problem of aging is not so much connected to the fact that each of our cells works worse, but that the number of these cells dramatically decreases with time. Senile sarcopenia, i.e. the reduction of the number of cells (myofibrils) in skeletal muscles, is a typical example of this phenomenon. Age-related weakening of the quality control could save many cells that otherwise would have been destroyed and thus would have exacerbated the reduction of cellularity. Accumulation of cells with random errors in DNA and proteins in the tissues of aging organisms would be a side effect of such a strategy. Gradual weakening of quality control, resulting in the accumulation of errors, is indeed observed in the course of aging; it serves as the main argument for the supporters of aging as the result of random damage. However, we should not forget that reduction of cellularity is likely to have been originally programmed in the genome as the final stage of ontogenesis. Thus, we come to the situation when aging, having begun as the result of the relevant program, is gradually turning into the process of accumulation of random (stochastic) damage to biopolymers, which remain unnoticed by the weakened systems of quality control of these polymers.
It is clearly the case that a few species have evolved death programs of one sort or another, such as a sudden collapse of tissue maintenance or organ function. Salmon are probably the most familiar example, but they are not the only species to decline and die very rapidly following reproductive efforts. The debate between research factions is not over whether these programs exist at all in the natural world, but whether they are usual, and more specifically whether aging in humans and other higher mammals is guided by programs or not. This is relevant to research strategies because efforts to produce rejuvenation should be targeted at primary causes, not secondary and later manifestations of aging.
THERE IS STILL NOT ENOUGH USE OF RESEARCH PRIZES IN MEDICINE
Establishing a research prize is a form of investment in progress only available in the philanthropic world. At the very high level it is easy to say that philanthropists pay people to work on specific tasks. This is simple enough for smaller amounts: transfer a few thousand dollars to a research group and you have bought a very small slice of the time and equipment needed to achieve any particular goal. When we start talking about much larger amounts of money, millions or tens of millions, then there are important secondary effects that occur when making such investments. In these amounts money has gravity, money makes people talk, and money changes behavior and expectations in a far larger demographic than just the recipients. This is well known, and thus investment activities, philanthropic and otherwise, become structured to best take advantage of this halo of effects. Most of the experience in doing this comes from the for-profit world: it doesn't take too long spent following the venture capital industry to see that investment is a lot more complicated than choosing a target and writing a check, and this is exactly because there are many secondary effects of a large investment that can be structured and harvested if investors go about it in the right way.
I theorize that the reason why research prizes remain comparatively rare is that firstly they are an investment strategy restricted to philanthropy, and thus people with the money to burn have little direct experience, and secondly the whole point of the exercise is not in fact paying people to do things directly, but rather creating a situation in which near all of the benefit is realized through the secondary effects generated by the highly publicized existence of a large sum of money. A research prize works by being a sort of extended publicity drive and networking event conducted over a span of years, a beacon to draw attention to teams laboring in obscurity, attract new teams, and raise their odds of obtaining funding. Connections are made and newly invigorated initiatives run beneath the light of a large sum of prize money, but at the end of the day that money becomes more or less irrelevant. It wasn't the important thing, it was merely the ignition point for a much greater blaze of investment and publicity. By the time a team wins, they are typically in a position to raise far more funding than the prize amount provides.
The ideal end result is that a field of science and technology is rejuvenated, taken from obscurity and thrust into the public eye, made attractive to investors, and numerous groups are given the attention and funding they need to carry on independently. This is how it worked for the Ansari X Prize for suborbital flight, and more quietly, for the Mprize for longevity science: in both cases the entire field changed as a result of the existence of the prize and the efforts of the prize organization to draw attention, change minds, and build new networks. But the award of money wasn't the transformative act, and in fact that award didn't really occur at all for the Mprize, but rather change was created through the sum of all of the surrounding effects.
So consider this: people who arrive at the state of being wealthy and wanting to change the world through philanthropy, often after decades of for-profit investment participation, don't have much in the way of comparable experience to guide them in the establishment and operation of research prizes. Thus creation of a research prize falls low in the list of strategies under consideration by high net worth philanthropists. Few people do it, and so there are few examples from which others can learn. It is the standard vicious circle of development, in which steady, grinding bootstrapping is the only way to create change.
Why care? Because research prizes work well. They work exceedingly well. Depending on how you care to plug numbers into equations, a well-run prize of at least a few million will generate 15 to 50 times as large an amount in varied investments in an industry, and that is just the easily measured result. Just as important is the following change and growth enabled by that initial burst of attention and funding. The Ansari X Prize spawned a number of other prizes in various industries, but I think it remains the case that medicine and biotechnology is poorly served in this respect. Outside of the efforts of the X Prize Foundation, the New Organ prizes, and other independent efforts such as the Palo Alto Longevity Prize, there is little going on. Given the proven utility of prizes there should be many more of them, and yet there are not.
In this context it is interesting to see the X Prize Foundation promoting the prize approach to a scientific audience, one of the demographics that should be more hospitable to prizes and participation in these efforts than is in fact the case.
Some inventors and innovators find themselves in a difficult spot, having advanced products beyond basic research - so that they do not usually qualify for government funding - but not near enough to commercialization to appeal to venture capitalists. To avoid this mid-stage "Valley of Death," life-science and technology innovators are spending more of their time searching for new funding sources. The Internet, with its reach and speed powered by social networking, provides a platform for crowdfunding, an area that is expected to grow over the next 10 years. Contributions from angel investors - typically well-connected, wealthy individuals who invest their own money - and incubator sources have doubled since 2007 in the U.S. and increased more than fivefold in Europe. However, these sources have high aversion to risk. There is another way to fill the funding void left by shrinking government budgets and tightening investor belts: incentivized competitions, which can catalyze innovations and accelerate their real-world impact.
At XPRIZE, formed in 1995, we create and foster high-profile competitions that motivate individuals, companies, and organizations across disciplines to develop innovative ideas and technologies to solve humanity's "Grand Challenges." Two of our prize competitions are specifically focused on medical technology. The XPRIZE model is different from that of governments, venture capitalists, or private investors. Our goal is to identify a health-care problem, define what needs to be addressed, and incentivize the development of a solution. There is often a commercial outcome, allowing the developers to get a return on their investment and provide a benefit to the general public. We are trying to focus on areas that are practical and that serve an existing market or will ultimately create a market that does not yet exist. In so doing, we provide an economic incentive for companies to redirect existing technologies towards new and relevant commercial opportunities. At the same time, we help innovators garner attention from investors and attract capital, support, and team members by creating consumer awareness and providing the general public with an early glimpse of performance. We are also able to connect teams with potential funding and sponsorship opportunities through various networking activities. And the evaluation of the products themselves allows for the assessment of competing technologies in a way that would be unlikely to happen until a product actually went to market.
In short, XPRIZE and other incentivized competitions are objective, unaffiliated, third-party catalysts for innovation, creating a channel for science and technology development in between early-stage work funded by the government and late-stage worked picked up by investors. By focusing on major needs in health that have not been met and incentivizing solutions with real commercial potential for delivery in the next three to five years, we can accelerate the pace of health-care improvements.
LATEST HEADLINES FROM FIGHT AGING!
PRELIMINARY EVIDENCE SUGGESTING LONG TERM MEMORY IS NOT STORED IN SYNAPSES
Monday, December 22, 2014
Long-term memory is thought to exist as structures within synapses, which is why the destruction of synapses in the earlier stages of neurodegenerative conditions such as Alzheimer's disease causes memory loss. If memory doesn't exist in the synapses, however, then there is more of a possibility of restoration through effective treatments for the condition. At this point models of long-term memory that put the data somewhere other than the synaptic connections between neurons has an uphill road to travel: past years have seen the accumulation of good evidence for synaptic memory storage, such as experiments in which memory in rats is erased and restored. Nonetheless, this is interesting work:
The new study provides evidence contradicting the idea that long-term memory is stored at synapses. "Long-term memory is not stored at the synapse. That's a radical idea, but that's where the evidence leads. The nervous system appears to be able to regenerate lost synaptic connections. If you can restore the synaptic connections, the memory will come back. It won't be easy, but I believe it's possible."
"If you train an animal on a task, inhibit its ability to produce proteins immediately after training, and then test it 24 hours later, the animal doesn't remember the training. However, if you train an animal, wait 24 hours, and then inject a protein synthesis inhibitor in its brain, the animal shows perfectly good memory 24 hours later. In other words, once memories are formed, if you temporarily disrupt protein synthesis, it doesn't affect long-term memory."
The scientists added serotonin to a Petri dish containing a sensory neuron and motor neuron, waited 24 hours, and then added another brief pulse of serotonin - which served to remind the neurons of the original training - and immediately afterward add the protein synthesis inhibitor. This time, they found that synaptic growth and memory were erased. When they re-counted the synapses, they found that the number had reset to the number before the training. This suggests that the "reminder" pulse of serotonin triggered a new round of memory consolidation, and that inhibiting protein synthesis during this "reconsolidation" erased the memory in the neurons.
If the prevailing wisdom were true - that memories are stored in the synapses - the researchers should have found that the lost synapses were the same ones that had grown in response to the serotonin. But that's not what happened: Instead, they found that some of the new synapses were still present and some were gone, and that some of the original ones were gone, too. There was no obvious pattern to which synapses stayed and which disappeared, which implied that memory is not stored in synapses.
A REVIEW OF THE ENDOCRINOLOGY OF AGING
Monday, December 22, 2014
Here is an open access review of what is known of changes in the endocrine system that occur with aging. This is many steps removed from the low-level cellular and molecular damage that causes degenerative aging. It is a good example of a body-wide set of linkages between organs and signals and processes in which every change or failure in one component part will cause corresponding reactions in all of the other components.
A sizable field of medicine continues to focus on these changes, trying to find ways to shift levels of hormone signals to be closer to measures taken in youth. In past decades this has produced some legitimate treatments for a variety of age-related conditions that are better than nothing, but unfortunately also a fraudulent network of false "anti-aging" claims and purported therapies that cloud the waters and make any online discussion of this topic difficult. Where legitimate, as an approach it is acting at the wrong level, chasing after secondary and later effects in a very complex system rather than addressing the root causes of changing hormone levels. Consequently it has been challenging to produce more than marginal benefits, which is much as you'd expect if you're trying to tinker a broken system into better performance without actually fixing the breakage. Still, here as elsewhere, there is enormous inertia and resistance to the new concepts of addressing root causes rather than messing with metabolism in this way, and researchers continue to work on ever more sophisticated ways of trying to make the broken machinery perform:
Despite the contribution of sustained improvements in health and social wellbeing to linear gains in life expectancy within the developed world, much of older age is impaired by detrimental changes in body composition and function. Complex alterations in hormonal networks which maintain homeostasis and regulate reproduction, metabolism, nutrition and growth may underlie this poor adaptation to later life. The secretion of hormones decreases within most axes, the impact of which is augmented by a reduction in the sensitivity of tissues to their action, and normal circadian rhythms are lost. Endocrine axes manifest these changes with clinically identifiable losses of function such as those seen in the ageing of the reproductive system (menopause and andropause), the growth axis (somatopause) and axes involving the adrenal gland (adrenopause).
The clinical sequelae of these changes are variable but include reductions in bone, skin and skeletal muscle mass and strength, derangement of insulin signalling, increases in adipose tissue and effects on immune function. Consequently, a number of studies have been carried out to assess the benefits of hormonal supplementation in the elderly, but the efficacy of these interventions remains relatively unclear. Both the menopause and subclinical thyroid disease demonstrate the difficulty in reversing endocrine changes in later life, with minimal impact from thyroxine therapy in subclinical hypothyroidism and multiple reports of harm resulting from hormone replacement therapy in peri- and post-menopausal women.
Given these findings, strategies to locally regulate hormone bioavailability by altering pre-receptor metabolism may offer greater therapeutic potential in the fight against age-related disease. This review aims to provide an overview of the ageing endocrine system and its potential impact on health and disease in the elderly. It will postulate that strategies to coordinate pre-receptor hormone metabolism and a greater understanding of putative hormonal longevity pathways may offer key new drug targets in the fight against ageing, and will argue against applying the conventional endocrine maxim of 'block and replace' to hormonal changes seen during ageing.
UPDATES ON THE BIODEMOGRAPHY OF AGING AND LONGEVITY
Tuesday, December 23, 2014
This is a review of published research in the biodemography of aging produced by one particular group over the past few years. A lot of their work sits within the framework of reliability theory, which is a fairly high-level but useful model of damage and failure in complex systems. When applied to demographic data on aging reliability theory can produce some interesting predictions, notably that we are all born with an initial load of damage - we don't start from a blank slate. This feeds into observations such as those below on statistical differences in longevity correlating with parental age:
Biodemography is a promising scientific approach based on using demographic data and methods for getting insights into biological mechanisms of observed processes. Recently, new important developments have happened in biodemographic studies of aging and longevity that call into question conventional aging theories and open up novel research directions. Recent studies found that the exponential increase of the mortality risk with age (the famous Gompertz law) continues even at extreme old ages in humans, rats, and mice, thus challenging traditional views about old-age mortality deceleration, mortality leveling-off, and late-life mortality plateaus. This new finding represents a challenge to many aging theories, including the evolutionary theory that explains senescence by a declining force of natural selection with age. Innovative ideas are needed to explain why exactly the same exponential pattern of mortality growth is observed not only at reproductive ages, but also at very-old postreproductive ages (up to 106 years), long after the force of natural selection becomes negligible (when there is no room for its further decline).
Another important recent development is the discovery of long-term 'memory' for early-life experiences in longevity determination. Siblings born to young mothers have significantly higher chances to live up to 100 years, and this new finding, confirmed by two independent research groups, calls for its explanation. As recent studies found, even the place and season of birth matter for human longevity. Beneficial longevity effects of young maternal age are observed only when children of the same parents are compared, while the maternal age effect often could not be detected in across-families studies, presumably being masked by between-family variation. It was also found that male gender of centenarian has a significant positive effect on the survival of adult male biological relatives (brothers and fathers) but not of female relatives. Finally, large gender differences are found in longevity determinants for males and females, suggesting a higher importance of occupation history for male centenarians as well as a higher importance of home environment history for female centenarians.
CELLULAR SENESCENCE IS COMPLICATED
Tuesday, December 23, 2014
Cellular senescence is a process that serves to reduce cancer risk by removing damaged cells from the cell cycle and irreversibly suppressing their ability to proliferate. Unfortunately it is also one of the root causes of degenerative aging, as when present in large numbers these cells cause significant damage to surrounding tissue structure and function. They don't go away either: by the time old age rolls around, a sizable fraction of skin cells are senescent, for example. Ideally these cells would be destroyed by the immune system, but that only happens for a fraction of them, and in any case the immune system itself progressively fails in all of its tasks due to the damage of aging.
As the tools of biotechnology rapidly become better and cheaper, researchers are discovering new complexities in every area of cellular metabolism, and senescence is no exception. Cells are exceedingly complicated machines. All of the consensus opinions on how senescence works might be thought of as high level generalities, but there are a lot of exceptions and new information. Senescence isn't as absolutely irreversible as thought; it plays a beneficial role in wound healing; it might steer embryonic development; there are a range of novel ways in which cells can enter a senescent state; and so forth.
Fortunately it is possible to short-cut all of this complexity and skip directly to destroying senescent cells. We know they are bad for us in volume regardless of how exactly they are coming into being, and thus the research community should aim at selective removal of these cells, producing a therapy for periodic application that is perhaps based on some of the work on targeting cell types taking place in the cancer research establishment. Say once a decade, since we know that humans can certainly live for at least three decades without significant impact from cellular senescence. Sadly the direct approach is poorly funded in comparison to ongoing investigations of senescence in detail, but this is par for the course in everything that might actually have some meaningful impact on aging. This must change. Meanwhile here is another research paper uncovering yet more of the complexity of cellular senescence:
Many cells within our bodies, including fibroblasts, hepatocytes, lymphocytes, stem cells and germ cells, are in the state of quiescence, defined as a reversible cell cycle arrest with temporary absence of proliferation. Quiescence is not a passive default state, but instead is actively maintained by specific molecular mechanisms. Some of these cells maintain a quiescent state for long periods of time, even years, and quiescent cells are defined to retain the ability to return into the cell cycle. In vivo, quiescence is considered to limit the uncontrolled proliferation of cells, especially stem cells, whose proliferation has to be controlled properly in order to maintain tissue function.
In order to be reversible, quiescence must grant the return into the cell cycle. Consequently, quiescent cells repress transition into terminal differentiation in which cell cycle arrest is irreversible. However, when transition into irreversible cell cycle arrest is suppressed, reversible non-dividing quiescent cells are less protected against cancer development and are subject to tumor development. While short-term quiescent cells were described to be protected against transition into senescence, long-term quiescent cells may protect themselves against malignant transformation by implementing a senescence-associated cell cycle arrest over longer periods of time. Indeed, most of a human foetal skin fibroblast cell population while being long-term quiescent, were observed to transit into senescence. It remains to be shown to what extent these findings, observed for cultured cells, also hold for cells in tissue.
Telomere shortening as a basic concept for aging assumes that each successive cell division acts as a mitotic counting mechanism inducing replicative senescence. According to this concept, induction of quiescence for a defined amount of time would be predicted to prolong the lifespan of fibroblasts in comparison to constantly proliferating cells. In contrast to this prediction, after long-term quiescence primary human foreskin fibroblasts (HFF) were observed to transit into senescence despite of negligible telomere shortening, questioning that cell division and telomeric attrition is necessarily required for senescence. Here we detect that during long-term quiescence also other human fibroblasts enter senescence. Thus, other effects than telomere shortening, like oxidative stress induced DNA damage, may be responsible for this transition. This is supported by the fact that mouse fibroblasts senesce in culture although mice have very long telomeres.
A ROLE FOR HYDROGEN SULFIDE IN CALORIE RESTRICTION
Wednesday, December 24, 2014
A great deal of effort over the past fifteen years has gone into efforts to fully understand how calorie restriction works to improve health and extend life. The research community would like to have sufficient knowledge to produce drugs that mimic this effect. At this point what researchers have is still a sketch, however: near everything in the operation of metabolism changes in response to reduced calorie intake, which has made it very challenging to figure out cause and effect. Meanwhile, new aspects of calorie restriction biochemistry are discovered on a regular basis these days, with no signs of an end in sight. Researchers here find that one of the benefits provided by calorie restriction is not, as thought, due to increased cellular antioxidant responses, but instead involves hydrogen sulfide (H2S) in some yet to be identified way:
Dietary restriction is a type of intervention that can include reduced overall food intake, decreased consumption of particular macronutrients such as protein, or intermittent bouts of fasting. It is known to have beneficial health effects, including protection from tissue injury and improved metabolism. It has also been shown to extend the lifespan of multiple model organisms, ranging from yeast to primates. The molecular explanations for these effects are not completely understood, but were thought to require protective antioxidant responses activated by the mild oxidative stress caused by dietary restriction itself.
[Researchers] demonstrated that one week of dietary restriction increased antioxidant responses and protected mice from liver ischemia reperfusion injury, but surprisingly, this protective effect was intact even in animals that could not mount such an antioxidant response. Instead, the researchers found that the protection required increased production of H2S, which occurred upon reduction of dietary intake of the two sulfur-containing amino acids, methionine and cysteine. When the diet was supplemented with these two amino acids, increased H2S production and dietary restriction benefits were both lost. The investigators also found that genes involved in H2S production were also required for longevity benefits of dietary restriction in other organisms, including yeast, worms, and flies.
Mammalian cells [produce] low levels of H2S, but this is the first time that this molecule has been linked directly to the health benefits of dietary restriction. "This finding suggests that H2S is one of the key molecules responsible for the benefits of dietary restriction in mammals and lower organisms as well. While more experiments are required to understand how H2S exerts its beneficial effects, it does give us a new perspective on which molecular players to target therapeutically in our efforts to combat human disease and aging."
HAIR REGROWTH AS A POINTER TO THE ROLE OF IMMUNE SYSTEM ACTIVITY IN TISSUE REGENERATION
Wednesday, December 24, 2014
The immune system is known to play an important role in regeneration, but the details are still being uncovered. Nonetheless at some point in the near future manipulation of immune cells may prove to be a viable alternative path in regenerative medicine, a different way to achieve faster healing or spur tissue regrowth where it does not normally occur.
Cells from the immune system called macrophages - those in charge of devouring invading pathogens, for example - are also responsible for activating skin stem cells and induce hair growth. The researchers did not investigate the relationship between macrophages and hair for fun. This work emerged more than four years ago from an observation [made] while working on another research project. The mice [at] that time received anti-inflammatory drugs, a treatment that also reactivated hair growth. Convinced that the explanation could reside in the existence of close communication between stem cells and immune cells [the researchers] began to experiment with the different types of cells involved in the body's defense system.
After years of investigation, they discovered that when stem cells are dormant, a fraction of macrophages die, due to a process known as apoptosis. This stimulated the secretion of factors from dying and living macrophages, which in turn activated stem cells, and that is when hairs began to grow again. Macrophages secrete a number of factors including a class of proteins called Wnt. Researchers demonstrated the participation of macrophage-derived Wnts by artificially reproducing the natural process by treating macrophages with a Wnt inhibitor drug encapsulated in liposomes. As expected, when they used this drug, the activation of hair growth was delayed.
From a more fundamental perspective, this research is an effort to understand how modifying the environment that surrounds adult skin stem cells can regulate their regenerative capabilities. "One of the current challenges in the stem cell field is to regulate the activation of endogenous stem cell pools in adult tissues to promote regeneration without the need of transplantation."
TOWARDS A SIGNATURE OF AGE IN BLOOD PLASMA
Thursday, December 25, 2014
Various tools are presently under development as means to measure age from tissue samples, such as by looking at DNA methylation patterns. A marker for biological age is very much needed in order to speed up development of treatments for aging, as it is presently very expensive and time-consuming to evaluate any sort of putative longevity-enhancing therapy. This is true even in rodents, where it can cost millions of dollars and take three to five years to run a single life span study - and the costs only grow for longer-lived mammals. If much of that could be replaced by a short test carried out immediately before and after treatment then research could proceed much more rapidly. Here is one example of work that might lead to such a marker for age:
Metabolomic and glycomics analysis of blood samples have successfully been used to identify key molecular mechanisms underlying human health and aging. Additional molecular signatures of health and aging can be found using high-throughput proteomics. However, due to the high cost, this has been relatively understudied. Recently, three studies on aging using high-throughput proteomics identified proteins whose plasma levels and cerebrospinal fluid (CSF) levels substantially change with increasing age. However, these studies either did not apply a correction for multiple testing or did not validate their findings in independent cohorts. Proteomics profiling in the CSF study was obtained using SOMAscan, a Slow Off-rate Modified Aptamer (SOMAmer)-based capture array. SOMAscan involves the use of SOMAmers (single-stranded DNA aptamers) to assay proteins in multiplex using DNA microarrays. As such, SOMAscan quantifies the level of the subproteome of proteins targeted by SOMAmers. A total of 1,129 of these SOMAmers are currently available.
The SOMAscan approach has previously been used by us and others to study plasma proteins related to Alzheimer and related phenotypes. In this study, we use the SOMAscan approach to assess the extent to which proteins are correlated with chronological age in a cohort of female twins with independent replication. We further investigate gene expression levels for those proteins that correlate with age using RNAseq data from whole blood in twins. Finally, we examine the association of specific proteins with factors relating to biologic aging such as birthweight and cardiovascular risk.
Eleven proteins were associated with chronological age and were replicated at protein level in an independent population. These were further investigated at gene expression level in 384 females from the TwinsUK cohort. The two most strongly associated proteins were chordin-like protein 1 and pleiotrophin. Chordin-like protein 1 was also significantly correlated with birthweight and with the individual Framingham 10-years cardiovascular risk scores in TwinsUK. Pleiotrophin is a secreted growth factor with a plethora of functions in multiple tissues and known to be a marker for cardiovascular risk and osteoporosis. Our study highlights the importance of proteomics to identify some molecular mechanisms involved in human health and aging.
FALLING MITOCHONDRIAL DNA COPY NUMBER IN TYPE 2 DIABETES
Thursday, December 25, 2014
A herd of bacteria-like mitochondria exist in every cell in the body, constantly dividing, fusing, and swapping component parts among one another, as well as being destroyed when damaged by cellular quality control mechanisms. Mitochondria are responsible for a range of tasks vital to the cell, but the best known involves the creation of ATP chemical energy stores used to power cell operations. Each mitochondrion has at least one copy of the small set of mitochondrial DNA, separate from the DNA in the cell nucleus. As long term readers know damage to this mitochondrial DNA is implicated as one of the primary causes of degenerative aging, leading to a Rube Goldberg chain of consequences that in the end produces a small population of very dysfunctional cells that export damaging reactive molecules to harm tissues both near and far in the body.
Mitochondrial DNA doesn't just become more damaged with age, the number of distinct mitochondrial genomes in a cell - called the copy number - falls dramatically in all cells in many tissues. This has no straightforward or well-understood relationship with mitochondrial damage: it isn't just the dysfunctional cells that have lower copy numbers, and higher copy numbers may be a response to damaged DNA. Falling copy number doesn't linearly correlate with number of mitochondria or the mitochondrial output in term of necessary energy stores for cellular processes, but it does seem to have a significant impact. As an example, researchers here suggest that reduced mitochondrial copy number and its effects on function are a proximate cause for lost insulin production in type 2 diabetes:
Type 2 diabetes is characterised by an age-related decline in insulin secretion. We previously identified a 50% age-related decline in mitochondrial DNA (mtDNA) copy number in isolated human islets. The purpose of this study was to mimic this degree of mtDNA depletion in MIN6 cells to determine whether there is a direct impact on insulin secretion. Transcriptional silencing of mitochondrial transcription factor A, TFAM, decreased mtDNA levels by 40% in MIN6 cells. This level of mtDNA depletion significantly decreased mtDNA gene transcription and translation, resulting in reduced mitochondrial respiratory capacity and ATP production. Glucose-stimulated insulin secretion was impaired following partial mtDNA depletion, but was normalised following treatment with glibenclamide.
This confirms that the deficit in the insulin secretory pathway precedes K+ channel closure, indicating that the impact of mtDNA depletion is at the level of mitochondrial respiration. In conclusion, partial mtDNA depletion to a degree comparable to that seen in aged human islets impaired mitochondrial function and directly decreased insulin secretion. Using our model of partial mtDNA depletion following targeted gene silencing of TFAM, we have managed to mimic the degree of mtDNA depletion observed in aged human islets, and have shown how this correlates with impaired insulin secretion. We therefore predict that the age-related mtDNA depletion in human islets is not simply a biomarker of the aging process, but will contribute to the age-related risk of type 2 diabetes.
ARE ADVANCED GLYCATION END-PRODUCTS PROTECTIVE AS WELL AS HARMFUL?
Friday, December 26, 2014
Some of the important processes in aging are known to be initially protective at lower levels and later harmful. Senescent cell accumulation is a good example, as it acts to suppress cancer incidence by permanently removing the most at risk cells from the cell cycle. Yet as senescent cells gather in numbers over the years their actions significantly degrade tissue and organ function.
In the paper quoted below researchers propose that the formation of advanced glycation end-products (AGEs) has a similar protective effect when it comes to cancer, and provide some other benefits besides. Yet their presence is definitely harmful in a number of ways when significant amounts of long-lived AGEs are present, causing chronic inflammation and degrading the mechanical properties of tissues such as skin and blood vessel walls by forming cross-links between structural proteins.
Fortunately in both of these cases periodic removal - of senescent cells or AGE cross-links - on a timescale of once every decade or so would allow us to have our cake and eat it. It would prevent pathological levels of these changes from emerging, as we know humans are quite capable of living for three decades without suffering serious consequences from aging, while still permitting lower and possibly protective levels to arise.
Non-enzymatic formation of advanced glycation endproducts (AGEs) is associated with degenerative diseases. Chronic accumulation of AGEs with age in tissues especially in the extracellular matrix is well known and at least in part responsible for e.g., collagen crosslinking, tissue stiffening and thus induction of high blood pressure or diastolic heart failure. Binding of soluble AGEs to the receptor for AGEs, RAGE, induces an inflammatory response whereas the soluble form of RAGE (sRAGE) can inhibit inflammatory tissue injury like arteriosclerosis in mouse models.
However, there are a number of indications that AGEs have protective effects as well. AGEs may inhibit lung tumor growth, glyoxal induced AGE modification of human heart muscle can reduce an ischemia reperfusion injury and AGEs from nutrition can reduce ROS induced cell damage. In summary, this indicates that protein glycation behaves like a double-edged sword. It induces tissue aging and degenerative diseases on the one hand, on the other hand, may also have protective effects, indicating a hormetic response.
MITOCHONDRIAL DNA DAMAGE IN ATHEROSCLEROSIS
Friday, December 26, 2014
Mitochondria, the power plants of the cell, have their own small genomes left over from their ancient origins as symbiotic bacteria. This mitochondrial DNA (mtDNA) becomes damaged in ways that evade cellular quality control mechanisms as a consequence of the normal operation of metabolism. Over the course of a human life span this leads to a small population of cells overtaken by dysfunctional mitochondria, emitting a flood of damaging reactive molecules into surrounding tissues. This contribution to degenerative aging could be removed entirely if we had the means to regularly replace and remove these damaged mitochondrial genomes, or alternatively to deliver an ongoing supply of mitochondrial proteins - as DNA damage is only significant because it removes or alters the blueprints required to generate specific proteins. It is the proteins that are needed for correct mitochondrial function to continue. Given a major research and development initiative working prototypes of these repair technologies are actually only a few years away, but despite a number of teams working on these approaches at a slow pace, until much more funding is devoted to this cause that few years away will continue to be the case.
Here is a recent open access review of the mechanisms by which mitochondrial DNA damage is thought to promote the development of atherosclerosis, such as - but not limited to - formation of oxidized low-density lipoprotein (LDL) molecules that aggravate cells in blood vessel walls into an ultimately harmful reaction. They draw in immune cells that try to consume and break down the LDL, but these cells can be overwhelmed to turn into foam cells or die to create a clot of debris that can grow to become a plaque. That in turn can cause a catastrophic blockage of blood flow, and death:
Atherosclerosis, by far the greatest killer in modern society, is a complex disease which can be described as an excessive fibrofatty, proliferative, inflammatory response to damage to the artery wall involving several cell types. Clinical manifestations of atherosclerosis, i.e. mainly coronary artery disease and stroke, are the leading causes of death in all economically developed countries, accounting for up to 65% of total mortality. Many factors appear to contribute to the development of atherosclerosis, [however] the precise mechanisms of atherogenesis are still unclear, even if it is well known that the deposition of intracellular lipids, mainly free and esterified cholesterol, as well as subsequent foam cell formation are the most typical features of early atherosclerotic lesion development. Modified low-density lipoprotein (LDL) is generally thought to be the source of accumulating lipids. Intracellular lipid deposition may act as a trigger mechanism for the development of advanced atherosclerotic lesions.
The mechanisms of mitochondrial genome damage in the development of chronic age-related diseases such as atherosclerosis are not well understood. There is very little data yet showing a causal relationship between mtDNA damage and atherosclerosis, although mitochondrial oxidative stress has been shown to correlate with the progression of human atherosclerosis. Mutations of the mitochondrial genome may play a pathogenic role in the formation of atherosclerotic lesions in arteries. The mitochondrial electron transport chain constantly produces superoxide radical anions, which, in the case of mitochondrial dysfunction, cause the escape of electrons that readily form hydroxyl radicals and hydrogen peroxide from superoxide. These extremely reactive oxygen species (ROS) are risk factors for atherosclerosis associated with lipid and protein oxidation in the vascular wall. ROS formation may trigger a cascade of events such as modification of LDL, inflammation, cellular apoptosis and endothelial injury.