Fight Aging! Newsletter, August 10th 2015

August 10th 2015

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, 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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  • Cell Spreading and Mitochondrial DNA Deletions
  • Aubrey de Grey AMA Held at /r/futurology Today
  • Arguing that Public Reluctance to Treat Aging as a Medical Condition is at Root a Categorization Problem
  • Recent Research on Exercise and Aging
  • Centrosome Loss and Lack of Heart Regeneration in Mammals
  • Latest Headlines from Fight Aging!
    • Engineered Microbes as Programmable Medical Tools
    • Further Investigation of the Endoplasmic Reticulum in Aging
    • Age-Related Increase in Clearance Time for Amyloid Protein
    • Antagonistic Pleiotropy and Free Radicals in Skin Tissue
    • Manipulating TWEAK and CD163 to Spur Muscle Regeneration
    • Trialing Young Blood for Older People
    • Intermittent SASP Disruption as Cancer Adjuvant Treatment
    • A Review of the State of Heterochronic Parabiosis Research
    • A Demographic Model of a World with Negligible Senescence
    • Insight Into the Cause of Thymic Involution


Researchers here argue for decreased cell spreading in old skin to be a cause of higher levels of mitochondrial DNA deletions in longer-lived skin cells. Their methodology leaves open the possibility of other possible causes for the data they have gathered, however. I don't believe that they have convincingly demonstrated causality at this point. Nonetheless worth reading, I think.

Why is this interesting? Because mitochondrial DNA damage is strongly implicated as a contributing cause of degenerative aging, but there is considerable debate over how and why this damage occurs and accumulates with age. The SENS rejuvenation research viewpoint is to skip the debate over causes and just repair the damage and measure the benefits that result, but this is not a popular viewpoint in the scientific community, where most participants are aiming for complete understanding at some indefinite future date rather than the production of useful therapies as soon as possible. So we are going to see much more research in the future exploring this aspect of biochemistry.

Mitochondria are the power plants of the cell, each cell containing a swarm of hundreds of these descendants of symbiotic bacteria, each of which contains at least one copy of the remnant DNA left over from that of their ancestors. Evolution has moved much of this DNA to the cell nucleus, or it has atrophied, leaving just a small number of genes that are passed from mother to child. Mitochondrial populations are very dynamic, constantly dividing and fusing, passing chunks of protein machinery between one another, and culled by cell quality control mechanisms when damaged. Damage occurs to cellular machinery all the time, and near all of it is repaired. Mitochondrial DNA (mtDNA) deletions can be a real problem, however: DNA encodes for the proteins needed for correct function, and there is a way in which a mitochondrion with just the right type of damage can fall into a malfunctioning state that provides it an advantage in replication and resistance to quality control. When that happens the whole cell is quickly taken over by the descendants of that dysfunctional mitochondrion. The cell itself becomes broken, exporting harmful reactive molecules into surrounding tissues. A small but influential population of cells are in this state by the time old age rolls around, and they cause significant harm.

Why does this DNA damage happen? Some researchers believe it is due to the proximity of mitochondrial DNA to the energetic processes by which mitochondria produce chemical energy stores, coupled with comparatively poor DNA repair processes available in the mitochondria. Other researchers consider that the damage happens during mitochondrial replication, and other changes taking place in cells over the course of aging might explain a rising level of errors that occur during this replication. There are other theories - in biochemistry there are always other theories - and the one described in the following open access paper is one such.

Age-associated reduction of cell spreading induces mitochondrial DNA common deletion by oxidative stress in human skin dermal fibroblasts: implication for human skin connective tissue aging

In human skin, dermal fibroblasts are responsible for collagen homeostasis. Consequently, impaired dermal fibroblast function is a major contributing factor in human skin connective tissue aging. We previously reported that a prominent characteristic of dermal fibroblasts in aged skin is reduced spreading and contact with collagen fibrils, causing cells to lose their typical elongated spindle-like morphology and become shorter with a rounded and collapsed morphology. In young healthy skin, dermal fibroblasts attach to intact collagen fibrils and achieve normal cell spreading and shape. However, in aged dermis the collagen fibrils are fragmented, which impairs fibroblast-collagen interactions. These alterations impair fibroblast spreading and function. While cell shape is known to regulate many cellular functions, the molecular basis of their impact on dermal fibroblast function and skin connective tissue aging are not well understood.

Although dermal fibroblasts are the major cell type responsible for the maintenance of dermal connective tissue homeostasis, little is known about the role of mtDNA common deletion in aging dermal fibroblasts. Dermal fibroblasts have a very low proliferative rate which would allow for an accumulation of mtDNA deletion. Additionally, the relationship between age-related reduced cell spreading, which is a prominent feature of aged dermal fibroblasts, and mtDNA common deletion has been virtually unexplored. Based on this information, we explored the possible connection between age-related reduced cell spreading and mtDNA common deletion in the dermis of human skin. We found that mtDNA common deletion is significantly increased in both naturally aged and photoaged human skin dermis in vivo, and that reduced fibroblast spreading induces the increase in mtDNA common deletion through increased endogenous reactive oxygen species (ROS).

We modulated the shape of dermal fibroblasts by disrupting the actin cytoskeleton with latrunculin-A (Lat-A), which rapidly blocks actin polymerization. As expected, disruption of the actin cytoskeleton impaired fibroblast spreading and resulted in a rounded shape. Reduced cell spreading was associated with a significant elevation of mtDNA common deletion. As mitochondrial morphology is crucial for normal mitochondrial function, we assessed mitochondrial morphology. These data indicated that the gross shape of mitochondria was similar between Lat-A treated cells and control cells. It has been reported that cellular damage from reactive oxygen species (ROS) likely plays an important role in mtDNA deletions as well as in the aging process. We therefore examined the relative oxidant levels in fibroblasts using redox-sensitive fluorescent dye. Normal well-spreading fibroblasts displayed a very low level of oxidant-generated fluorescence. In contrast, reduced-spreading fibroblasts displayed intense oxidant-generated fluorescence.

We next investigated whether boosting cellular antioxidant capacity could protect against mtDNA common deletion associated with reduced cell spreading. We chose N-acetyl-cysteine (NAC), which is an antioxidant and metabolic precursor of glutathione. Reduced cell spreading increased mtDNA common deletion in a time-dependent manner, and that the increase was significantly prevented by NAC treatment. These results indicate that the deleterious effects of endogenous oxidative exposure are responsible, at least in part, for reduced-cell-spreading-associated mtDNA common deletion.

I have to think that the conclusion to be drawn here is that messing with the cell cytoskeleton is a bad thing, not that lack of cell spreading is a bad thing (though it probably is, just not demonstrated to be via this methodology). An item that immediately springs to mind is that progeria involves disruption of cytoskeletal structure in cells, and I'm sure people with more experience than I could come up with other off the cuff examples of cytoskeleton dysfunction producing cellular dysfunction. So here I'd want to see a replication of the mitochondrial DNA deletion data using another completely distinct methodology of preventing cell spreading before giving this too much consideration. It is easy to break things in biochemistry and produce results that look somewhat like aging, since breakage causes damage, and aging is an accumulation of damage. It is, however, hard to prove that any given artificial breakage is relevant to normal aging, and most are not.

To finish up for today I'll again make the point that the research community could skip this painstaking investigative work in order to focus on producing methods of repairing mitochondrial DNA damage, or delivering the proteins via another method, such as the allotopic expression technology funded by the SENS Research Foundation and presently under active development by Gensight. Fix the damage and see what happens, and if the repair is good enough and frequent enough then it doesn't matter how the problem occurs. Then, with the luxury of time, back to the labs to figure out every last detail of what happens if you don't take the treatments. The present status quo seems back to front, given that we're all aging to death.


Aubrey de Grey of the SENS Research Foundation is an advocate and scientist focused on advancing the state of rejuvenation research, progress towards therapies capable of repairing the cell and tissue damage that causes degenerative aging. He put forward the Strategies for Engineered Negligible Senescence (SENS) research proposals some fifteen years ago, and since then has raised funding, organized research programs, cofounded the Methuselah Foundation and SENS Research Foundation, and traveled the world to speak at scientific conferences and meetings of supporters.

Back when this all began, members of the scientific community were very reluctant to speak openly about treating aging as a medical condition, the press treated the prospect of therapies for aging as a joke, and the public at large gave no attention to the topic. Yet the potential was there, with many disparate branches of research into age-related diseases demonstrating even then that scientists understood more than enough to get started on meaningful therapies to repair the damage of aging. The problem has always been cultural: that no-one cares, that funding is non-existent, that few are willing to step up and speak out on the issue, that the status quo of suffering and disease is accepted. With the help of people like de Grey and his allies the last decade has seen a real sea change in the research community and the media, however, as well as in the actuarial and the futurist communities, and the years ahead will see that change in attitudes spread to the population at large. If we keep working at this by the mid 2020s I expect the average individual in the street to think of aging in the same way as he or she thinks of cancer today: a fearsome medical condition that causes great suffering, researchers need to work harder at fixing it, and charities raising funds for research are a worthy cause.

Over at the Reddit /r/futurology community today de Grey was answering questions in an AMA (Ask Me Anything) event. It is worth remembering that every Reddit community of any size is a collection of widely divergent interests. Thus /r/futurology is a mix of folk who follow progress in computing technology, basic income advocates, popular science buffs, futurists of all stripes, both for and against longevity enhancement, and various other less categorizable groups. So the forum can host a respectful AMA for de Grey packed by people who look forward to progress in rejuvenation research just a day after a long discussion on a recent aging research paper in which most of those involved were opposed to human life extension. It is a big world, communication is making it smaller, and we're all rubbing shoulders these days.

Ask Aubrey de Grey anything!

Buck-Nasty: I'm curious about how the advent of CRISPR affects the development of SENS therapies?

Aubrey de Grey: It's huge. It will be central to the delivery of the many SENS components that involve somatic gene therapy.

Buck-Nasty: Does it speed up the development timeline at all?

Aubrey de Grey: A lot, yes.

Jay27: Kind of a shame, because it looks to me like deep learning algorithms will be plowing their way through a million genomes in 2020. You'd think they'd yield some valuable genemod insights which can then be applied with CRISPR.

Aubrey de Grey: We don't need insights right now - we need implementation of what we already know or are developing. That's why CRISPR is so important.

Senf71: Is it fair for me to be telling my friends and others I tell about this stuff, that considering the modest amount a month I donate to SENS and the many dozens of people I have educated about SENS and curing aging in general, many quiet successfully educated, that I may have personally saved the lives of 100,000 people at this point? Along that line is this something it would be good for you and your people to really emphasize during talks? To tell people that they can feel good about them selves for going out and advocating and donating even a meager amount of money because doing so means they are very truthfully saving the lives or 10s or 100s of thousands of people?

Aubrey de Grey: This is by far the best question yet on this AMA. Thank you! First: I think you can say something like that (depending on how long it's been that you've been sending us that modest amount). I believe that 1 billion right now would hasten the achievement of LEV by about 10 years; you can do the rest of the maths, but it comes out to about two dollars per life - and of course "saving" means a great deal more in terms of extra years than it does for other ways of saving lives, so arguably it's more like a few cents per life. And yes, I think I should emphasise this more. I probably will.

Spats_Mgee: Several aspects of your SENS proposal are essentially destructive in nature (removing intra/extracellular junk, killing errant cells, etc). Your proposal to deal with these problems involves utilizing enzymes found in other species to break down these molecular structures. I'm curious if you've weighed the pros and cons of this (let's say "organic") approach to the "inorganic" approach of using gold nanoparticles for targeted photothermal ablation of these cellular/molecular structures.

Aubrey de Grey: We've looked at this approach and we haven't rejected it out of hand. A big issue is penetration: how does one irradiate deep within the body?

Lavio00: I watched a video from you back in 2013 where you commented the announcement from Larry Page about Calico. You mentioned that Calico - if they're focused on early stage research - might highly benefit the battle against aging. What is your comment regarding Calico's research now that a couple of years have passed? More/less excited about their potential?

Aubrey de Grey: Cautious. They are structured perfectly: they are doing a bunch of highly lucrative irrelevant short-term stuff that lets them get on with unlucrative critical long-term stuff without distraction. But the latter may be getting too curiosity-driven and insufficiently translational. We'll see. Here "highly lucrative irrelevant stuff" = drugs for specific diseases of aging, "unlucrative critical stuff" = work leading to actual longevity escape velocity.

SirT6: One thing that has always struck me about your vision for extending human lifespan is that you don't seem particularly interested in attempting to leverage the molecular genetics of aging. Numerous animal studies have implicated a number of genes which may serve as pharmacological targets for ameliorating aging and age-related pathologies. Studies of human centenarians have also validated the idea that modulation of these genes or their protein products may be a viable option for extending lifespan. And from an evolutionary perspective, this seems to make sense - many genes exhibit antagonistic pleiotropy (good when young, bad when old), so inhibiting these genes/proteins as people age is likely to reduce the burden of age-related disease. I suppose you could argue that this won't drastically increase human lifespan, but it seems to be a far more tractable approach in the near term (clear molecular targets, easier biomarkers, simplified drug development etc.). I would be curious to hear your thoughts on the issue. Thanks!

Aubrey de Grey: You put your finger on it - tractability versus magnitude of effect. As I think you know, I subscribe to the school of thought that CR-mimicking genetic or pharmacological manipulations cannot to much in long-lived species. I don't want to suppress such research, but I do think that the field has been immensely harmed over the past 20 years by overoptimism concerning the CR-mimicking approach and consequent lack of interest in alternatives. Antagonistic pleiotropy has very little to do with this.

akerenyi: I believe that the distinction you make between SENS-type of research focusing on damage from ageing and research on age-related diseases (ARDs) is purely arbitrary and misleading. For example you correctly claim that ageing and ARDs are pretty much the same thing, but than go on the criticize research on ARDs for not focusing on the right thing, while even further you plan to use therapeutics coming from this research, like Alzheimer's vaccines for rejuvenation (correctly so). I think the reality is that research on ARDs does involve more basic, mechanistic work as well as more later-stage, symptomatic approaches, compared to your engineering approach. However, I think the former gave and will give the targets for SENS, like beta-amyloid or tau, while the latter gave us drugs like levadopa, which while being crude and non-definitive, did improve the quality of life of millions of patients, while stem-cell therapy or gene therapy is being developed. Please clarify whether you still think such a distinction is desirable or meaningful.

Aubrey de Grey: The issue is relative funding. Illustration: it is absolutely accepted that atherosclerosis, the #1 killer in the western world, starts with the inactivation of macrophage lysosomes by oxidised cholesterol. Yet, about two labs in the world are focused on that step. I'm very satisfied indeed with the amyloid-beta vaccine results - they eliminate plaques. Same with gene therapy.

jimofoz: Can you give us any updates on the research towards allotopically expressing all 13 protein coding mitochondrial DNA genes?

Aubrey de Grey: It's going really well. We've made big breakthroughs this year and we'll be publishing something soon.

jimofoz: How pleased are you that Gensight is now taking the allotopic mtDNA expression technology whose development SENS partially funded into stage III clinical trials?

Aubrey de Grey: Overjoyed. We funded the Corral-Debrinski lab early on. Our work is leaning heavily on their early discoveries.

Rdapt85: I haven't heard any development in GlycoSENS since the discovery of synthesizing glucosepane in the lab 2 years ago. How is it going?

Aubrey de Grey: It's tough as hell but yes, we are plugging away. Watch this space.


There is an ongoing debate in the research community over whether aging should be considered a disease, formally or colloquially. It has been running for a few years, but has picked up steam of late, and more of the discussion is in the form of open access papers these days. To pick a few examples from earlier this year you might take a look at a paper by David Gems or the thoughts of other European researchers associated with Heales. Here I'll point out a recent addition to the discussion in which the author opens with this summary:

The aging of the population represents one of the largest healthcare challenges facing the world today. The available scientific evidence shows that interventions are available now that can target fundamental "aging" processes or pathways. Sufficient economic evidence is available to argue convincingly that this approach will also save enormous sums of money which could then be deployed to solve other urgent global problems. However, as yet this scenario has barely entered the public consciousness and, far from being a point of vigorous debate, seems to be ignored by policy makers.

Understanding why this lethargy exists is important given the urgent need to deal with the challenge represented by population aging. In this paper I hypothesize that one major cause of inaction is a widely held, but flawed, conceptual framework concerning the relationship between aging and disease that categorizes the former as "natural" and the latter as "abnormal." This perspective is sufficient in itself to act as a disincentive to intervention by rendering those who hold it prone to the "naturalistic fallacy" but can give rise to active hostility to biogerontology if coupled with loose and/or blurred understanding of the goals and potential of the field.

One of the biggest puzzles of our time is why, given the obvious potential for biomedical research to treat the causes and progression of the aging process, is next to no-one interested in making this happen? We live in a culture in which it is taken for granted that treating cancer, heart disease, and Alzheimer's is the right thing to do. All of these are conditions caused by aging: they are not magically separate from the aging process. They arise from the same underlying forms of cell and tissue damage that cause all of the other manifestations of disability and frailty. Yet when asked about developing treatments for the underlying causes of aging, treatments that can be made more effective as therapies for age-related diseases than the present state of the art, there is a lack of interest and even outright hostility. Further, it isn't too hard to see that the same people who reflexively oppose the treatment of aging today would accept and use these treatments without question had they merely been born fifty years or a century from now. The whole situation seems very irrational.

I have been following this research and advocating for faster progress towards rejuvenation therapies like those of the SENS research programs for going on fifteen years now. Yet I still couldn't give you a good answer as to why the populations of the world are happy to walk towards a slow, crumbling suicide rather than support progress in medicine for aging. We all have our theories as to why things are the way they are, and no way to prove them: it is still too early on the path towards popular acceptance and support to draw any conclusions from the success of one message over another. The people in our community, who are choosing to make charitable donations to SENS and other research programs, are those who have had the big realization and have a better than average understanding of the research situation. We're not at the stage yet where SENS and other branches of aging research enjoy the support of a large fraction of the population in the same fashion as cancer research, donations given primarily for cultural rather than intellectual reasons.

Here are thoughts on the matter, some of which you might agree with, some of which you might not. As I said, everyone has their theories. Regardless of those, the small history lesson on changing views of aging and disease in the middle of this paper is interesting in and of itself:

Should we treat aging as a disease? The consequences and dangers of miscategorisation

The accusation that early gerontologists deliberately invented the distinction between ageing and disease because "by ring fencing their area of work intellectually, gerontologists hoped to ring-fence it financially" is unfounded and unfair. These early researchers were not making some cynical bid for a separate pot of grant money. Instead, they were echoing a medical tradition about the relationship between ageing and disease which predated not just the scientific method, but the English language.

Perhaps unfortunately for all concerned, this conceptual distinction between "natural" (and normal) aging and "unnatural" disease is ripe with the potential for fundamental philosophical error and "moral concern." At the inception of the field this was of limited importance because the potential for clinical intervention in later life problems was very limited. However, this has changed. In retrospect, the publication of Normal Human Aging in 1984 occurred at a gerontological watershed. The mid 1980s could be said to be a period in which something was known about why aging occurred, much was known about what changed as humans aged, but almost nothing about how this happened.

It is now clear that the finite capacity to replace lost cells plays a causal role in mammalian aging. Senescence is the permanent entry of individual cells into a viable, but non-dividing state, usually as the result of repeated cell division. The molecular pathways which trigger this process are complex but are now relatively well understood. Most recently it has been shown that interdiction of key nodes of the pro-survival gene expression networks upregulated in senescence (either pharmacologically or using siRNA) killed senescent cells, but not their proliferating or quiescent, counterparts. In vivo this resulted in extended healthspan. Since the production costs of these first generation "senolytics" are low such treatments are likely to be cost-effective.

Crucially, the same mechanisms of cellular senescence cause both age-related diseases, and features of aging considered in the past to be "natural changes" (e.g., the accumulation of senescent cells in the skin contributes to wrinkling, a "natural change" and to cardiovascular disease, an "age-related disease"). If the distinction between aging and age-related disease is false then the practical consequences of maintaining that such a distinction exists could be severe.

The proposition that aging and disease are distinct is easy to grasp, coherent and compelling. But it is important to recognize that it is essentially just an exercise in logic resting upon the definition of "disease" as abnormal function. Thinking about aging and disease like this raises surprising conceptual barriers to intervention. To illustrate this, imagine a land (let us call it "Nofruit") where everyone has scurvy. Following this logic, in Nofruit scurvy is considered by the population to be a "natural condition". Thinking like this is, in itself, a disincentive to research. In Nofruit the line of thinking would go: Diseases have "magic bullets" or cures. Most authorities think scurvy is not a disease so it cannot, by definition, have a cure. Thus, most Nofruit scientists wouldn't even try to find a cure for scurvy even though orange juice represents about as cheap and effective a "magic bullet" as can be imagined. The "problem" of scurvy would be tacitly ignored, much the way the possibility of successful intervention in aging is tacitly ignored in the real world.

It is important to recognize that the Nofruit arguments do not require aging and age-related disease to share causal mechanisms. Both may cause harm in different ways. However, in actuality the mechanisms which cause aging and age-related disease really do overlap very substantially. Thus distinguishing between "aging" and "age-related disease" probably represents an artificial distinction; human understanding has drawn an arbitrary line on the complex phenotype which is later life. Maintaining an artificial aging-disease distinction give rise to a contradiction. What is the ethical rationale for treating entities classified as "diseases" caused by senescent cells (like cardiovascular disease) but not treating entities classified as "natural changes" (like wrinkles) which are also caused by senescent cells? As yet this problem does not seem to have been fully recognized by bioethicists, probably because the science on which it is based is so new that it has not yet been disseminated. The little which has been said on the topic however, offers gerontologists little reassurance that our work will be well received.

However, research into public attitudes to gerontological research in the UK indicated a desire among the participants for a long and active life rather than to serve as object lessons in deliverance from suffering. It has been suggested that the concerns shown about extended lifespans by some participants in the Pew Research survey may result from their belief that these would be associated with the kind of morbidity seen in aging Americans today. If so this reinforces the key message that healthspan is the outcome most desired by our populations. The most effective way to facilitate this would be to significantly increase the funding available for research into the fundamental biology of aging and facilitate the rapid translation of its discoveries into the clinical arena.


There is a mountain of evidence to show that regular exercise and maintaining a state of fitness is good for health and longevity. That mountain continues to grow, new papers arriving on a weekly basis to reinforce these points: don't be sedentary and don't get fat, or you'll pay the price of greater medical expenses over a shorter, less healthy life. A few examples are linked below, spanning a range of topics including associations between fitness and age-related structural damage and decline in the brain, exercise and mortality in middle age, and exercise as a therapeutic option for the elderly.

Regular moderate exercise is among the safest of ways to influence health, and it produces an expected benefit to long-term health that is modest in the grand scheme of things, but for basically healthy individuals still larger than that provided by any other available methodology aside from the practice of calorie restriction. You can't exercise your way to living to 100, a target that less than 1% of the population will reach in the environment of today's medical science, and exercise only modestly improves your 20% odds of making it to 90 in the environment of today's medical science. If exercise required multi-billion-research programs and decades before it could be safely used, then I would be just as dismissive of it as I am of efforts to develop drugs to slightly slow the aging process. But exercise is free, available now, reliable, and backed by an enormous weight of evidence, and that makes all the difference as to whether or not to take advantage.

It is true that the future of practical, low-cost rejuvenation therapies will render academic all questions of whether or not we would gain a year in health here or a year there due to a healthier lifestyle. We'll be gaining decades of healthy life, and losing the marks and damage of age, thanks to therapies that target the causes of degenerative aging and age-related disease. The big question for those of us who stand today at the cusp of age and opportunity, at the whim of small chances that will spiral out to speed or slow the timeline for future medical development, is whether or not we will live long enough to benefit from rejuvenation treatments. That is where the year here and the year there become far more important, especially as the pace of progress in all technologies continues to accelerate.

Cardiorespiratory fitness is associated with white matter integrity in aging

Age-related decline in cerebral macrostructure, such as reductions in gray and white matter volume, is well-documented. More recently, diffusion tensor imaging (DTI) has been used to assess in vivo cerebral white matter microstructure and to evaluate specific white matter fiber bundles that underpin information transmission between gray matter regions. Age-related reductions in white matter microstructure have been reported in healthy older adults (OA), and decreased white matter microstructure in OA has been linked to poorer performance on tasks tapping processing speed, executive functions, and episodic memory.

The pervasive evidence for neural decline in OA has led to substantial interest in individual difference factors that are associated with age-related reductions in cerebral integrity. One such factor is cardiorespiratory fitness (CRF), an indicator of the ability of one's circulatory and respiratory systems to supply oxygen to skeletal muscle during sustained moderate to vigorous physical activity.

Exercise during teen years linked to lowered risk of cancer death later

Women who exercised during their teen years were less likely to die from cancer and all other causes during middle-age and later in life, according to a new study. The investigators used data from the Shanghai Women's Health Study, a large ongoing prospective cohort study of 74,941 Chinese women between the ages of 40 and 70. The women enrolled in the study between 1996 and 2000. Each participant was interviewed at enrollment about exercise during adolescence, including participation in team sports, as well as other adolescent lifestyle factors. They were also asked about exercise during adulthood and other adult lifestyle factors and socioeconomic status, and participants were interviewed again every two to three years. Investigators found that participation in exercise both during adolescence and recently as an adult was significantly associated with a 20 percent reduced risk of death from all causes, 17 percent for cardiovascular disease and 13 percent for cancer.

A Cluster Randomized Controlled Trial of Nonpharmacological Interventions for Old-Old Subjects with a Clinical Dementia Rating of 0.5: The Kurihara Project

The boundary or transitional state between normal aging and dementia, which is defined in various ways such as mild cognitive impairment (MCI) or a Clinical Dementia Rating (CDR) of 0.5, is recognized as a state of being at high risk of dementia. Although it is a serious challenge to control the risk of dementia in these people, pharmacological interventions remain unsuccessful. Meanwhile, recent studies have suggested potential benefits of nonpharmacological interventions. Among a variety of nonpharmacological methodologies, most popular and potentially beneficial interventions to date include cognitive interventions (CI), physical activities (PA) and a group reminiscence approach with reality orientation (GRA).

Previous studies have suggested that exercise may be one of the promising strategies for improving cognitive functions. Resistance as well as aerobic trainings may positively impact cognitive functioning and result in functional plasticity in healthy older adults. Furthermore, exercise training may have cognitive benefits for seniors with MCI, especially improvements in selective attention and conflict resolution, processing speed and verbal fluency in senior women with amnestic MCI. Thus, many previous studies have emphasized the positive impact of PA on the executive functions of subjects in the boundary state between normal aging and dementia. Indeed, our results support these previous findings; however, they also show that the benefit for executive functions may be a nonspecific effect that may occur with CI or the GRA as well. Nevertheless, we cannot exclude the secondary benefit of PA on cognitive functions, because an improvement in physical ability may potentially ameliorate cognition in the course of subsequent daily life.

Physical Activity Is Linked to Greater Moment-To-Moment Variability in Spontaneous Brain Activity in Older Adults

Higher cardiorespiratory fitness (CRF) and physical activity (PA) in old age is associated with greater brain structural and functional integrity, and higher cognitive functioning. In this study we extend our understanding of the different and overlapping roles of CRF and PA in brain resting state function in healthy but low-active older adults. Depending on brain region and task, greater CRF is associated with either increased or decreased change in blood oxygenation level dependent (BOLD) signal, a proxy for neural activity. As a result, it is unclear whether high or low amplitudes of BOLD signal reflect optimal functional brain health. Here we employed a more general measure of neural function: moment-to-moment variability in the BOLD signal during spontaneous brain activity. Moment-to-moment variability in the BOLD signal (SDBOLD) is known to reflect the dynamic range of neural processing, such as the modulation of functional networks and is suggested to be a promising tool in mapping neural correlates of cognitive abilities in aging. Specifically, lower SDBOLD in certain brain regions is associated with older age, slower, and less consistent performance on a perceptual matching task.

In this study, we sought to determine how the level of physical fitness (measured as CRF) and PA (measured via accelerometer) are related to functional brain health measured as SDBOLD. To this end, we collected resting functional magnetic resonance BOLD data from 100 healthy older participants (60-80 years). Given that: 1) advancing age is associated with decreasing SDBOLD; and 2) greater CRF, PA, and lower sedentariness are associated with better cognitive and brain health outcomes in older adults, we predicted that greater SDBOLD in certain regions would reflect greater brain health and therefore positively correlate with CRF and PA, and negatively with sedentariness. We found that older adults who spend more time daily on light PA (LI-PA; housework, gardening, relaxed walking) and moderate-to-vigorous PA (MV-PA, e.g. jogging, walking stairs, biking) had greater SDBOLD in multiple brain regions, and this relationship was positively associated with white matter microstructure.


The mammalian heart regenerates very poorly, which is one of the reasons why cardiovascular disease kills so many of us. In the research noted below scientists investigate a possible reason as to why this is the case, uncovering what they believe to be a meaningful difference in the structure of heart cells when compared with those of non-mammalian species in which the heart is capable of regrowth. A cell structure known as the centrosome, important in cellular replication, is lost in heart cells early on in mammalian development, but retained in other species known for the regenerative prowess, such as salamanders and zebrafish.

You might consider this a sort of regenerative research, but quite different in focus from work on stem cells and signals intended to spur heart tissue to regenerate where it would not normally do so. In this case it is suggested that perhaps it might be possible alter heart cells to be more like other muscle cells, more capable of ongoing self-repair. This is of course much more speculative than stem cell therapies at this stage, but all new medicine must start somewhere.

Heart cells are generated early in life and there is little turnover or reconstruction following injury in comparison to other tissues. Looking at other species, the hearts of zebrafish and salamanders regenerate exceptionally well over the whole life span. Remove a whole chunk of heart tissue and it will grow back. Is this a matter of signal environments, as is presently thought to be the case, or is it differences in the complex relationship between the immune system and tissues in regulation of healing, which is looking likely based on salamander studies, or is it inherent in the internal state of the cells themselves? Or all of the above?

Why the human heart cannot regenerate

Heart failure is the most common cause of death worldwide. The main reason for this is that damage to the human heart causes cardiac muscle cells to die, which in turn leads to reduced heart function and death. However, this is not the case for zebrafish or amphibians. If their hearts become damaged and cardiac muscle cells die, their remaining cardiac muscle cells can reproduce, allowing the heart to regenerate. The ability of most cardiac muscle cells to reproduce disappears in humans and all other mammals shortly after birth. What remains unclear, however, is how this happens and whether it is possible to restore this ability and therefore to regenerate the heart.

'In our study we discovered that the centrosome in cardiac muscle cells undergoes a process of disassembly which is completed shortly after birth. This disassembly process proceeds by some proteins leaving the centrosome and relocating to the membrane of the cell nucleus in which the DNA is stored. This process causes the centrosome to break down into the two centrioles of which it is composed, and this causes the cell to lose its ability to reproduce.' The centrosome is an organelle found in almost every cell. In recent years, experiments have shown that if the centrosome is not intact, the cell can no longer reproduce. This raised the key question to what extent centrosome integrity could be manipulated - such as in cancer where cells reproduce at an uncontrolled rate. 'We were incredibly surprised to discover that the centrosome in the cardiac muscle cells of zebrafish and amphibians remains intact into adulthood. For the first time, we have discovered a significant difference between the cardiac muscle cells of mammals and those of zebrafish and amphibians that presents a possible explanation as to why the human heart cannot regenerate.'

Developmental alterations in centrosome integrity contribute to the post-mitotic state of mammalian cardiomyocytes

Increasing evidence supports the requirement of a functional centrosome for cellular proliferative potential. Centrosome disassembly appears to be a very effective way to achieve a post-mitotic state. But why do cardiomyocytes disassemble their centrosomes? Upon birth, the neonatal heart, and the cardiomyocytes therein, undergo increased hemodynamic stress. Effective cardiomyocyte function in response to increased hemodynamic stress may require a cytoskeletal architecture more conducive to handling postnatal physical stresses. Thus, centrosome disassembly may be a result of cytoskeletal reorganization. In this scenario, proliferative potential might be sacrificed for postnatal function.

The ability of zebrafish and newts to regenerate their heart has gained extensive interest in recent years. One major question is what distinguishes mammalian cardiomyocytes from those of zebrafish and newts with regards to their proliferative potential. Our data demonstrate that the state of cellular differentiation of cardiomyocytes from various species is not evolutionary conserved. The fact that adult zebrafish and newt cardiomyocytes maintain their centrosome integrity indicates that factors promoting adult zebrafish cardiomyocyte proliferation might not necessarily induce adult mammalian cardiomyocyte proliferation.

Collectively, our data provide a novel mechanism underlying the post-mitotic state of mammalian cardiomyocytes as well as a potential explanation for why zebrafish and newts, but not mammals, can regenerate their heart.


Monday, August 3, 2015

Entirely artificial medical nanorobots will one day exist to augment or greatly improve on functions presently carried out by cellular machinery. Long before then, however, we will see the widespread use of modified cells and bacteria, altered to form programmable tools such as drug manufactories that travel to where they are needed and take the appropriate actions in response to local circumstances.

A successful microbial diagnostic or therapeutic agent must to able to detect a particular signal with high fidelity, integrate this signal through precise intracellular circuitry, and respond to this signal at the appropriate level. Researchers have recently described genetic tools that allow the commensal bacterial species B. thetaiotaomicron to efficiently perform all three of these functions. Notably, they show that circuits integrating signal detection, genetic memory, and CRISPR interefence function as expected when engineered B. thetaiotaomicron is introduced into the gut microbiome of mice.

In the future, one can imagine the use of these mechanisms to tightly regulate the expression of different genes in a biosynthetic gene cluster for a small molecule therapeutic (e.g., an antibiotic), engineered in a microbiome-derived Bacteroides strain. The in vivo expression of this gene cluster could be controlled by the level of a carbohydrate administered in the diet, or preferably, by a specific small molecule produced by the target pathogen itself. Decoupling of the synthesis and secretion of the small molecule (e.g., to reach an effective local therapeutic dose) can be achieved by putting the export machinery under the control of an inducible circuit that responds only to high intracellular levels of the small molecule, or by engineering a time delay between the synthesis and secretion of the molecule. Once the therapeutic effect has been achieved (e.g., the elimination of a pathogen), CRISPR interference can be used to knock down residual expression of the therapeutic genes or to eliminate the chassis itself by targeting an essential gene. This final step could be triggered by a second signal administered in diet, or by the absence of the pathogen-derived small molecule. This entire series of events could be recorded on memory switches and read through analysis of the Bacteroides genome in host feces, providing timely snapshots of what is happening in vivo.

Although it is still early days for its approval, using engineered commensal microbes to produce therapeutic molecules may be preferred over using oral or systemic drugs for several reasons. First, commensals naturally occupy specific niches in the gastrointestinal tract, allowing drug delivery to a very defined site. Subsequently, the dosage needed to obtain a local therapeutic effect would be much lower than needed if orally administered, and many adverse effects could in turn be eliminated. Second, because the production of a therapeutic molecule can be precisely controlled in engineered bacteria, long-term control of diseases can be achieved using a single organism that produces the drug only when needed. Last, using an engineered bacterium to produce and deliver one or more therapeutic molecules could provide an economical alternative to the costly production, formulation, distribution, and storage of drugs. This is even more applicable in the cases where a drug is specially formulated or administered via intramuscular or subcutaneous injection to avoid degradation in the stomach.

Monday, August 3, 2015

Researchers here outline recent discoveries relating to changes in the endoplasmic reticulum inside cells that occur over the course of aging. All cellular machinery falters with age due to accumulating damage, and the primary goal of the research community remains to catalog and fully understand these changes, with doing something about coming it a distant second where it is a focus at all. The endoplasmic reticulum is the site of protein synthesis, and since all cellular machinery is built out of proteins, it is not unreasonable to look for links between changes in the endoplasmic reticulum - and its many component parts - and the disruption of proteostasis in aging. In older tissues there are many more broken and misfolded proteins, and this may turn out to have as much to do with issues in production as with issues in quality control and damage repair.

Each cell consists of different compartments. One of them is the endoplasmic reticulum (ER). Here, proteins which are then secreted e.g. into the bloodstream, such as insulin or antibodies of the immune system, mature in an oxidative environment. A type of quality control, so-called redox homoeostasis, ensures that the oxidative milieu is maintained and disulphide bridges can form. Disulphide bridges form and stabilise the three-dimensional protein structure and are thus essential for a correct function of the secretory proteins, e.g. those migrating into the blood. Researchers have now shown that the ER loses its oxidative power in advanced age, which shifts the reducing/oxidising equilibrium - redox for short - in this compartment. This leads to a decline in the capacity to form the disulphide bridges that are so important for correct protein folding. As a consequence, many proteins can no longer mature properly and become unstable.

Although, it was already known that increased protein misfolding occurs with the progression of ageing, it was not known whether the redox equilibrium is affected. Likewise, it was not known that the loss of oxidative power in the ER also affects the equilibrium in another compartment of the cell: in reverse, namely, the otherwise protein-reducing cytosol becomes more oxidising during ageing, which leads to the known oxidative protein damage such those caused by the release of free radicals. "Up to now, it has been completely unclear what happens in the endoplasmic reticulum during the ageing process. We have now succeeded in answering this question." At the same time, the scientists were able to show that there is a strong correlation between protein homoeostasis and redox equilibrium. "This is absolutely new and helps us to understand why secretory proteins become unstable and lose their function in advanced age and after stress. This may explain why the immune response declines as we get older. We gained a lot of insight, but have also learned that ageing is much more complex than previously assumed." Thus, for example, the mechanism of the signal transduction of protein folding stress to the redox equilibrium - both within the cell from one compartment to another and also between two different tissues - remains completely unclear.

Tuesday, August 4, 2015

The amyloid associated with Alzheimer's disease builds up with age, and much more so in people eventually diagnosed with Alzheimer's. Many lines of evidence indicate that the underlying problem is one of slowly failing clearance of amyloid proteins: various systems and mechanisms falter with age due the accumulation of cell and tissue damage. Until amyloid proteins gather in large enough numbers to form lasting clumps, their presence are fairly dynamic, created and cleared on a timescale of hours. Researchers here provide direct evidence of slower clearance rates in older people:

The greatest risk factor for Alzheimer's disease is advancing age. After 65, the risk doubles every five years, and 40 percent or more of people 85 and older are estimated to be living with the devastating condition. Researchers have identified some of the key changes in the aging brain that lead to the increased risk. The changes center on amyloid beta 42, a main ingredient of Alzheimer's brain plaques. The protein, a natural byproduct of brain activity, normally is cleared from the brain before it can clump together into plaques. Scientists long have suspected it is a primary driver of the disease. "We found that people in their 30s typically take about four hours to clear half the amyloid beta 42 from the brain. In this new study, we show that at over 80 years old, it takes more than 10 hours." The slowdown in clearance results in rising levels of amyloid beta 42 in the brain. Higher levels of the protein increase the chances that it will clump together to form Alzheimer's plaques.

For the study, the researchers tested 100 volunteers ages 60 to 87. Half had clinical signs of Alzheimer's disease, such as memory problems. Plaques had begun to form in the brains of 62 participants. The subjects were given detailed mental and physical evaluations, including brain scans to check for the presence of plaques. The researchers also studied participants' cerebrospinal fluids using a technology known as stable isotope-linked kinetics (SILK), which allowed the researchers to monitor the body's production and clearance of amyloid beta 42 and other proteins.

In patients with evidence of plaques, the researchers observed that amyloid beta 42 appears to be more likely to drop out of the fluid that bathes the brain and clump together into plaques. Reduced clearance rates of amyloid beta 42, such as those seen in older participants, were associated with clinical symptoms of Alzheimer's disease, such as memory loss, dementia and personality changes. Scientists believe the brain disposes of amyloid beta in four ways: by moving it into the spine, pushing it across the blood-brain barrier, breaking it down or absorbing it with other proteins, or depositing it into plaques. "Through additional studies like this, we're hoping to identify which of the first three channels for amyloid beta disposal are slowing down as the brain ages. That may help us in our efforts to develop new treatments."

Tuesday, August 4, 2015

Antagonistic pleiotropy is a term used to describe the results of a trait or mechanism that is beneficial in youth but then causes harm in later life. Evolutionary processes appear to select such traits due to their impact on early reproductive success, and that is one of the reasons why we age. Here, researchers illustrate this point while investigating one of the many roles played by free radicals in mammalian tissues:

When scientists bred mice that produced excess free radicals that damaged the mitochondria in their skin, they expected to see accelerated aging across the mouse lifespan - additional proof of the free radical theory of aging. Instead, they saw a surprising benefit in young animals: accelerated wound healing due to increased epidermal differentiation and re-epithelialization. Free radicals are especially reactive atoms or groups of atoms that have one or more unpaired electrons. They are produced in the body as a by-product of normal metabolism and can also be introduced from an outside source, such as tobacco smoke, or other toxins. Free radicals can damage cells, proteins and DNA by altering their chemical structure. Excessive amounts of free radicals are known to cause cellular damage that leads to aging, but in some mouse models and human studies lowering free radicals with antioxidants have not always conferred the expected benefits.

While increased free radical production showed benefit in younger animals, the mice paid a price over time. Mitochondrial damage from excess free radicals caused some of the skin cells to go into senescence - they stopped dividing and started accumulating. Over time the energy available to the epidermal stem cells was depleted - the stem cells simply became too scarce and the mice showed expected signs of aging, thin skin and poor wound healing. "In this case, we found unexpected pleotropic effects, mechanisms that benefit us when we're young cause problems as we age." Mitochondrial stress caused by the increase in free radicals also forced the skin cells in the younger animals to differentiate faster than normal, further depleting the pool of stem cells available to renew the skin over time. "This is not a simple process. It may be that nature used free radicals to optimize skin health, but because this process is not deleterious to the organism until later in life, past its reproductive age, there was no need to evolve ways to alter this mechanism." There could be one practical implication of the study: taking large amounts of anti-oxidants might have deleterious effects, at least in the skin.

Wednesday, August 5, 2015

The immune cells known as macrophages are involved in the regulation of regeneration, mostly in a beneficial sense, though here researchers identify an activity that suppresses excessive regeneration in muscle tissue. Sometimes excessive regeneration is exactly what is desired for medical purposes, however:

By removing the protein CD163 from mice, scientists have boosted muscle repair and recovery of blood flow after ischemic injury (damage caused by restriction of blood flow). The findings point to a target for potential treatments aimed at enhancing muscle regeneration. CD163 was known to scientists, mostly as a molecule involved in scavenging excess hemoglobin from the body, but its role in regulating muscle repair was not. Mice lacking CD163 showed increased blood flow and muscle repair, compared with controls, after an injury coming from a restriction of blood flow in one leg. Examining the mice lacking CD163, researchers were surprised to find that blood vessels and muscle fibers also grew substantially (roughly 10 percent) in their uninjured legs. "We were astonished. Why would something we did, which caused an injury to one leg, help tissue in the other leg regenerate when it wasn't injured in the first place?"

Potentially, researchers could try to achieve the effect of removing CD163 in humans by giving patients an antibody against CD163, but more research is needed to know how this might work. CD163 levels have been found to increase in aging humans in multiple studies. Macrophages, which are a type of white blood cell, appear to release a soluble form of CD163 in response to injury. In the blood, CD163 soaks up and counteracts another protein called TWEAK, which stimulates muscle cells to multiply. In CD163's absence, TWEAK can have a greater effect, and can apparently stimulate muscle growth distant from the site of injury. When infused into normal mice, TWEAK does not have any effect on muscle growth, possibly because of circulating CD163.

Scientists that study muscle cells have been interested in TWEAK for several years, but some studies have suggested that TWEAK negatively regulates muscle regeneration - the opposite of what this team observed. To prove that TWEAK was needed for the extra repair seen in mice lacking CD163, the researchers showed that if they injected an antibody against TWEAK, thus removing it from the blood, it eliminated the extra repair activity. "I think our results show a specific mechanism by which muscle regeneration takes place. TWEAK can be a pro-regenerative factor, but its effects have to be transient and limited."

Wednesday, August 5, 2015

This popular science article looks at some of the present outcomes of heterochronic parabiosis research, in which the circulatory systems of two animals are linked, one older, one younger. This produces beneficial effects in the older animal, in particular a reactivation of stem cell populations and greater tissue maintenance. While some research groups are chasing down the molecular signals responsible, others are attempting to see if blood transfusions from young donors to old recipients could recapture any of the effect.

Personally I'm not optimistic with regard to the direct approach of transfusions based on the null results obtained from experiments in mice carried out to date. It is quite possible that the useful factors are very short-lived, or that the beneficial processes involved in heterochronic parabiosis require some interaction between old tissue and young tissue, and in either case straightforward transfusions of young blood are not going to be useful. Even when a method of recapturing parabiosis benefits is produced, as I'm sure it will be sooner or later, this still only partially addresses one of the causes of degenerative aging. Researchers still need to clear out metabolic waste, address mitochondrial damage, and so forth - the rest of the slate of SENS rejuvenation therapies are required.

On an August morning in 2008, Tony Wyss-Coray sat in a conference room at the Veterans Affairs hospital in Palo Alto, California, waiting for his lab's weekly meeting to begin. Saul Villeda, an ebullient PhD student with slick black hair and a goatee, had spent the past year engrossed in research that called to mind the speculative medical science of the middle ages. He was investigating whether the old and frail could be rejuvenated by infusions of blood from the young. Villeda had conducted pilot studies with pairs of surgically conjoined mice that shared a blood supply for several weeks. Young mice received blood from older mice, and old mice received blood from younger ones.

Villeda got three hours' sleep that night. The next morning, he stood up at the lab meeting and revealed to his colleagues what young blood did to the ageing brain. "There was a palpable electricity in the room," Wyss-Coray recalled. "I remember seeing the images for the first time and saying, 'Wow.'" Old mice that received young blood experienced a burst of brain cell growth in the hippocampus. They had three to four times as many newborn neurons as their counterparts. But that was not all: old blood had the opposite effect on the brains of young mice, stalling the birth of new neurons and leaving them looking old before their time.

Since that meeting seven years ago, research on this topic has moved on dramatically. It has led some to speculate that in young blood might lie an antidote to the ravages of old age. But the apparent rejuvenating properties of young blood must be treated with healthy scepticism. The hopes they raise rest solely on mouse studies. No beneficial effects have ever been proven in humans. Then again, no one has ever looked. That is about to change. In October 2014, Wyss-Coray launched the first human trial of young blood. At Stanford School of Medicine, infusions of blood plasma from young people are being given to older people with Alzheimer's disease. The results are expected at the end of the year. It is the greatest test yet for the medical potential of young blood.

Big questions lie ahead. Even if none of the patients benefit from young plasma, the research is far from finished. The plasma for the trial comes from donors under 30, and it may not be potent enough. The patients on the trial have dementia already, and may be too far gone to rescue. Earlier this year, John Hardy of University College London, who is the most cited Alzheimer's researcher in Britain, saw Wyss-Coray's latest data at a meeting in London. "It's really interesting work," he told me. "It's woken everybody up." Nonetheless, Hardy is cautious; he suspects that young plasma will be less effective in people than in mice, because people live so much longer, and in far more varied environments. But, he said: "I would guess this will still point us towards pathways involved in ageing more generally."

Thursday, August 6, 2015

Researchers here demonstrate the merits of intermittently disrupting the senescence-associated secretory phenotype (SASP) in conjunction with standard cancer treatments. SASP is the name given to the tendency of senescent cells to release various signals and active molecules that change nearby cell behavior, promote inflammation, and harm the structure of tissue. Senescent cells accumulate with age, and although initially helpful in suppressing cancer risk by removing the most cancer-prone cells from the picture, eventually there are enough senescent cells for SASP to become very damaging and tip the balance back towards cancer promotion.

The researchers here are using rapamycin as a SASP-disrupting agent, but there are no doubt better methods awaiting discovery, designed drugs with fewer side-effects than those accompanying the use of this one. Rapamycin is known to extend life in mice, and there has been some debate over whether it does so by slowing aging or merely because it is good at reducing cancer incidence in that species.

While scientists have demonstrated benefits in this research, the better path forward is probably outright removal of senescent cells: don't try to engage in the long and expensive process of tinkering with cell behavior, just take the targeted cell-killing technologies under development in the cancer research community and turn them against cellular senescence. Senescent cells have a range of distinct chemical signatures, so this is a very plausible plan for near future development.

Intermittent dosing with rapamycin selectively breaks the cascade of inflammatory events that follow cellular senescence, a phenomena in which cells cease to divide in response to DNA damaging agents, including many chemotherapies. Researchers showed that rapamycin reduced the secretion of inflammatory cytokines from senescent cells in culture and in mice by suppressing the mTOR pathway, which promotes growth. The team gave rapamycin to mice with prostate cancer - after they had been treated with DNA-damaging chemotherapy that causes senescence, both to the tumor and its microenvironment. The tumor shrinks but the immediate tissue environment is inflamed. "We think signals from those inflamed cells trigger residual cancer cells to grow again. In the mice, rapamycin suppressed the ability of the tumor cells to relapse." Most importantly, the results may help explain why rapamycin has had mixed results as a treatment for cancer. "It's being given to patients as a way of stopping the growth of tumors. But we think that rapamycin may also be beneficial for those tumors that are driven by inflammation. It needs to be tested in a population most likely to benefit."

"Senescence-activated inflammation could be driving the increased incidence of cancer that we see with aging. While this study took place in mice, the work sets the scene to do early clinical trials in humans. Inflammation has a role in almost all tumor development and some cancers are more inflammatory than others. It would be interesting to see the effect that rapamycin has on those tumors and the surrounding tissue." The potential of intermittent dosing is based on the fact that it takes time for the inflammatory loop (fueled by the senescence-associated secretory phenotype or SASP) to form and time for it to re-establish itself after a brief treatment of rapamycin. Rapamycin blocks the production of a protein called IL-1alpha. This in turn, suppresses IL6, a well-known inflammatory cytokine, at the level of transcription, which prevents the production of the IL6 protein. Because it acts at a deeper level within the cellular process it takes longer for it to get started again. Treatment with rapamycin selectivity impacts the SASP, preserving the function of factors essential for wound healing. "It's an elegant solution - imagine using a small hammer to delicately knock out one thing that is causing problems. We knocked it out and it stayed out long enough to benefit the health of the animal."

Thursday, August 6, 2015

To follow on from yesterday's article on trials of blood transfusions from young to old, here is an open access review paper from some of the researchers involved. A range of tests and scientific programs have grown out from heterochronic parabiosis research in which the circulatory systems of an old and a young laboratory animal are joined. This produces benefits in the older animal and negatively impacts the younger animal. Researchers are now searching for the underlying mechanisms and signals that cause these reactions, so as to build therapies that might, for example, increase stem cell activity in the old.

In the modern medical era, more diverse and effective treatment options have translated to increased life expectancy. With this increased life span comes increased age-associated disease and the dire need to understand underlying causes so that therapies can be designed to mitigate the burden to health and the economy. Aging exacts a seemingly inevitable multisystem deterioration of function that acts as a risk factor for a variety of age-related disorders, including those that devastate organs of limited regenerative potential, such as the brain.

Rather than studying the brain and mechanisms that govern its aging in isolation from other organ systems, an emerging approach is to understand the relatively unappreciated communication that exists between the brain and systemic environment. Revisiting classical methods of experimental physiology in animal models has uncovered surprising regenerative activity in young blood with translational implications for the aging liver, muscle, brain, and other organs. Soluble factors present in young or aged blood are sufficient to improve or impair cognitive function, respectively, suggesting an aging continuum of brain-relevant systemic factors.

The age-associated plasma chemokine CCL11 has been shown to impair young brain function while GDF11 has been reported to increase the generation of neurons in aged mice. However, the identities of specific factors mediating memory-enhancing effects of young blood and their mechanisms of action are enigmatic. Here we review brain rejuvenation studies in the broader context of systemic rejuvenation research. We discuss putative mechanisms for blood-borne brain rejuvenation and suggest promising avenues for future research and development of therapies.

Friday, August 7, 2015

Few serious efforts have been made to generate robust demographic models of a near future in which radical life extension is achieved through rejuvenation therapies such as those of the SENS research programs. There is a paper from 2010 and little prior to that. Here a more recent model adds consideration of economic factors; the purpose isn't to predict what will happen, but to try to explore the likely nature of relationships between therapies to treat aging and extend healthy life spans, demography, and economic line items such as energy use and retirement.

Since the model used only explicitly factors in progress in technology via increased productive life span and GDP, I suspect the authors overstate concerns regarding energy and food. Even so, within their model the situation is hardly the Malthusian disaster predicated by people who subscribe to the overpopulation myth. The same model run in the 1930s, well before the green revolution in agricultural output, would probably have indicated far worse issues for food supplies, and also for the environment given the state of power generation technologies back then. Technology is not static, and efforts to improve it in specific ways are carried out in reaction to perceived shortcomings and expenses.

There is near certainty that the world will experience rapid population aging throughout this century, thanks primarily to widespread and substantial reductions in fertility and, secondarily, to ongoing extensions of life expectancy. Even as debate persists on biological limits to life, a growing body of demographic evidence suggests that improvements in human longevity are not diminishing, and may even be accelerating at older ages. At the same time, new breakthroughs in regenerative medicine and anti-aging therapies point to the possibility of improvements in longevity that are dramatic rather than incremental, and that reduce morbidity along with mortality. Yet, forecasts produced by governmental and intergovernmental organizations continue to assume a fairly narrow range of upside longevity variation, amounting to at most 10 years of added life expectancy. In this study, we take the opposite approach, exploring a future of very rapidly expanding life expectancy coupled with very low senescence. Using International Futures, a large-scale, long-term, integrated forecasting system, we explore the demographic, socioeconomic and ecological consequences of, and necessary adaptations to, such a world.

The purpose of this paper, then, is to consider the issues raised by a future of very rapidly expanding life expectancy coupled with very low senescence. More specifically, we want to look at how the world might evolve were there to be, over a 20-year period beginning as early as 2020, a rapid development and deployment of technologies that nearly eliminated mortality and morbidity from disease as well as eliminating infecundity. We label this world that of a Negligible Senescence scenario. We juxtapose this world with a Base Case scenario of more slowly progressing extension of life expectancy, accompanied by delayed but not ultimately reduced senescence (a more common forecast than that of negligible senescence). Our goal is not to model a likely future world, but rather to frame our understanding of the potential consequences of negligible senescence by evaluating the effects of a rapid and universal transition to such a regime.

We find that a world of negligible senescence would pose a number of immense challenges that go well beyond increased population size. The most obvious and immediate challenge lies with disseminating and paying for the life-saving intervention set itself. We estimate that rollout of such an intervention on a widespread basis would be infeasible even in the wealthiest countries if the initial price were set at 10,000 per year of healthy life added. At the price of 5000 per added healthy-life-year that we assumed through much of this paper, the initial financial burdens would be manageable for wealthy countries and would, over time, yield considerable reductions in disease-related expenditures that would more than offset the cost of the intervention. Yet poor and also middle-income countries would struggle to finance such an intervention even if, as we assumed, up to 95% of the costs in the poorest countries were defrayed through price reductions of the sort that have recently been observed for high-impact antiretroviral treatments.

With these caveats in mind, a world of negligible senescence would likely yield a still growing population of 14.8 billion by the year 2100, a considerable increase over the 7 billion today or the 10.1 billion forecast in our Base Case in 2100. Uncertainty in fertility, arising from the potential pronatalist impact of increased fecund spans and, on the other hand, the public interest in reducing fertility to check population growth, could yield a population with as many as 20 billion or as few as 11.6 billion.

A revolutionary jump in human longevity would require a comparable revolution in the meaning and timing of retirement. We explore scenarios that would see the average age of retirement rising to 114 by 2100 if fertility remained moderate. Even these relatively aggressive increases in retirement age necessitated a rise in savings from 22% today to 29% and doubling public pensions as a share of GDP, from 6% to something more like 14%. These increases would seem to be at the absolute edge of feasibility, and thus our retirement age scenarios should probably constitute something of a lower bound. On a positive note, individuals would still be able to enjoy decades of post-retirement life if they so chose, or embark on new patterns of employment, education, and leisure that are less defined by imminent mortality than the current pattern.

The potential addition of billions of people would concern many, especially given that this population (in the absence of negative feedbacks from environmental constraints) would see a GDP per capita 30% above the already substantial economic growth built into our Base Case. Energy demand levels, even with quite optimistic assumptions about efficiency gains and renewable contributions, would drive atmospheric CO2 levels above 600 ppm and, if coal were more heavily drawn upon without carbon sequestration, to 800 ppm or above. In the absence of food production technologies that are currently not on the forecast horizon, it might become nearly impossible to reduce the portion of the world's population that is undernourished.

Friday, August 7, 2015

Researchers here investigate the mechanisms involved in thymic involution, the atrophy of the thymus that occurs early in adulthood. The scientists propose that this atrophy occurs because thymus tissue is deficient in natural antioxidant compounds, and is thus unable to resist even normal levels of oxidative stress in the body.

The thymus plays an essential role in the process of generating new immune cells to tackle threats such as viruses, bacteria, and rogue cells. In childhood this organ is very active, but in adult life the flow of new immune cells slows to a trickle as a result of atrophy of the thymus. This is one of the factors contributing to the age-related decline of the immune system, and a number of research groups are investigating ways to rejuvenate or replace the thymus so as to provide a larger supply of active, useful immune cells to adults. This research on the cause of thymic involution is probably less relevant to rejuvenation, as the damage is already done in those of us needing a new thymus, but it may be useful when it comes to the ongoing protection and maintenance of a rejuvenated or replaced thymus.

The development of interventions to slow the progression of thymus atrophy has been limited by the lack of knowledge about the underlying mechanisms. The prevailing theory suggests that sex hormones play a key role, but this explanation does not account for the accelerated speed at which the thymus diminishes in size in comparison to other tissues. Researchers developed a computational approach for analyzing the activity of genes in two major thymic cell types - stromal cells and lymphoid cells - in mouse tissues, which are very similar to human thymic tissues in terms of function and the properties of atrophy. They found that stromal cells were deficient in an antioxidant enzyme called catalase, resulting in the accumulation of free radical and metabolic damage.

To test whether catalase deficiency plays a causal role in thymus atrophy, the researchers performed genetic experiments to enhance catalase levels in mice. By 6 months of age, the size of the thymus of the genetically engineered mice was more than double that of normal mice. Moreover, mice that were treated with two common antioxidants from the time of weaning achieved nearly normal thymus size by 10 weeks of age. "Our studies show that, rather than an idiosyncratic relationship to sex steroids, thymic atrophy represents the widely recognized process of accumulated cellular damage resulting from lifelong exposure to the oxidative byproducts of aerobic metabolism."

Taken together, the findings provide support for the free-radical theory of aging, which proposes that reactive oxygen species such as hydrogen peroxide cause cellular damage that contributes to aging and a variety of age-related diseases. These toxic molecules, which form in cells as a natural byproduct of the metabolism of oxygen, have been linked to progressive atrophy in many organs and tissues as part of the normal aging process. However, these are generally slow, progressive processes that do not become apparent until late in life and often go mostly unnoticed.


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