After controlling for other factors, hypertension risk increases as excess fat tissue increases, according to the data from a recent epidemiological study. The more overweight you are, the greater your blood pressure, all other things being equal. Hypertension is no small thing: raised blood pressure damages delicate tissue throughout the body, such as via ruptures in tiny blood vessels in the brain, and it leads to the growth and weakening of heart muscle that ends in heart failure. Hypertension also accelerates the progression of atherosclerosis, and it raises the risk that blood vessels compromised by atherosclerotic plaque will rupture, causing a fatal stroke or heart attack.

It isn't hard to suggest mechanisms that might link visceral fat tissue to hypertension. Visceral fat produces chronic inflammation through a range of mechanisms: inflammatory signaling by fat cells; greater numbers of inflammatory senescent cells; the creation of oxidized lipids; debris from dead fat cells; and more. Chronic inflammation in turn is thought to impair the operation of smooth muscle responsible for constriction and relaxation of blood vessels. When blood vessels cannot react to the environment as well as they should, when they stiffen, then hypertension follows. This seems the most plausible mechanistic link between weight, aging, and blood pressure.

The present study was undertaken to provide a better insight into the relationship between different levels of body mass index (BMI) and changing risk for hypertension, using an unselected sample of participants assessed during the Longevity Check-up 7+ (Lookup 7+) project. Lookup 7+ is an ongoing cross-sectional survey started in June 2015 and conducted in unconventional settings (i.e., exhibitions, malls, and health promotion campaigns) across Italy. Candidate participants are eligible for enrollment if they are at least 18 years of age and provide written informed consent. Specific health metrics are assessed through a brief questionnaire and direct measurement of standing height, body weight, blood glucose, total blood cholesterol, and blood pressure.

The present analyses were conducted in 7907 community-living adults. According to the BMI cutoffs recommended by the World Health Organization, overweight status was observed among 2896 (38%) participants; the obesity status was identified in 1135 participants (15%), with 893 (11.8%) participants in class I, 186 (2.5%) in class II, and 56 (0.7%) in class III. Among enrollees with a normal BMI, the prevalence of hypertension was 45% compared with 67% among overweight participants, 79% in obesity class I and II, and up to 87% among participants with obesity class III. After adjusting for age, significantly different distributions of systolic and diastolic blood pressure across BMI levels were consistent. Overall, the average systolic blood pressure and diastolic blood pressure increased significantly and linearly across BMI levels. In conclusion, we found a gradient of increasing blood pressure with higher levels of BMI. The fact that this gradient is present even in the fully adjusted analyses suggests that BMI may cause a direct effect on blood pressure, independent of other clinical risk factors.

Link: https://dx.doi.org/10.3390/nu10121976

Why do people with the APOE4 variant of APOE have a much greater risk of Alzheimer's disease? Past work has focused on its role in accelerating amyloid-β accumulation by disrupting recycling mechanisms in some way. Evidence is provided here for the relevant mechanisms to trace back to the acidity of the environment within parts of the cellular recycling system which APOE operates. APOE4 is more prone to dysfunction in that environment than is the case for other APOE variants. Manipulating the regulators of acidicity may thus enable Alzheimer's disease to be slowed down at its very earliest stage - though the size of that effect in patients is a question mark. It seems plausible that it will have little effect on people with variants other than APOE4, for example.

ApoE is a lipid and cholesterol carrying protein that is primarily produced by the liver and is responsible for plasma lipid homeostasis. It occurs in three major isoforms in humans known as ApoE2, ApoE3 and ApoE4, with ApoE3 being the most frequent allele (~77% homozygosity) followed by ApoE4 (~15-20% allele frequency) which is present in more than 50% of late onset Alzheimer's disease patients. The effect of ApoE4 on amyloid-β (Aβ) accumulation through impaired Aβ turnover, increased aggregation, and thus plaque formation is allele dosage-dependent and this can partly explain its effect on the earlier age of disease onset. However, ApoE4 can independently impair synapse function and Ca2+ homeostasis by disrupting the endocytic transport and recycling of synaptic ApoE receptors and the excitatory AMPA and NMDA type glutamate receptors that are regulated by those ApoE receptors and that are consequently trapped with them in the same vesicles.

The molecular basis by which ApoE4 causes the disruption of normal endosomal vesicle transport and recycling is most likely the result of its propensity to unfold and assume a 'molten-globule' conformation upon entering an acidic environment. ApoE4 differs from ApoE3 by a single amino acid, which alters its isoelectric point to coincide with the pH of ~6.5 that is present in the early endosome. We hypothesized that this isoelectric charge neutralization would make ApoE4 prone to aggregation, which could be the molecular basis for the ApoE4-induced and gene dosage-dependent recycling defect.

pH in the early endosome is maintained by the opposing functions of the proton pump, which decreases vesicular pH, and the Na+/H+ exchanger NHE6, which increases it. Here, we have investigated the role of NHE6 inhibition as a means of lowering endosomal pH, away from the isoelectric point of ApoE4. We found that this simple pharmacological intervention releases the endosomal ApoE4 block, restores the normal trafficking of ApoE receptors and glutamate receptors in neurons and corrects the functional defects in vitro and in vivo. Together these findings suggest that drugs that make vesicles in neurons more acidic may have the potential to help prevent individuals that carry the ApoE4 protein from developing Alzheimer's disease. Current drugs that target NHE6 also affect other molecules, which can often lead to side effects. A next step will be to develop tailor-made, small molecule drugs that can enter the brain efficiently and selectively block NHE6.

Link: https://doi.org/10.7554/eLife.40048

A golden future is ahead of us. Humanity will build wonders upon the Earth, cities on the moon and Mars. There will be arcologies to touch the skies, artificial general intelligences that surpass the minds of humanity, molecular assemblers constructing the necessities of life from soil, resurrected dinosaurs grazing alongside de novo unicorns, and probes departing for the nearest stars. There will be wealth beyond measure, in an age of plenty for all. Hunger and disease will be banished, even as we engineer all of the greatest dreams of past visionaries into reality.

But what does any of this matter without longevity, without radical life extension, without an end to aging? The present, seen from the perspective of futurists two or three centuries past, already appears a golden age of staggering, near-magical machineries. An era of grand wealth and comfort, in which even the poorest of the wealthy nations live the lives of nobility, immune to famine and pestilence. But our cities and our achievements, the towering spires and the internet, the freeways and clinics, are little more than monuments to their originators. The engineers and the creators and the visionaries of this modern world of ours are long dead or even now dying of old age.

It is a noble thing to build a greater technology, to generate the wealth of choice and capability that will aid billions in years to come. To contribute to the construction of the golden future, one step at a time, is right and proper. Yet without biotechnologies to control aging, whatever you or I choose to build will be nothing more than a bigger and better monument to our passing, one increment greater than the monuments of our predecessors, and what difference that to the dead? It will become one of the countless tombstones of our age, of the all too short span of years in which we and our fellow travelers lived. Then we will be gone, and only the tombstones remain, and then even those will crumble.

We put fences around graveyards. That is a foolish thing, a wished-for separation of concerns that does not and cannot exist. Every city, every building, every road is a marker of the dead. Every last cultivated part of our environment was touched by someone who is now no more, gone to oblivion. When we walk into the doors, or drive over the asphalt, it becomes a marker for us as well. For our generation. This will be the way of it. Whatever we strive to build, no matter how noble, no matter how useful, it will be nothing more than a tombstone, a monument, a marker destined to be worn down to nothing while we no longer exist. What is the point to this?

The true value of building a better future can only exist when we are all assured of living to participate in that future, in health and vigor, of sound mind and body. A house can only be a house and not a tomb if its architect and resident is alive. Yes, we should build wonders, because we can, because we can dream into existence a far better world. But of greater importance than any other technology, we must build the means to end aging, to enable life to continue for as long as desired. Until we do, we are merely marking time amidst grave sites that will all too soon be our own, and therefter the grave sites of the next generation, and ever on until we break this cycle. Until we do, all that we achieve is ultimately meaningless. There is no continued story, there is no progression, there is simply death, oblivion, and an end, too soon, over and over again.

We can divide aging into primary aging and secondary aging. Primary aging is inherent to the operation of our biochemistry, a relentless accumulation of damage that historically we could do little about, while secondary aging is driven by the environment, such as the pathogens we encounter, particulate air pollution, bad choices in diet, and a sedentary lifestyle. There is a very large gray area where primary aging meets secondary aging, and indeed it is far from settled where the line lies. The commentary here, proposing the concept of the envirome, falls into this area of inquiry.

To determine what is primary and what is secondary in aging, we would need a comprehensive model of the detailed progression of aging. I don't expect that model to be produced any time soon. Firstly, it is a truly massive undertaking that will only be completed in this century given significant technological progress over the next few decades. Secondly, the progression of aging will become a moving target in the near future era of rejuvenation therapies. Who will care about the degree to which a specific mechanism of damage results from primary or secondary aging when it can be controlled near completely through periodic repair? The impetus to fund the deep, detailed investigation of aging will fade with the control of aging.

Although variations in the rate of aging across species suggests a strong role of genetics, the heritability of lifespan observed within each species is less than 35%, indicating that the environment plays an predominant role in aging. The reliability theory of aging portrays organisms as mechanical systems that contain components with varying probabilities of failure. Complex organisms have redundancy in vital systems (perhaps better understood as the capacity to self-repair) so that every occurrence of damage does not result in death, but rather, the organism accumulates defects (due to inefficient repair) that ultimately exhaust reparative capacity.

While, in the context of this theory, the frequency and severity of damage has been thought to be determined, at least in part, by the environment, there are few, if any, conceptual models with robust explanatory power and predictive capacity to account for the influence of the environment on the rate of aging. In this regard, the concept of the envirome, analogous to the genome, could provide a useful ontological model for studying the relationship between the environmental circumstance and genetic predisposition.

Broadly, the envirome could be thought of as an integrated set of natural, social, and personal environmental domains. The natural domain of the environment consists of ecological and geographic conditions, whereas the social environment, which lies within the natural environment, includes the built environment, social networks, and culture. Lastly, the personal environment lies within the social environment and includes the factors specific to an individual. In this model, interactions of the natural and social domains of the envirome with the genome could be viewed as the major determinants of aging. Aging, in turn, could be viewed as a progressive accrual of damage or unrepairable injury that results from a mismatch between the envirome and the genome and from exposure to adverse environmental conditions such as low socioeconomic status, smoking, or air pollution.

Link: https://doi.org/10.18632/aging.101709

Researchers here report on a mechanism that increase the regenerative capacity of brain cells following the damage of a stroke, at least in mice. There are now a few similar approaches demonstrated in the laboratory, but it remains to be seen whether any of them will lead to therapies in the near future. It is certainly the case that mammalian cells do not respond to structural damage and loss of blood supply in the most optimal way; many of their reactions make matters worse, not better. Perhaps that can be adjusted safely and soon, though it would be far preferable to focus on potential ways to prevent that sort of event from occurring at all, such as better maintenance of blood vessels, control of atherosclerosis, and the like.

Stroke is a leading cause of death and chronic disability in adults, causing a heavy social and economic burden worldwide. However, no treatments exist to restore the neuronal circuitry after a stroke. The mammalian brain has only a limited ability to regenerate neuronal circuits for functional recovery. While most neurons are generated during embryonic brain development, new neurons continue to be produced in the ventricular-subventricular zone (V-SVZ) of the adult brain.

In a rodent ischemic stroke model induced by transiently blocking the middle cerebral artery, the most commonly affected vessel in human patients, some V-SVZ-derived neuroblasts migrate toward the lesion, where they mature and become integrated into the neuronal circuitry. However, the number of these new neurons is insufficient to restore neuronal function. Within a few days after stroke, astrocytes, a major population of macroglia, in and around the injured area become activated, exhibiting larger cell bodies, thicker processes, and proliferative behavior. The migrating neuroblasts must navigate through this astrocyte meshwork to reach the lesion.

The research team demonstrated that neuroblast migration is restricted by the activated astrocytes in and around the lesion. In normal, olfaction-related migration, neuroblasts secrete a protein called Slit, which binds to a receptor called Robo expressed on astrocytes. Slit alters the morphology of activated astrocytes at the site of neuroblast contact, to move the astrocyte surface away and clear the neuroblast's migratory path. However, in the case of brain injury, the migrating neuroblasts actually down-regulated their Slit production, crippling their ability to reach the lesion for functional regeneration. Notably, overproducing Slit in the neuroblasts enabled them to migrate closer to the lesion, where they matured and regenerated neuronal circuits, leading to functional recovery in the post-stroke mice.

Link: https://www.eurekalert.org/pub_releases/2018-12/nion-ans120918.php

As the year draws to a close, more than half of the SENS Patron 2018 challenge fund remains to be claimed. Fight Aging! and the other fund donors challenge you to make a commitment to the SENS Research Foundation and progress towards rejuvenation therapies that can bring an end to the suffering and debility that accompanies aging. Become a SENS Patron by setting up a monthly donation to the SENS Research Foundation, and we will match the next year of your gifts in support of the research programs ongoing in the network of labs and scientists dedicated to aging research.

It has never been as easy as it is today to help ensure that the decline and death of late life ceases to be inevitable. Competent, proven organizations such as the SENS Research Foundation and Methuselah Foundation offer reliable ways to direct funds to this goal, and making a charitable donation takes just a few moments online. Become a SENS Patron to support the SENS Research Foundation with regular donations, or join the Methuselah 300 to do the same for the Methuselah Foundation programs. Thanks to the efforts of the past twenty years, the first rejuvenation therapies are accepted and on their way to the clinic. No longer must we argue over the plausibility of turning back aging; now we only argue over how best to go about it.

As it happens, the best way forward in the matter of treating aging as a medical condition, a condition that can be controlled and minimized, is outlined by the SENS rejuvenation research programs. It involves building new therapies that can repair the well-known and well-cataloged forms of cell and tissue damage that lie at the root of aging. Yet even as easy as it is to make charitable donations to support this work, most of the SENS agenda is still poorly funded and little worked on when compared with the mainstream of medicine, in which tens of thousands of scientists and physicians engage in heroic, futile efforts to stave off aging, failing because they are not focused on repairing its causes. The consistent failures of the past have led to a culture in which failure is expected - but this is only the result of a bad choice of strategy. It can be changed.

The first rejuvenation therapies, involving senolytic drugs to selectively destroy senescent cells, are a going concern, but we are far from where we should be when it comes to the rest of the rejuvenation biotechnology toolkit. The philanthropic research programs that aim to unblock and open up important lines of research into repairing the causes of aging are still very important and very necessary. They still lack sufficient funding and support for meaningful progress. Our bodies are packed with scores of forms of metabolic waste, and few of the approaches needed to clear that waste are close to the point at which clinical development can begin. We have a lot of work to do!

This is how I can, on alternate days, first celebrate our progress (and we should celebrate, as we have achieved a great deal since the days in which rejuvenation therapies based on repair of damage were only a tenuous vision) and then the very next day bemoan the state of funding and limited focus. Collectively, our community has launched the senolytic revolution in medicine, but another dozen revolutions in the treatment of aging must still be brought to the point of readiness. All of the damage must be repaired, not just one thin fraction of it. So please, help us to move faster towards this goal.

The Life Extension Advocacy Foundation recently published an interview with Aubrey de Grey of the SENS Research Foundation, on the occasion of the Longevity World Forum in Valencia, Spain. This interview ties in nicely with recent questions regarding whether we should be optimistic or pessimistic about progress toward human rejuvenation over the next ten to twenty years. It is not easy to predict the future, and it is true that even people closely connected to specific ares of work tend to overestimate the progress of a decade and underestimate the progress of two decades. For my part, I am of the opinion that, given the accelerating pace of the underlying science, when moving out to longer time frames the enormous, unnecessary costs and slowdown imposed by regulation of medicine becomes the largest determining factor governing clinical availability of new classes of medical biotechnology.

It was published recently that a therapy to reverse aging will be a reality within five years. What will be its mechanism of action, roughly?

There will not be just one medicine; there will be a lot of different medicines, and they will all have different mechanisms of action. For example, some of them will be stem cells, where we put cells back into the body in order to replace cells that the body is not replacing on its own. Sometimes, they will be drugs that kill cells that we don't want. Sometimes, they will be gene therapy treatments that give cells new capabilities to break down waste products, for example. Sometimes, they will be vaccines or other immune therapies to stimulate the immune system to eliminate certain substances. Many different things. In five years from now, we will probably have most of that working. I do not think that we will really have it perfect by then; probably, we will still be at the early stages of clinical trials in some of these things. Then, we will need to combine them, one by one, to make sure that they do not affect each other negatively. So, there will still be some way to go. But, yes, I think it's quite likely that in five years from now, we will have everything, or almost everything, in clinical trials.

Then clinical trials for seven years until it's perfected. Don't clinical trials usually take a long time?

It depends. For example, in aging, because there is this progressive accumulation of damage, you could have therapies that slow down the rate at which damage accumulates, or you could have therapies that repair the damage that has already happened. The second type of therapy is what we think is going to be most effective and is going to be easiest to do, and you can see results from that very quickly, like in one or two years. Now, of course, you still want to know what happens later on, but the first thing is to determine whether this is working at all, and as soon as it starts to work, then you can start to make it available. Clinical trials are changing in that way. Historically, clinical trials had to be completed before anybody could get these drugs, but now we are getting new policies; there is a thing called adaptive licensing, which is becoming popular in the US and elsewhere, where the therapy becomes approved at an earlier stage, and then it's monitored after that.

Beyond the humanitarian perspective of avoiding the pain and suffering that comes with old age, if increasing the years of healthy life in people will significantly reduce health care spending by governments, why don't they promote research in this area?

You're absolutely right. It's quite strange that governments are so short-sighted. But, of course, the real problem is psychological: it's not just governments that are short-sighted. Almost everybody in the world is short-sighted about this. The reason I believe why that's true is people still can't quite convince themselves that it's going to happen. Since the beginning of civilization, we have known that there is this terrible thing called aging, and we have been desperate to do something about it, to get rid of it. And people have been coming along, ever since the beginning of civilization, saying, "Yes, here's the solution, here's the fountain of youth!" And they've always been wrong. So, when the next person comes along and says they think they know how to do it, of course, there is going to be some skepticism until they have really shown that it's true. Of course, if you don't think it's going to work, then you're not going to support the effort financially. It's very short-sighted, but it's understandable.

Why do you think that the pharmaceutical industry does not devote its research and development efforts to this area, which causes the death of 100,000 people every day?

Today, the pharmaceutical industry is geared toward keeping old people alive when they are sick. It makes its money that way. It's not just the pharmaceutical industry, it's the whole of the medical industry. And so, most people say that they are worried that maybe the pharmaceutical industry will be against these therapies when they do come along. I don't think that's true at all. I think they will be in favor because people will be in favor, but people are not really in favor yet. People don't really trust preventive medicine. They think "Okay if I am not yet sick…" They don't trust medicine in general; they know that this is experimental. So, when they are not yet sick, they think "Well, I'll wait until I am sick," but we can change that. Eventually, people will understand that it's going to be much more effective to treat yourself before you get sick, and then the whole medical industry will just respond to that; they will make the medicines that people want to pay for.

Link: https://www.leafscience.org/aubrey-de-grey-valencia/

Researchers here find that the beneficial effects of regular exercise on bone density and strength are mediated in part by irisin, which acts on a receptor found on the surface of osteocytes. Osteocytes are a class of cell responsible for the constant remodeling of bone tissue that takes place throughout life, alongside osteoclasts and osteoblasts. The loss of density and strength in bone that occurs in later life, known as osteoporosis, is an imbalance between creation and destruction of bone. It might be reduced by means of modifying the behavior of the cells responsible for these activities, though to my eyes it would be preferable to identify the forms of underlying damage in aging that lead to this imbalance and then work to repair them.

Researchers have proposed that the irisin hormone serves as a link between exercise and its beneficial effects on health, including burning fat, strengthening bones, and protecting against neurodegenerative diseases. Until now, however, researchers hadn't identified a specific molecular receptor for irisin - in effect, a docking structure allowing irisin to bind to cells and tissues. They are now reporting that the irisin receptor is a group of proteins called integrins situated on the surface of osteocytes.

Osteocytes are cells that act as the "command and control unit" for bone remodeling - that is, the loss and replenishment of bone that occurs both normally and in pathological states. Some research previously found that intermittent injections of irisin increased bone density and strength in mice. Now that it has shown that irisin targets the osteocyte through a specific receptor, the irisin-bone connection can be explored more mechanistically.

Osteocytes gradually die off with age, and their loss is believed to be a cause of age-related osteoporosis, the thinning and weakening of bones. In cell culture, the scientists observed that treating osteocytes with irisin protected them from being killed by hydrogen peroxide - a simulation of age-related death. The experiments also showed that treating osteocytes with irisin increased their production of sclerostin, a protein that triggers bone remodeling, and injecting irisin into mice raised their sclerostin levels. Sclerostin actually triggers the breakdown of bone, which might seem harmful rather than helpful. However, the intermittent breakdown of bone seems to be interpreted as a signal to remodel and build bones. So how could manipulating irisin be used therapeutically? Some form of intermittent irisin treatment might work.

Link: https://www.dana-farber.org/newsroom/news-releases/2018/exercise-related-hormone-irisin-found-to-target-key-bone-cells/

In older mice and humans, the immune system becomes dysfunctional. It is overactive, producing chronic inflammation that leads to harmful cellular behavior throughout the body, but at the same time it is much less capable when it comes to destroying pathogens and errant cells. In today's open access research, scientists investigate the incapacity of naive T cells in older mice. This population of T cells is necessary for a strong immune response, but their numbers decline due to the involution of the thymus. T cells begin life as thymocytes in the bone marrow, and then migrate to the thymus where they mature into T cells of various types. With advancing age the thymus atrophies, and the active tissue needed for T cell maturation is replaced with fat. The supply of new T cells diminishes, and thus so does the fraction of the overall immune cell population that is made up of naive T cells capable of meeting new threats.

In the research here, it is found that those naive T cells that do remain in old mice are dysfunctional, far less capable than their young counterparts. The mitochondria, the power plants of the cell, are altered and diminished. Many important mechanisms are thus likely compromised, or operating at levels far beneath what is minimally required for adequate cellular function. This mitochondrial malaise is observed in all tissues, but possibly best studied in the context of muscle and brain, both energy-hungry tissues that are greatly affected by a reduced supply of chemical energy store molecules packaged by mitochondria. Clearly similar problems exist in all cells.

Fixing this age-related alteration in mitochondrial structure and function is an interesting challenge. The problem is only peripherally related to the mitochondrial DNA damage of the SENS rejuvenation research program, and appears to be a downstream consequence of some combination of other molecular damage and altered signaling inside and outside cells. There is no clear view of which forms of repair would be most effective, as there is no solid link established between any of the known forms of molecular damage that lie at the root of aging and this general mitochondrial decline. Thus efforts to override specific mitochondrial mechanisms are further ahead as of the moment; providing additional NAD+ to cells, for example, perks up mitochondrial activity. That can be enough to provide incremental benefits to tissue function, as recently demonstrated in a small human trial. There are no doubt other similar possibilities. These are all limited in their upside by the fact that they don't address the underlying causes; there is a great need for more research and development focused on repair of those underlying causes.

The 'Graying' of T Cells

Researchers looked for overall differences between old and young T cells. They isolated T cells from the spleens of young and old mice and noticed that, in general, older mice had fewer T cells. Next, to gauge the cells' immune fitness, the researchers activated the T cells by mimicking signals normally turned on by pathogens during infection. The older T cells showed diminished activation and overall function in response to these alarm signals. Specifically, they grew more slowly, secreted fewer immune-signaling molecules and died at a much faster rate than young T cells. The researchers also observed that aged T cells had lower metabolism, consumed less oxygen and broke down sugars less efficiently. They also had smaller than normal mitochondria, the cells' power-generators that keep them alive

To pinpoint the metabolic pathways behind this malfunction, the scientists analyzed all the different proteins in the cells, including those that might be important for coaxing a T cell from dormancy into a fighting state. The team found that the levels of some 150 proteins were lower-than-normal upon activation of the aged T cells, compared with young T cells. About 40 proteins showed higher than normal levels in aged versus young T cells. Many of these proteins have unknown functions, but the researchers found that proteins involved a specific type of metabolism, called one-carbon metabolism, were reduced by nearly 35 percent in aged T cells.

One-carbon metabolism comprises a set of chemical reactions that take place in the cell's mitochondria and the cell cytosol to produce amino acids and nucleotides, the building blocks of proteins and DNA. This process is critical for cellular replication because it supplies the biologic material for building new cells. The team's previous work had shown that one-carbon metabolism plays a central role in supplying essential biological building blocks for the growing army of T cells during infection. So, the scientists wondered, could adding the products of this pathway to weakened T cells restore their fitness and function?

To test this hypothesis, the team added two molecules - formate and glycine, the main products of one-carbon metabolism - whose levels were markedly reduced in aged T cells. Indeed, adding the molecules boosted T cell proliferation and reduced cell death to normal levels. The researchers caution that while encouraging, the effects were observed solely in mouse cells in lab dishes rather than in animals and must be confirmed in further experiments.

Defective respiration and one-carbon metabolism contribute to impaired naïve T cell activation in aged mice

T cell-mediated immune responses are compromised in aged individuals, leading to increased morbidity and reduced response to vaccination. While cellular metabolism tightly regulates T cell activation and function, metabolic reprogramming in aged T cells has not been thoroughly studied. Here, we report a systematic analysis of metabolism during young versus aged naïve T cell activation.

We observed a decrease in the number and activation of naïve T cells isolated from aged mice. While young T cells demonstrated robust mitochondrial biogenesis and respiration upon activation, aged T cells generated smaller mitochondria with lower respiratory capacity. Using quantitative proteomics, we defined the aged T cell proteome and discovered a specific deficit in the induction of enzymes of one-carbon metabolism. The activation of aged naïve T cells was enhanced by addition of products of one-carbon metabolism (formate and glycine). These studies define mechanisms of skewed metabolic remodeling in aged T cells and provide evidence that modulation of metabolism has the potential to promote immune function in aged individuals.

Earlier this year, researchers provided evidence for expression of TIGIT to mark senescent and exhausted T cells in the immune systems of older individuals. Here, new results reinforce the point that TIGIT-expressing T cells are a burden. These cells cause issues, contributing to the inflammatory and weakened state of the aged immune system. Selectively destroying them should help, and senolytic drugs may achieve this goal, as least insofar as the biochemistry of TIGIT-expressing T cells overlaps with that of better studied varieties of senescent cell in tissues. To what degree this is the case remains to be determined; researchers in the cellular senescence field have far more analysis of this nature in front of them than can possibly be accomplished over the next few years, and this particular case is probably still a fair way down the list by priority.

Researchers have identified that an immune cell subset called gamma delta T cells that may be causing and/or perpetuating the systemic inflammation found in normal aging in the general geriatric population and in HIV-infected people who are responding well to drugs. The team measured many markers on the surface of immune cells in the blood of people either with or without HIV (uninfected controls) that were sub-divided into two groups: younger (less than 35 years) and older (over 50 years) and compared that data with levels of inflammatory proteins in their plasma.

Researchers found a marker on these gamma delta T cells, called TIGIT, that tracked significantly with plasma inflammatory markers in both the HIV+ and uninfected subject groups, and therefore could be targeted to potentially stop this "inflammaging" found in both HIV+ people and the general geriatric population. "Our study indicates that there's a previously uninvestigated cell subset new player in the immune landscape that could be driving widespread illnesses and with targeted gamma delta therapeutics maybe there may be a chance of reducing onset, symptoms, and/or severity of inflammation-related diseases."

Link: https://www.eurekalert.org/pub_releases/2018-12/buso-rdu121118.php

At this year's RAADfest event, the interviewer noted here was taking an informal survey of optimistic versus pessimistic attitudes towards progress in the decades ahead. Apparently I was on the pessimistic end of the spectrum. Once past the present highly active development of senolytic therapies to remove senescent cells from old tissues, I think it quite plausible that we'll see a gap of a decade before the next class of SENS-like rejuvenation therapy arrives at the point of availability via medical tourism. The likely candidates include clearance of cross-links and restoration of the immune system via thymic regrowth.

Surprise progress in advance of the end of the 2020s seems implausible, with the exception of the discovery that an existing small molecule drug or otherwise widely available low cost compound breaks down significant amounts of some form of molecular waste, such as oxidized cholesterol or glucosepane cross-links. That is possible to engineer, given the resources, but so far as I know next to no-one is screening the compound libraries with this in mind. It is an expensive task with uncertain chances of success. This present state of the market, that there is a gulf of further required development ahead, is perhaps a little obscured by the excitement over senolytics. There is, however, a continued need for philanthropic support of lines of research that remain poorly funded. If senolytics are to be closely followed by the rest of the rejuvenation toolkit, then we still have a great deal of work to do.

What are the most promising near-term therapies that may actually turn back the clock on biological aging?

Senolytic treatment, obviously, is the one that is here already and is presently available. It is fortunate that some of the first drugs identified to have this effect are, to a significant degree, already widely used and cheap. The animal results are far better in terms of robustness and reproducibility than any of the calorie restriction mimetic and other stress response tinkering work. The first human data from formal trials will arrive late this year or in early 2019. These first-generation approaches are killing only about half of the senescent cells at best (and far fewer than that in some tissues) but are nonetheless very effective in comparison to any other approach to age-related inflammatory disease.

The next approach to arrive that will likely have a similar character and size of effect is breaking of glucosepane cross-links, but since that involves a completely new enzyme-based therapy, we're unlikely to see it in people any sooner than a decade from now. If there is interest in that field, someone might uncover a useful small molecule prior to then, but it seems unlikely.

Other than that, over that same timeframe: (a) advances in stem cell medicine, moving beyond the simple transplantation therapies that do little other than suppress inflammation towards ways to actually replace damaged populations and have them get to work; (b) removal of amyloids through means other than the immunotherapies that are the present staple of that field; (c) forms of immune system restoration, such as via thymic regrowth, replacement or enhancement of hematopoietic stem cells, and clearance of problem immune cells.

I'm not convinced that there is an enormous benefit to be realized from approaches to enhance mitochondrial function, such as NAD+ precursors and mitochondrially targeted antioxidants, that get a lot of hype and attention. They may have a small positive effect on metabolism in later life, which would make them worth taking when cheap and safe. They are not in any way reversing aging - they are forcing a damaged machine to work harder without addressing any of the causes of failure. One can paint the same picture when discussing ways to enhance stem cell function without addressing the underlying damage, such as telomerase therapies and the use of signaling molecules. It may meet the cost-benefit equation, but it also may not, since these are much more expensive propositions.

Why is breaking extracellular crosslinks so important?

This is important because cross-links cause stiffening of tissues. The stiffening of blood vessels is the cause of hypertension, and hypertension is (like inflammation) a major way in which low-level biochemical damage is translated into many different forms of structural damage: pressure damage to delicate tissues; rupture of capillaries in the brain; remodeling and weakening of the heart; increased risk of atherosclerotic lesions causing stroke or heart attack. High blood pressure is very damaging. It is so harmful that ways to reduce blood pressure that work by overriding signaling systems - which do absolutely nothing to eliminate the root cause, the biochemical damage of aging - can still produce large reductions in mortality risk.

All of that can be greatly reduced by cross-link breaking, and there is only one major class of cross-links in humans that needs targeting to obtain that benefit: those involving glucosepane. Thus, like senolytics, once there is some motion towards achieving this end, we should see a very rapid expansion of the industry and delivery of benefits to patients. Glucosepane is hard to work with, so very few groups have done anything meaningful - the first big advance that the SENS Research Foundation achieved in this field was to fund the creation of the tools needed to move forward at all in this part of the field. Even now, there is really only one group working earnestly on it that I know of, David Spiegel's team at Yale, with a couple of others doing some investigative work around the edges of the challenge. The Spiegel approach is to mine the bacterial world for enzymes that degrade glucosepane and then refine the successes into therapeutic drugs. His team is a fair way along, and work is progressing in a funded startup company at this point.

Link: https://www.leafscience.org/an-interview-with-reason-near-term-life-extension-therapies/

There are any number of reasons why promising lines of research get stuck. Simple abandonment is a surprisingly common one; people outside the scientific community have little appreciation of the degree to which the floor of the forest is littered with valuable raw materials, just waiting for someone to spend the effort to forge them into useful goods. Many researchers have little interest in implementation, or fail to convince funding sources to continue their initial exploration, or the people involved move on, or the tools are hard to use and no-one else wants to make the effort to replicate the discoveries. It is sometimes amazing that anything is accomplished, watching the way in which most academic labs organize themselves.

Another common problem is the lack of suitable tools to manipulate a mechanism of interest, related to disease or aging. Once researchers find a mechanism, and have the means to probe its operation, the next step is to build ways to influence it. Some of the most common traditional tools are genetically engineered animal lineages, in which genes of interest are inserted or removed in the germline, gene therapies that increase or decrease protein levels in cells and adult animals, and small molecules that can increase or decrease protein levels, or interfere in or enhance protein interactions. Of those, only small molecules have traditionally resulted in clear path to clinical application, though gene therapies are starting to become more practical for those purposes.

What happens when researchers have an interesting mechanism, but don't have a small molecule that can manipulate that interesting mechanism? Well, they are stuck when it comes to moving closer to the clinic, unless they can raise a fairly sizable amount of funding for screening, as well as produce a sufficiently cheap screening methodology to allow a very large number of compounds from the standard libraries to be tested. The cost of a comprehensive screening exercise to find candidate small molecule drugs can be a few million dollars, which is why there are a sizable number of companies working on ways to reduce that cost and raise the odds of success. Expending these sizable resources offers no guarantee of finding a viable compound, or even a viable starting point. That is why many projects just stop right there, and remain halted until the slow grind of grant-writing and incremental discovery leads to a potential candidate compound in some other way.

In recent years, the new ability to cultivate arbitrary bacterial species from soil, rather than the tiny minority that has traditionally been the case, has unlocked the door for compound discovery relating to destruction of problem molecules. Every molecule in the human body can be consumed and broken down by at least one species of soil bacteria. Finding the tools that bacteria use for that purpose is low-cost and reliable in comparison to old-style screening from compound libraries: just grab a soil sample, separate the bacteria, drop in the protein that needs destruction, and see which of the bacteria thrive on that diet. A number of research groups have produced proof of principle results with modest budgets.

While that works just fine for targets such as the 7-ketocholesterol associated with atherosclerosis, as well as glucosepane cross-links, both of which are implicated in the aging process, and that we'd be far better off without, the approach doesn't work when the objective is to alter rather than destroy aspects of cellular metabolism. For example, it would be very useful to have drugs that interfere in the operation of alternative lengthening of telomeres (ALT), a mechanism that is only active in cancer cells. All cancers must lengthen their telomeres constantly in order to maintain rampant growth. If both ALT and telomerase-based telomere lengthening could be suppressed, then cancers would wither.

Work on finding ways to manipulate ALT is essentially stuck on the point that someone needs to spend a few million dollars in order to buy a chance at finding a candidate small molecule drug. No-one really wants to take that wager, and would much rather wait on incremental progress in the field to turn up a possible path forward. Perhaps that will happen in a year, perhaps not for twenty years, no-one can tell. It seems to me that for those areas of research blocked in this way, and where success would be very valuable, then paying for the screening would be a sensible act of high net worth philanthropy. For that to take place, however, it would require either a good understanding of the field on the part of more wealthy individuals, or a good packaging of the ideas involved on the part of a non-profit entity.

Macrophages of the innate immune system play an important role in coordinating the intricate dance of cell populations that takes place during regeneration from injury. Differences in macrophage behavior may be key to the exceptional regenerative capacities of species such as salamanders that can regrow entire organs, and possibly also in the few mammalian species and genetically altered lineages capable of noteworthy feats of regeneration.

Researchers here make a most interesting discovery, finding that in mice there are populations of macrophages capable of coordinating greater than normal regeneration following injury to the heart, such as that resulting from a heart attack. This regeneration doesn't take place because the macrophages arrive too late to prevent the formation of scar tissue; regeneration is already well advanced by the time they are present in any significant number. This suggests that regenerative therapies based on manipulation of macrophage behavior are plausible for the near future, as it is always easier to adjust an existing mechanism than it is to build something completely novel.

Macrophages are white blood cells that live in organs and are key components of our immune system. They have a well-established ability to fight infections, but more recently, have been shown to help promote repair and regeneration of tissues. Researchers have found that instead of a single type of macrophage, there are at least four types that live within the uninjured heart, and that number increases to 11 after a heart attack, which indicates the immune system behaves in much more complex fashion than was imagined.

First, they found that neonatal-like macrophage cells are lost after a heart attack in adults, which could explain why the adult heart may not heal itself as well as the neonatal heart. In very young animals, neonatal macrophages increase in number and are very effective at triggering the regrowth of heart muscle and blood vessel cells. "Genetically removing neonatal-like macrophages at the time of the heart attack in adult animals worsens heart function most profoundly at the region of the heart separating injured and uninjured heart muscle - the only zone of the adult heart where they increase in number."

Researchers also found large numbers of macrophages are attracted to the heart after a heart attack, and a small number enter into the neonatal state, except, too late. By the time they arrive on site after a heart attack, a scar has formed in the heart in the place of heart muscle. "Each cell has a unique role to play in the human body, but our next question is: how can we guide a cell that enters the heart into a neonatal state more efficiently and, ultimately, more effectively?"

Link: https://www.uhn.ca/corporate/News/Pages/Study_finds_macrophage_cells_key_to_helping_heart_repair_and_potentially_regenerate.aspx

One way to identify the important mechanistic links between metabolism and longevity is to examine the genomes of unusually long-lived species. This has long been underway for naked mole rats and some smaller bats, species that live many times longer than similarly sized near relatives. The same sort of longevity occurs in parrots; other birds of their size live for perhaps a decade or two, but parrots exhibit a similar life span to that of humans, given a safe and supportive environment. Scientists here report on their initial investigations of the parrot genome, and a comparison with less long-lived birds. As for the case for all similar research, it remains an open question as to whether any of the findings will turn out to be of practical use when it comes to developing the means to significantly lengthen healthy human life spans.

Parrots are one of the most distinct and intriguing groups of birds, with highly expanded brains, highly developed cognitive and vocal communication skills, and a long lifespan compared to other similar-sized birds. Yet the genetic basis of these traits remains largely unidentified. To address this question, we have generated a high-coverage, annotated assembly of the genome of the blue-fronted Amazon (Amazona aestiva) and carried out extensive comparative analyses with 30 other avian species, including 4 additional parrots.

We identified several genomic features unique to parrots, including parrot-specific novel genes and parrot-specific modifications to coding and regulatory sequences of existing genes. We also discovered genomic features under strong selection in parrots and other long-lived birds, including genes previously associated with lifespan determination as well as several hundred new candidate genes. These genes support a range of cellular functions, including telomerase activity; DNA damage repair; control of cell proliferation, cancer, and immunity; and anti-oxidative mechanisms.

We also identified brain-expressed, parrot-specific paralogs with known functions in neural development or vocal-learning brain circuits. Intriguingly, parrot-specific changes in conserved regulatory sequences were overwhelmingly associated with genes that are linked to cognitive abilities and have undergone similar selection in the human lineage, suggesting convergent evolution. These findings bring novel insights into the genetics and evolution of longevity and cognition, as well as provide novel targets for exploring the mechanistic basis of these traits.

Link: https://doi.org/10.1016/j.cub.2018.10.050

Today's research results, published a few months ago, are one of a number of examples from recent years of a possible way to suppress or destroy persistent herpesviruses such as cytomegalovirus (CMV). These viruses cannot be effectively cleared from the body by the immune system; they remain latent to reemerge time and again. CMV itself is of particular interest because it is strongly implicated in the age-related dysfunction of the immune system. Research suggests that in old age an unsustainable fraction of immune cells become devoted to CMV, and since the decline of the thymus and hematopoietic stem cells ensure that the supply of replacement immune cells is reduced to a trickle, too few capable immune cells remain to adequately address other threats.

A range of studies provide evidence for people with greater exposure to CMV have a worse prognosis in later life, but it is far from clear as to whether (a) this is a burden that accumulates over time, and length of exposure is important, as studies of childhood adversity suggest, or (b) the burden arrives near entirely in later life, despite life-long infection with CMV, and requires some initial decline in immune function to start the process in earnest. The interesting question is whether it is worth trying to clear CMV from the body, given that it is largely harmless to young people, or whether the real target is the damage done to the immune system.

That damage, in the form of too many specialized immune cells and too low a rate of generation of new immune cells, will remain in effect even if CMV can be banished from the body of an older individual. The deficits of the aged immune system will have to be addressed via other approaches, such as targeted removal of CMV-specialized cells and regeneration of thymus and hematopoietic stem cells to restore a more youthful supply of new immune cells. Achieving those goals may well make CMV irrelevant. That said, it is worth considering getting rid of CMV might be more or less effective as a way to improve health in later life depending on when and how rapidly the consequent immune damage emerges.

Scientists Find a New Way to Attack Herpesviruses

Human cytomegalovirus is a leading cause of birth defects and transplant failures. As it's evolved over time, this virus from the herpes family has found a way to bypass the body's defense mechanisms that usually guards against viral infections. Until now, scientists couldn't understand how it manages to do so. Normally, when a virus enters your cell, that cell blocks the virus's DNA and prevents it from performing any actions. The virus must overcome this barrier to effectively multiply. To get around this obstacle, cytomegalovirus doesn't simply inject its own DNA into a human cell. Instead, it carries its viral DNA into the cell along with proteins called PP71. After entering the cell, it releases these PP71 proteins, which enables the viral DNA to replicate and the infection to spread.

"The way the virus operates is pretty cool, but it also presents a problem we couldn't solve. The PP71 proteins are needed for the virus to replicate. But they actually die after a few hours, while it takes days to create new virus. So how can the virus successfully multiply even after these proteins are gone?" The researchers found that, while PP71 is still present in the cell, it activates another protein known as IE1. This happens within the first few hours of the virus entering the cell, allowing the IE1 protein to take over after PP71 dies and continue creating new virus. To confirm their findings, the team created a synthetic version of the virus that allowed them to adjust the levels of the IE1 proteins using small molecules.

"We noticed that when the IE1 protein degrades slowly, as it normally does, the virus can replicate very efficiently. But if the protein breaks down faster, the virus can't multiply as well. So, we confirmed that the virus needs the IE1 protein to successfully replicate." The new study could lead to a new therapeutic target to attack cytomegalovirus and other herpesviruses.

Feedback-mediated signal conversion promotes viral fitness

A fundamental signal-processing problem is how biological systems maintain phenotypic states (i.e., canalization) long after degradation of initial catalyst signals. For example, to efficiently replicate, herpesviruses (e.g., human cytomegalovirus, HCMV) rapidly counteract cell-mediated silencing using transactivators packaged in the tegument of the infecting virion particle. However, the activity of these tegument transactivators is inherently transient - they undergo immediate proteolysis but delayed synthesis - and how transient activation sustains lytic viral gene expression despite cell-mediated silencing is unclear.

Using an HCMV mutant, we find that positive feedback in HCMV's immediate-early 1 (IE1) protein is of sufficient strength to sustain HCMV lytic expression. Single-cell time-lapse imaging and mathematical modeling show that IE1 positive feedback converts transient transactivation signals from tegument pp71 proteins into sustained lytic expression, which is obligate for efficient viral replication, whereas attenuating feedback decreases fitness by promoting a reversible silenced state. Together, these results identify a regulatory mechanism enabling herpesviruses to sustain expression despite transient activation signals - akin to early electronic transistors - and expose a potential target for therapeutic intervention.