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Fight Aging! Newsletter, December 2nd 2019

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Posted 01 December 2019 - 02:02 PM

Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,please visit:https://www.fightaging.org/newsletter/

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  • Notes on the 1st Alcor New York Science Symposium
  • Slower DNA Damage Accumulation in Immune Cells Correlates with Species Life Span
  • The Tight Junctions of the Blood-Brain Barrier in Aging and Neurodegeneration
  • Werner Syndrome is Strongly Mediated by Mitochondrial Dysfunction
  • Cardiac Amyloid Buildup Correlates with Risk of Atrial Fibrillation
  • Upregulation of Autophagy Improves Vascular Function in an Animal Model of Type 2 Diabetes
  • To What Degree Does Loss of Skeletal Muscle with Age Contribute to Immunosenescence?
  • In Search of Genes that Were Lost in Longer-Lived Mammals
  • Topical Rapamycin Evaluated as a Treatment for Skin Aging
  • Common Mechanisms of Blood-Brain Barrier Dysfunction to Underlie Many Forms of Damage to the Brain
  • Nanotics Aims at Preventing Senescent Cells from Evading Immune Surveillance
  • Towards Small Molecule Drugs that Suppress α-Synuclein Aggregation
  • SHMT2 in the Age-Related Decline of Mitochondrial Function
  • Reporting on the Aging Research and Drug Discovery Meeting Held at BASAL Life 2019
  • Exercise Reduces Inflammatory Leukocyte Production, Slowing Development of Atherosclerosis

Notes on the 1st Alcor New York Science Symposium

This past weekend, I was in New York City for a meeting organized by Alcor New York, a cryonics community group that is presently seeking to set up a more robust Biostasis Society of New York complete with well-organized standby capacity to help people achieve a successful cryopreservation at the end of life. Setting aside technical issues, the greatest challenge in cryopreservation is the fact the euthanasia, and thus the ability to arrange time of death, remains largely illegal. Hence there must be expensive standby operations, suboptimal deaths that cause significant damage to the brain, and a scramble to ensure rapid cooldown and preservation when death does occur. Since there are only two reputable cryonics providers in the US, local organizations capable of coordinating standby and transport are essential.

A number of folk in the cryonics community can be found in and around New York of late; Aschwin de Wolf and Chana Phaedra of Advanced Neural Biosciences, for example. In the introduction to the meeting, it was noted that early cryonics of the 60s and 70s started as much in New York as in California - there was a Cryonics Society of New York, and restoring that entity seems a worthy goal. There were a few noteworthy visitors from elsewhere, such as one of the Nectome folk, and a representative of the European Biostasis Foundation in Switzerland - this is not CryoSuisse, interestingly enough, but a distinct initiative with some overlapping members.

The talks at the meeting were divided between discussions of progress towards slowing aging or attaining rejuvenation, and discussions of cryonics itself. In general, cryonicists have a strong interest in not dying if all possible, and thus most are quite interested in what is going on in the newly formed longevity industry. The weight given to cryonics is tempered by expectations as to how soon rejuvenation therapies will arrive, and how effective they will be over time.

Joao de Magelhaes presented remotely from the UK, and gave his view on where things stand in working towards therapies to treat aging and thereby slow or reverse age-related degeneration and mortality. He is fairly conservative and pessimistic; he doesn't think that there will be enough progress in our lifetimes to achieve actuarial escape velocity, but he does think that we will see a slowing of aging in our later lives. Therefore cryonics is very important, and it is particularly important to achieve for cryonics the same that has already been achieved for work on the treatment of aging - to move it from a small, comparatively poorly regarded fringe concern to a field with notable technical successes and greater financial support. In this, there is little substitute for the hard work of bootstrapping, advocacy, research in resource constrained environment, and so forth. On the cryonics side of the house, de Magelhaes is involved in setting up the UK Cryonics and Cryopreservation Research Network to spur more academic research into relevant technologies.

Ben Best spoke about NAD+ upregulation and senolytics; he works at the Life Extension Foundation, and the principals there have recently started to heavily promote these approaches to treating aging. To the extent that they work, this is an example of what will happen to the "anti-aging" industry of fraud and hope and supplements that do little good: many of the people involved are motivated to do something about aging, and thus the good should chase out the bad, given time and therapies that actually work. Ben Best has experimented with these approaches to therapy, as one of the physicians connected with the LEF is willing to prescribe the senolytic dasatinib and NAD+ infusions, but committed the cardinal sin of not assessing metrics before and after. This is sadly prevalent in the self-experimentation community. If you don't measure, nothing happened. Still, there is evidence for both NAD+ upregulation and senolytics to be beneficial in older people, and sooner or later ever more physicians will become comfortable enough with the evidene to prescribe these therapies the many who might benefit.

Mike Perry gave a fascinating talk on the early history of cryonics, starting in the mid-1960s. It is eye-opening just how much information can be lost even at a distance of a mere fifty to sixty years. For example, James Bedford was the second preserved individual; the first may have been a woman called Sarah Gilbert, but this is uncertain. Of the fifteen people cryopreserved from 1966 to 1973, only Bedford remains. All of the others were lost to the haphazard, unprofessional nature of the early initiatives. Perry exhibited a short film made in 1968 by members of the New York Cryonics Society, showing the process of cryopreservation in one of the dewars of the time. It is quite the artifact of its era.

Chana Phaedra gave a presentation on paths towards optimization of cryopreservation. The success of cryopreservation depends upon delivery of cryoprotectant to the brain, efficiently and rapidly. At present, even in the best of circumstances the perfusion of cryoprotectant isn't optimal. This is challenging on a number of fronts: the skull is in the way; you can't just push fluid through tissue at high pressures; the blood-brain barrier blocks all cryoprotectants to some degree. The present conclusion based on work at Advanced Neural Biosciences is that the low-hanging fruit here is finding ways to bypass or open the blood-brain barrier. That may mean new cryoprotectants, or some chemical way of disrupting the blood-brain barrier rapidly and selectively. Other options to improve the situation: faster perfusion, less ischemia, and better assays that can be used in animal studies or on preserved human brains to reliably establish the quality of the preservation.

Aschwin de Wolf discussed the prospects for revival of patients who were frozen rather than vitrified, in part or in whole. The present wisdom is that straight freezing - which can and does occur in sections of the brain given a suboptimal perfusion of cryoprotectant - is highly destructive and causes large amounts of ice crystal formation. Can people with this sort of damage be repaired? De Wolf argued that the best approach, conceptually, is some form of low-temperature repair, via nanomachinery capable of operating in a preserved tissue at liquid nitrogen temperatures. The more interesting part of the discussion was a presentation of straight frozen and then thawed brain tissue that doesn't appear to have anywhere near as much damage as we might expect. The state of the tissue is worse than the same case for vitrification, but perhaps not as much worse as thought. More work is needed to assess this conjecture, however.

Since one of the presenters was ill, I filled in and gave an impromptu talk on self-experimentation: how to do it responsibly and effectively. We might consider four classes of self-experimentation at increasing levels of sophistication. Class 1: the sort of thing that everyone does with dieting for weight loss or eating foods and supplements for benefits. Class 2: compounds that are easy to obtain, easy to use, have great human safety data, and that may have effects on aging, such as metformin (a poor idea, I think) or senolytics (a better prospect). Class 3: treatments that are logistically challenging, and that may need a personal lab. Few people would be able to safety inject themselves with myostatin antibodies, for example. Get that wrong, and you die. But it is technically plausible, and helpful in terms of spurring muscle growth, given the evidence. Class 4: treatments that require a company or other significant effort to create. Liz Parrish's efforts with Bioviva , in order to self-experiment with telomerase gene therapy, for example. Or cryonics, for that matter. In near all cases, from dieting to quite sophisticated efforts, people tend self-experiment poorly. They do not do the one fundamental thing, which is to measure the effects.

Researchers in the fields of neurobiology and cryobiology gave a couple of technical presentations. One was an interesting outline of methods that could be used to evaluate the quality of brain preservation protocols, not limited to cryonics. It essentially boils down to examining labelled dendritic spines in neural tissue, which can be done before and after an experimental preservation to see how well the fine structures survived. It is even in principle possible to do this in a brain, rather than just in sections of brain tissue. The second presentation was on the use of computer modelling and machine learning to optimize cryopreservation procedures. There are many variables that can be tweaked, from cooldown trajectory to type and mix of cryoprotectants. Modelling could be used to find optimal parts of this large state space more effectively than other forms of experimentation.

The European Biostasis Foundation (EBF) representative outlined their efforts to build a professional cryonics provider in Switzerland, which would be the first in Europe if they are successful. I liked a lot of what he had to say, particularly that customer focus and scalability are the weak points of the present cryonics industry, given its non-profit roots. Thus one of the initial projects is to ramp up the professionalization of signup and standby. They are launching a brand called Tomorrow, which streamlines the process of signing up for cryopreservation, making it an entirely online process that runs more smoothly and requires less work on the part of the individual. They are also looking into how to make a for-profit cryonics organization viable through the path of long-term asset management, meaning partnership with life insurance companies. As you may know, most cryopreservations are funded by life insurance policies, making it quite cost-effective, particularly if started at a younger age. Middlemen in the the life insurance industry are a well established business model, and so this might be a path towards for-profit cryonics. Beyond these early stage efforts, EBF supports research efforts to improve the quality and reliability of cryopreservation, and is planning a storage facility, but this will be contingent on success in the initial for-profit path, opening the door to capital investment.

Unfortunately I had to leave before the final keynote by Robin Hanson, but it was an interesting event. The cryonics community needs to grow and find success: we live in a strange world, in which there is an alternative to oblivion and the grave, but it is poorly capitalized, poorly supported, and rarely used. Cryonics, as happened for the treatment of aging as a medical condition, must find its way to success and growth. I think that this will be achieved in part by the slow process of building technologies that work, such as reversible vitrification of donor organs, carried out in research communities that presently have little funding for rapid progress, and in part by efforts such as those of the EBF, the process of discovery in business models and persuasion.

Slower DNA Damage Accumulation in Immune Cells Correlates with Species Life Span

Today's open access research is an assessment of DNA damage accumulation in a variety of species, showing the pace of mutational damage correlates with species life span, at least as assessed here in immune cells from blood samples, and using a marker that identifies the response to short telomeres as well as forms of DNA damage. The DNA of the cell nucleus, the genetic blueprint for near all of the proteins produced in a cell, accumulates damage over time due to the normal haphazard chemical reactions that take place constantly inside cells. These mutational changes are largely irrelevant to cellular operation, but some can cause disruption in metabolism, or, worse, make a cell cancerous, by causing certain proteins to be produced in a broken or altered state. Near all mutational damage to DNA is quickly repaired by the highly efficient array of DNA repair mechanisms that a cell is equipped with. But some inevitably slips past.

The way in which mutation leads to cancer is fairly straightforward, but it is less obvious as to how random mutation in single cells can contribute meaningfully to other aspects of aging, such as widespread tissue dysfunction. The present consensus is that the important mutations are those that occur in stem cells and progenitor cells, able to spread widely throughout a tissue via the replication of daughter somatic cells created by those stem cells and progenitor cells. It was also recently suggested that DNA damage, even when repaired, and more or less regardless of what is damaged in DNA, leads to epigenetic changes characteristic of aging, and these epigenetic changes are what causes cell function to decline. In this view, a larger amount of unrepaired DNA damage, the marker usually measured, is indicative of the true cause of harm, which is more frequent DNA repair and thus epigenetic change.

The authors here are primarily focused on DNA damage markers that occur due to critically short telomeres in additional to mutational damage. Average telomere length in tissues, and the fraction of cells with critically short telomeres, is most likely downstream of stem cell function. Telomeres shorten inexorably with each cell division in somatic cells, and cells eventually self-destruct, or become senescent and are destroyed by the immune system. Stem cells use telomerase to maintain long telomeres, and deliver daughter somatic cells with long telomeres into tissues to make up the losses. So telomere length in tissues is a function of how rapidly cells divide and how frequently replacement cells are delivered by the supporting stem cell population - the pace of the latter is well known to decline with age.

Slower rates of accumulation of DNA damage in leukocytes correlate with longer lifespans across several species of birds and mammals

Different species have very different lifespans ranging from less than 1 day for mayflies to more than 400 years for the Greenland shark. However, the exact cause of these differences in longevity are still largely unknown. Our group recently showed that the rate of telomere shortening with age correlates with lifespan in a variety of species from birds to mammals. Species with very fast telomere shortening rates such as mice have very short lifespans, and species with very slow telomere shortening rates such as humans have very long lifespans. It is interesting to note that species that share a similar longevity in spite of being evolutionarily distant like flamingos and elephants, also show a similar rate of telomere shortening, while evolutionarily closer species like mice and elephants, show very different longevities and also have very different rates of telomere shortening.

These findings suggest that longevity can be determined, at least in part, by epigenetic traits, such as the rate of telomere shortening. Furthermore, these findings pose the interesting question of which is the molecular determinant by which higher telomere shortening rates lead to shorter longevities. An obvious answer is that higher rates of telomere shortening will be associated to faster accumulation of critically short/dysfunctional telomeres, which are known to contribute to activation of a persistent DNA damage response stemming from telomeres, which leads to loss of cell viability and aging phenotypes. Thus, species that shorten telomeres at faster rates will reach telomere exhaustion and trigger a persistent DNA damage response earlier than those species that are able to maintain telomeres protected for a longer period of time. A short/dysfunctional telomere is recognized by the cell as an irreparable DNA double strand break (DSB), triggering a persistent DNA damage response which results in phosphorylation of γH2AX, and which eventually leads to cell death and/or senescence. In turn, induction of cellular senescence either owing to critically short telomeres or to other insults is also associated with increased γH2AX levels, involving in some instances the mTOR pathway. Thus, accumulation of cells with DNA damage throughout lifespan should also correlate with species longevity.

Here, we find that increased global rates of DNA damage, as determined by the DNA damage marker γH2AX which detects occurrence of double stranded DNA breaks in the genome, inversely correlates with species longevity. In particular, we determined here the rates of increase of the DNA damage marker γH2AX in leukocytes of phylogenetically distant species of birds and mammals in parallel and using the same experimental method. Previous studies have also shown a correlation between certain types of DNA damage and aging. Indeed, DNA damage accumulation with aging and telomere shortening may be related processes. Critically short telomeres as the result of cell proliferation throughout life to repair damaged tissues trigger a DNA damage signal specifically at telomeres.

We also measured the percentage of short telomeres of the species in this study, and we found that all of the species showed an increase in the percentage of short telomeres with age. This result is concomitant with the fact that average telomere length shortens with age in many species. Several studies have suggested that the percentage of short telomeres is more indicative of health and senescence than average telomere length. The percentage of short telomeres is an important metric since it is the length of the shortest telomere in a cell that induces a DNA damage response and cell senescence rather than the average telomere length of the telomeres on all of the chromosomes. Here we also noticed a mild trend for species with longer maximum lifespans to have a lower rate of increase of percent short telomeres, thus accumulating short telomeres more slowly with age. We also observed that species with the highest rates of γH2AX increase have the highest rates of increase of percent short telomeres with age. These results make a connection between γH2AX DNA damage, short telomeres, and lifespan. As cells accumulate DNA damage and short telomeres, they will enter into a state of senescence, thus accelerating the aging process and shortening lifespan.

The Tight Junctions of the Blood-Brain Barrier in Aging and Neurodegeneration

Today's open access paper is a review of the tight junction structures of the blood-brain barrier in aging and neurodegeneration. The blood-brain barrier is a structure of specialized cells that lines the blood vessels that pass through central nervous system tissue. The barrier allows only certain molecules and cells to pass between blood vessels and the central nervous system, thus preserving its separation from the rest of the body. Unfortunately the integrity of the blood-brain barrier breaks down with advancing age, and the entry of unwanted molecules and cells into the brain then contributes to inflammation and tissue dysfunction.

A number of studies have shown links between blood-brain barrier dysfunction and the progression of neurodegenerative conditions. Researchers have identified leakage of fibrinogen into the brain as a cause of inflammation and synaptic damage. The inappropriate passage of molecules across the blood-brain barrier begins when the behavior of endothelial cells changes for the worse, and there is also a progressive loss in the number of pericyte cells. These changes correlates with cognitive decline even in the absence of other signs of pathology, such as protein aggregates. Interestingly, the amyloid-β characteristic of Alzheimer's disease has been shown to cause blood-brain barrier dysfunction.

The Blood-Brain Barrier and Its Intercellular Junctions in Age-Related Brain Disorders

The functional state of the central nervous system (CNS) is greatly dependent on the quality of the vasculature. As the centuries old saying goes: "A man is as old as his arteries". Today, especially for the brain, this concept should be redefined: You are as old as your microvessels and capillaries. There is increasing evidence that the cerebral microvasculature and the neurovascular unit play a critical role in age-related brain dysfunctions. The multitude of brain microvascular changes accompanied by aging includes endothelial dysfunction, blood-brain barrier (BBB) breakdown, decrease in blood flow, microhemorrhages, vessel rarefication, and neurovascular uncoupling.

Cerebral endothelial cells (CECs) lining brain capillaries are considered the principal barrier forming endothelial cells. They are interconnected by a continuous line of tight junctions and characterized by a high number of mitochondria and low number of caveolae. These characteristics contribute to the formation of a paracellular and transcellular barrier.

With aging, the density of brain vasculature is decreased and cerebrovascular dysfunction appears to precede and accompany cognitive dysfunction and neurodegeneration. Cerebrovascular angiogenesis is decreased and cerebral blood flow is inhibited by anomalous blood vessels such as tortuous arterioles and thick collagen deposits in the walls of veins and venules. In most mammals, the capacity of CECs to divide is limited and endothelial cells are prone to be senescent. Aging is associated with endothelial dysfunction, arterial stiffening, and remodeling, impaired angiogenesis, defective vascular repair and with an increasing prevalence of atherosclerosis. In the aging brain cerebral blood flow declines and perfusion pressure either is constant or increases.

The paracellular barrier properties of CECs are determined by the tight junction (TJ), which are composed of transmembrane proteins that control the transport across the intercellular space between adjacent cells and cytoplasmic plaque. Limited data is available on what changes develop in the function of the BBB and the composition and structure of endothelial TJs in the healthy aging human brain. In a meta-analysis of BBB permeability studies, the barrier function was negatively impacted by age. Though there were some discrepancies, paracellular permeability was generally increased in the aged human brain. Permeability changes are likely the result of decreased expression and disorganized localization of TJ proteins.

With the building evidence that dysfunction of the microvasculature is not just coincident but is part of the underlying mechanisms of aging and associated neurovascular and neurological disorders, new therapeutic possibilities are opened. The significant heterogeneity of BBB disruption data in studies using aging postmortem brain tissue suggests that more data is necessary to clearly understand the role of BBB disruption and to see whether it is a symptom or a cause. Thus further comprehensive BBB TJ and permeability studies are needed in the field of aging and aging associated disorders.

Werner Syndrome is Strongly Mediated by Mitochondrial Dysfunction

Researchers here report that NAD+ upregulation to improve mitochondrial function, via supplementation with nicotinamide riboside and nicotinamide mononucleotide, does a decent job of rescuing the life span of flies and worms with the genetic mutation that causes Werner syndrome. It is not quite all the way restored to match wild-type animals, but close. Werner syndrome is a DNA repair deficiency condition in which patients exhibit, at the high level, what appears to be accelerated aging: early onset of a range of age-related conditions, early mortality. It is not, however, accelerated aging. Natural aging stems from rising levels of molecular and cellular damage, but damage of a particular blend of varieties. Werner syndrome is one specific class of damage, stochastic nuclear DNA damage, elevated to a very large degree. There are important differences, and it is never all that clear as to whether we can apply lessons learned in DNA deficiency conditions to normal aging - it depends greatly on the fine details in each case.

The most interesting point here is that, in at least short-lived species such as flies and worms, the harm done by this particular DNA repair deficiency is to a large degree mediated by an early collapse in mitochondrial function. It remains to be see whether this is also true in mammals: the literature might lead us to expect that high levels of stochastic mutational damage to nuclear DNA could be causing all sorts of other harms. Mitochondria are the power plants of the cell, responsible for packaging the chemical energy store molecule ATP needed to power cellular operations. NAD+ is vital to mitochondrial operation, and its levels decline with age, alongside mitochondrial function. Artificially boosting NAD+ levels has been shown to restore the ability of mitochondria to function in a more youthful fashion, but as yet there is only the one small clinical trial to show health benefits in older humans.

Can we take this paper as evidence for mitochondrial decline to be very important in normal aging? That would be the question. If I were speculatively joining pieces of the jigsaw puzzle, I would take this study, and put it next to the recent finding that suggests double strand breaks in nuclear DNA will cause epigenetic drift of the sort observed in aging. So the more of this sort of DNA damage, more epigentic change. Problems with mitochondria are perhaps proximately caused by changing levels of specific proteins, such as those necessary for the process of fission. Too little fission results in ever larger mitochondria that are not easily cleared out by the maintenance processes of mitophagy when they become worn and damaged. Protein levels are, of course, under epigenetic control. Perhaps this all fits together, but it still needs a lot of work to shore up the relevant evidence; it should be treated as speculative.

NAD+ augmentation restores mitophagy and limits accelerated aging in Werner syndrome

We report that Werner syndrome (WS) is associated with a significant mitochondrial dysfunction, mainly manifested as defective mitophagy. This is reflected in lower NAD+ levels across species from worms to humans. NAD+ supplementation improves mitochondrial function and other age-related metabolic outcomes. Mitochondrial disease can manifest itself in multiple clinical outcomes amongst which neurodegeneration and impaired metabolism are common. Some features of WS may be explained by genomic instability due to mutation in the gene encoding the Werner protein (WRN), an important DNA helicase/exonuclease involved in DNA repair, telomere and heterochromatin maintenance, and cancer regulation. However, the relationship between WRN mutations and the syndrome's severe dysregulation of energy metabolism is unclear.

Mitochondrial quality and function decline with age, contributing to insulin resistance and metabolic diseases in the elderly. Mitochondrial quality control is regulated by biogenesis and mitophagy. Mitophagy involves the targeting of damaged mitochondria to the lysosomes wherein the mitochondrial constituents are degraded and recycled. Defective mitophagy is prominent in aging and age-predisposed disorders, including metabolic diseases and neurodegeneration. However, the role of mitophagy in WS has not been investigated.

The metabolic molecule nicotinamide adenine dinucleotide (NAD+) is emerging as a fundamental regulator of mitochondrial homeostasis, genome stability, neuroprotection, healthy aging, and longevity. Interestingly, genetic and/or pharmacological upregulation of intracellular NAD+ levels protects against obesity and type 2 diabetes in rodents, and against age-related diseases and neurodegenerative diseases such as Alzheimer's disease.

We therefore examined whether mitochondrial dysfunction and NAD+ depletion occur in WS, and if so, how it contributes to the molecular pathology in WS. We report that NAD+ depletion is a major driver of the severe metabolic dysfunction in WS through dysregulation of mitochondrial homeostasis. At the organismal level, NAD+ repletion remarkably extends lifespan and delays accelerated aging, including stem cell dysfunction, in Caenorhabditis elegans and Drosophila melanogaster models of WS. Our findings suggest that accelerated aging in WS is mediated by impaired mitochondrial function and mitophagy, and that bolstering cellular NAD+ levels counteracts WS phenotypes.

Cardiac Amyloid Buildup Correlates with Risk of Atrial Fibrillation

Amyloids are misfolded proteins that become insoluble in their incorrect configuration, forming structures that encourage other molecules of the same protein to also misfold in the same way. These structures spread, grow, and clump together into solid deposits in and around cells. Only a handful of proteins can form amyloid, and many are associated with age-related disease. Consider the amyloid-β characteristic of Alzheimer's disease, for example. The better understood forms of amyloid are known to be accompanied by a surrounding halo of toxic biochemistry that harms cells and cell function.

Setting aside genetic diseases in which proteins are created in a damaged form, more prone to amyloid formation, there are a couple of forms of amyloid that tend to show up in heart tissue with age, light chain amyloid and transthyretin amyloid. The present consensus is that light chain amyloidosis is more common to heart disease in comparison to the presence of transthyretin amyloid, but this may or may not in fact be the case, given (a) the comparatively lack of rigorous data for the subclinical, early stage of amyloidosis, and (b) work of recent years showing a greater prevalence of transthyretin amyloid in patients than previously suspected.

Everyone accumulates transthyretin amyloid as aging progresses, transthyretin amyloidosis is the major cause of death of supercentenarians, but it is far from clear as to how much harm is being done - relative to other issues - in earlier old age. Consider that aging is an accumulation of damage, and amyloids are a form of damage that degrades tissue function, but the clinical community tends to only declare a diagnosis of amyloidosis somewhere well past the point at which meaningful long-term harm is probably resulting.

The study here is an attempt to gain data on just how much damage might be taking pace to heart function in older individuals as a result of subclinical levels of amyloid in the heart. The authors do not distinguish between types of amyloid, but I think that this sort of effort is useful. You might compare it to a paper from recent years in which researchers discovered a significant presence of transthyretin amyloid in a minority of heart failure cases. The more evidence that is obtained, the more support there will be for development programs that can clear transthyretin amyloid, not just slow down its accumulation, such as that undertaken at Covalent Bioscience.

Atrial Fibrillation in the Elderly: The Role of Sub-Clinical Isolated Cardiac Amyloidosis

Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is associated with considerable morbidity and mortality. The prevalence of AF increases with increasing age and is related to the increasing prevalence of comorbidities and structural remodelling of the atria that is believed to occur with aging. Increasing atrial fibrosis is known to be associated with more frequent paroxysms of AF, persistent AF, and refractoriness to medical therapy.

Recently, a considerable proportion of elderly patients with heart failure with preserved ejection fraction (HFpEF) have been found to have isolated amyloid deposits in the heart. Further, a proportion of patients with valvular heart disease have been found to have clinically undetected amyloid deposits on atrial biopsies obtained during cardiac surgery and such deposits have been shown to be associated with an increased risk of AF. The role of such clinically undetected atrial amyloid deposits in the aetiopathogenesis of AF occurring in the absence of valvular heart disease has not been previously evaluated.

In this study, we sought to assess the prevalence of AF in patients with clinically undetected isolated cardiac amyloidosis (ICA) detected at autopsy and identify electrocardiographic (EKG) markers of such amyloid deposits. A total of 1083 patients were included in the study and 3.1% of patients were found to have asymptomatic ICA. Patients with ICA were older and had a higher odds of AF independent of age and CHA2DS2VASc score. Amongst patients with AF, those with ICA were more likely to have persistent forms of AF and had a lower sinus rhythm P-wave amplitude. Further studies are required to further define this entity, identify imaging modalities to aid in antemortem diagnosis of ICA and to establish the optimal management strategies in these patients.

Upregulation of Autophagy Improves Vascular Function in an Animal Model of Type 2 Diabetes

Autophagy is the name given to a collection of cellular maintenance processes that recycle damaged structures, unwanted protein, and other metabolic waste. Many forms of stress, such as heat, lack of nutrients, and so forth spur greater autophagy, and this is thought to be a large part of why mild, temporary stress can produce lasting benefits to health - a process known as hormesis. Cell function is improved, and thus tissue function is improved. Many of the methods shown to modestly slow aging in laboratory species involve increased autophagy, and at least some, such as the practice of calorie restriction, have been shown to depend on functional autophagy for their benefits.

Rather than applying stress to generate autophagy, development programs focus on the use of small molecule drugs to influence the gene networks that regulate stress responses - such as targeting mTOR through rapamycin and analogous mTOR inhibitors. The research results here are an example of the type, showing that forcing a greater pace of autophagy helps to resist some of the metabolic consequences of type 2 diabetes - though of course this compares unfavorably with low calorie diets and consequent reduction in excess visceral fat tissue, the cause of the condition, as an approach to therapy in this specific case.

Vascular dysfunction is a major complication in type 2 diabetes (T2D). It has been suggested dysregulation of autophagy is associated with various cardiovascular diseases. However, the relationship between autophagy and vascular dysfunction in T2D remains unclear. Thus, we examined whether reduced autophagy is involved in vascular dysfunction and stimulation of autophagy could improve vascular function in diabetes.

Ten to 12-week old male type 2 diabetic (db-/db-) mice and their control (db-/db+) mice were treated with rapamycin or trehalose. Mesenteric arteries (MAs) were mounted in the arteriography and diameter was measured. Western blot analysis and immunofluorescence staining were assessed. Myogenic response (MR) was significantly increased, whereas endothelium-dependent relaxation (EDR) was significantly attenuated in the MAs of diabetic mice. These results were associated with increased expressions of LC3II, p62, and beclin-1 in diabetic mice.

Treatment of autophagy stimulators significantly reduced the potentiation of MR and improved EDR in the diabetic mice. Furthermore, autophagy stimulation normalized expressions of LC3II, p62, and beclin-1 in the diabetic mice. In addition, phosphorylation level of eNOS was decreased in diabetic mice, which was restored by rapamycin and trehalose. In conclusion, T2D impairs vascular function by dysregulated autophagy. Therefore, autophagy could be a potential target for overcoming diabetic microvascular complications.

To What Degree Does Loss of Skeletal Muscle with Age Contribute to Immunosenescence?

Sarcopenia, the progressive loss of muscle mass and strength, is characteristic of aging. A perhaps surprisingly large fraction of the losses can be averted by strength training, but there are nonetheless inexorable processes of aging that, until therapies exist to repair this damage, will cause decline in muscle tissue over time even for those who maintain their fitness as best as possible. Researchers here consider the evidence for skeletal muscle tissue to do more than just move us around, but also to be an active participant in many aspects of metabolism. The focus in this open access paper is on the immune system: to what degree does sarcopenia contribute to the loss of immune function that also occurs with age?

In the last two decades, the perception of skeletal muscle as a pure locomotors unit has shifted. Muscle is increasingly recognized as an organ with immune regulatory properties. As such, skeletal muscle cells modulate immune function by signalling through different soluble factors, cell surface molecules, or cell-to-cell interactions. Although our knowledge of the muscle-immune system interplay has advanced considerably, the impact of age is relatively unknown. Sarcopenia may severely disturb this interaction, providing a potential explanation for the observed clinical outcomes of sarcopenic patients

Muscle is increasingly recognized as an endocrine organ producing and releasing cytokines and other peptides, which exert autocrine, paracrine, and endocrine activity on numerous tissues. Consequently, these soluble factors are commonly termed myokines. Proteomic profiling has been applied to the secretome of skeletal muscle and identified more than 300 potential myokines. Myokines such as IL-6, IL-7, IL-15, or LIF have been shown to modulate the immune system. Remarkably, serum concentrations of myokines such as IL-7 and IL-15 are inversely correlated with age, suggesting a link between skeletal muscle and age-dependent loss of immune system function.

As humans age, the immune system undergoes drastic changes. The umbrella term immune senescence is used to encompass these changes. Moreover, ageing is associated with increased serum levels of pro-inflammatory molecules. Skeletal muscle exhibits immune regulatory properties and that chronic, low-grade inflammation may induce muscle wasting. The concept of skeletal muscle as a regulator of immune function is relatively new and adds a new layer of complexity to the muscle-immune system link. Consequently, the muscle-immune system connection might be bidirectional: chronic, low-grade inflammation induces muscle catabolism via pleiotropic mechanisms mediated by the inflammatory secretome. Concurrently, homeostasis of skeletal muscle is, in part, responsible for healthy immune function. However, when dysregulated, insufficient myokine signalling, alteration of membrane bound factors towards a pro-inflammatory profile and impaired regenerative capacities of immune cells might result in disruption of immune system function.

We propose that biological aging may disturb the equilibrium of muscle-immune system homeostasis with skeletal muscle acting as a potential central link between sarcopenia and immune senescence. Healthy muscle function is gradually lost in an aging biological system due to physical inactivity, metabolic changes and the accumulation of chronic, low-grade inflammation. In turn, impaired muscle function curtails skeletal muscle cell signalling needed for immune regulation and maintenance, culminating in a vicious cycle in which immune and muscle system dysfunction sustain each other.

In Search of Genes that Were Lost in Longer-Lived Mammals

Researchers here describe an interesting approach to improving the understanding of how differences in species longevity arise from differences in the operation of cellular metabolism. They report on a search for genes in short-lived mammals, mice in this case, that have been lost in long-lived mammals such as our species. Finding such genes can then lead to an investigation of specific aspects of cell and tissue function relevant to life span. As is often the case in this field, the work is of scientific interest, but not really all that relevant to near future efforts to produce rejuvenation. A complete understanding of how exactly aging progresses in detail and which mechanisms are more or less important would be helpful, but it is by no means necessary. The research and development community can forge ahead to repair the known causes of aging without a full understanding of aging - indeed, this is already progressing quite well in the matter of stem cells and senescent cells.

The genetic propensity of certain species for longevity and anti-aging is a challenging problem in vertebrate biology. Of particular interest are the genes that influence life expectancy differences among species. These genes are expected to be the real longevity genes of interest and should explain the wide differences in the rate of aging among diverse species and why similarly sized rodents or primates sometimes have anomalous life expectancies - such as naked mole-rats or humans.

No such genes have been unequivocally identified. We performed a computer-aided analysis of data relevant to lifespan and made a bioinformatic search for the genes, the loss of which might modulate lifespan. This search is based on the general idea that such genes are lost in a predefined set of species but are present in another predefined set of species. Examples of such pairs of sets include long-lived vs short-lived, homeothermic vs poikilothermic, among others. Species are included in one of two sets depending on the property of interest, such as longevity or homeothermy. A bioinformatics method and software relevant to the idea are universal towards these sets and the property that defines them.

Here, the proposed method was applied to study the longevity of Euarchontoglires species. It largely predicted genes that are highly expressed in the testis, epididymis, uterus, mammary glands, and the vomeronasal and other reproduction-related organs. In conclusion, the developed method and its software allowed us to identify a short list of presumably lost genes associated with a long lifespan in Euarchontoglires. The predicted lost genes largely demonstrate specific expressions in reproductive organs, which agrees with Williams' hypothesis concerning the reallocation of the physiological resources of the body between self-maintenance and reproduction (transition from r-strategy to К-strategy in the species evolution). The loss of some predicted vomeronasal and olfactory receptor genes in human and naked mole-rat conforms to their specific anatomical features. We suggest that the loss of certain genes in evolution is one of the essential determinants of lifespan. Overall, it is a likely driving force for many aspects of species evolution in vertebrates.

Topical Rapamycin Evaluated as a Treatment for Skin Aging

Given the attention that descends upon any prospect of reversing skin aging, I should probably open by saying that much of the data here for extended low dose topical treatment with rapamycin over eight months, that regarding visible skin aging and collagen production, is no more exciting than that obtained by any number of other approaches, such as topical application of keratinocyte growth factor (KGF). Effect sizes are the only thing that matters, and also the one thing that all too many observers fail to consider. Looking at the paper, I would say that the primary point of interest is the 50% reduction in markers of cellular senescence in skin. Given what is known of rapamycin this seems unlikely to be a senolytic effect, so not destruction of existing senescent cells, but rather a reduction in the number of cells becoming senescent. This in turn suggests that there remains some meaningful level of ongoing natural clearance of lingering senescent cells at older ages.

This study demonstrates a clear impact of rapamycin treatment on both the molecular signature associated with senescence and the clinical signs of aging in the skin. These data support the idea that a reduction in the burden of senescent cells underlies these improvements. The results could reflect a modification of the senescent cells present in the skin or a reduction in the number of senescent cells. Although rapamycin has been shown to reduce pro-inflammatory secretions produced by senescent cells, the fact that p16INK4A is reduced suggests that the absolute number of senescent cells in the epidermis is reduced. This implies that rather than simply modifying senescent cells present in the tissue, rapamycin treatment is either reducing the number of cells entering senescence or increasing the clearance of senescent cells. Based on our studies demonstrating that rapamycin prevents the senescence transition and improves functionality in vitro, we favor the concept that rapamycin reduces entry into senescence, but we cannot rule out an additional role for clearance of senescent cells. Whether the reduction in senescent cells is due to reduced entry or increased clearance, a reduction in the burden of senescent cells would be expected to improve functionality.

Senescent cells produce pro-inflammatory cytokines, matrix metalloproteins, and reduced levels of anti-angiogenic factors, creating a secretory profile known as the Senescence-Associated Secretory Phenotype (SASP). Thus, we anticipate that rapamycin treatment reduces inflammatory cytokines in the skin, although the verification of this change represents a technical challenge due to the fact that such cytokines are present in picomolar amounts. One quantifiable aspect of skin biology that is improved by the rapamycin treatment is the incorporation of collagen VII into the basement membrane, which represents a functional measure of skin quality that is improved upon treatment with rapamycin. Collagen VII is essential for a functional skin barrier, and the levels of collagen VII decrease with age and specifically beneath wrinkles. Although the mechanism whereby rapamycin may increase collagen VII protein levels is not clear at this time, the known effects of rapamycin on autophagy and intracellular trafficking of vesicles may allow for intracellular processing of misfolded collagen and increase proper localization at the cell periphery and basement membrane.

A notable aspect of this study is the use of such a low dose of rapamycin (10 μM, or 0.001%) for topical application. Topical treatment with higher concentrations (0.1-1%) has been employed for the treatment of tuberous sclerosis complex (TSC) in adults and children and has shown efficacy. We chose to use rapamycin at a ten-fold lower dose because the concentrations used in TSC patients are intended to inhibit cell growth, while our aim was to improve cell function while maintaining proliferative potential and preventing senescence. The positive impact of our treatment regimen suggests that age-related therapy with rapamycin may be feasible at doses far below those associated with side effects; however, this possibility will require careful evaluation in each specific clinical setting.

Common Mechanisms of Blood-Brain Barrier Dysfunction to Underlie Many Forms of Damage to the Brain

Researchers here note a signature of blood-brain barrier dysfunction that is common in many forms of damage and injury to the brain, suggesting it to be more broadly relevant to pathology than suspected. There is already good evidence for dysfunction of the blood-brain barrier to be an early feature of neurodegenerative diseases. The specialized cells of the blood-brain barrier line blood vessels that pass through the central nervous system, managing the passage of molecules and cells. When the barrier fails, unwanted molecules such as fibrogen can enter the brain to cause inflammation - and chronic inflammation in the brain is known to be important in the progression of neurodegeneration.

Whether in the wake of a stroke, seizure, massive neuroinflammation, or a blow to the head, the endothelial cells of the blood-brain barrier (BBB) respond with remarkable similarity, according to a new study. Researchers reported that the endothelial cells that make up the BBB normally express a suite of genes that distinguishes them from the endothelia of other organs. However, BBB cells damaged in various ways lost this specialized signature, changing over to an expression profile more akin to endothelial cells in other parts of the body. The findings suggest that common mechanisms of BBB dysfunction underlie different brain injuries and diseases. "This raises the possibility that successfully preventing (or increasing) endothelial cell gene-expression changes that occur in one disease may lead to a potential therapy for other types of CNS disorders."

Tasked with shielding the precious brain from toxic insults while allowing crucial nutrients to cross, the blood-brain barrier is highly selective. Ergo, the endothelial cells that line the brain's vessels are highly specialized, forming ultra-tight junctions and mobilizing molecular transporters not typically found in vessels supplying other organs. Disruption of the barrier is thought to play a hand in the pathogenesis of multiple injuries and diseases.

How do brain endothelial cells change in the face of injury or disease? The researchers tracked gene-expression changes following four different insults known to disrupt the barrier: seizures, stroke, trauma, and experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis. They then tracked the permeability of the barrier at three time points. In the earliest, or "acute" phase of each injury, the researchers found only minimal disruption of the BBB. However, in the so-called "subacute phase," which was one or two days later depending on the model, the leakiness of the BBB reached its peak. About a month later, in the "chronic phase," the barrier had partially or fully regained its integrity.

Each injury induced a bevy of gene-expression changes in brain endothelial cells. They varied substantially among injuries in the acute phase, but shared striking commonalities in the subacute phase, when the barrier was leakiest. By the chronic phase, gene expression had largely returned to normal in the stroke, seizure, and traumatic brain injury models, but remained highly altered in the EAE model. Interestingly, the researchers found that the genetic signature of the healthy BBB endothelium was most downregulated in the acute phase of traumatic brain injury, and the subacute phase of stroke, seizure, and EAE. Conversely, genes expressed predominantly in endothelial cells outside of the brain were turned up in the brain endothelium at these time points. Together, the findings suggest that while brain endothelial cells may initially respond differently to unique insults, they soon converge on a gene-expression profile that resembles those of endothelial cells in other organs of the body. Among other functions, these gene-expression changes likely ramp up interactions between the endothelium and circulating immune cells.

Nanotics Aims at Preventing Senescent Cells from Evading Immune Surveillance

Nanotics works on a nanoparticle platform that can modulate cell signaling via depletion of arbitrary target signaling molecules, something that has a great many potential uses, such as altering the behavior of the immune system. Given the present level of interest in clearance of senescent cells as an approach to treating aging, it isn't surprising to see platform companies of this ilk turning their attention to the production of senolytic treatments in addition to their existing pipelines. Here the approach is to deny lingering senescent cells the capacity to protect themselves against immune surveillance, and thus enable the immune system to destroy a greater fraction of these errant cells than would otherwise be the case.

Many cell signals are normally delivered in an intelligent cell-mediated way, meaning that one cell actually moves through the body until it's quite close to a target cell, before releasing the appropriate signal molecules. This greatly increases the likelihood that only the target cell - and not an "off-target" cell - will receive the signal. However, in various diseases, the delivery of the signal molecule is dysregulated in some way, sometimes because a cell is secreting a signal molecule systemically rather than focally to a target cell. The cell that receives this signal molecule - which it would not have received under normal circumstances - may do something it shouldn't do, which can manifest at the tissue level as disease. But the target cell may in fact be responding in a perfectly appropriate way to an incorrect signal. Most medicine still focuses on tissues and organs, rather than the underlying cells and signal molecules.

In cancer, the main problem is not the existence of cancer cells - which the immune system routinely clears out - but rather that cancer cells sometimes persist long enough to erect an inhibitory shield. The secreted molecules inhibit either the immune system's killer cells or the "death signals" those cells produce. There are times when this type of inhibitory signaling is completely appropriate. For instance, the fetus must inhibit the mother's immune system in order to survive, given that's genetically only half the mother and thus looks like an invader. Cancer not only mimics the process used by the fetus/placenta but employs many of the same molecules to do it.

For anti-aging, one would deplete the various known pathogenic signaling molecules that increase with age. Many of these are inflammatory and are responsible for what's termed inflammaging. We are also designing an approach to deplete immune inhibitors secreted by senescent cells for their defense, as a new generation of senolytic therapy. For the vast majority of non-genetic diseases, the drivers or enablers of the disease are signal molecules or molecular signal inhibitors. All of these targets can be depleted by our approach, without drugs and thus without the side effects of drugs.

Towards Small Molecule Drugs that Suppress α-Synuclein Aggregation

Researchers here report on efforts to find small molecules that can interfere in the molecular biochemistry of synucleinopathy. Parkinson's disease is the best known of the synucleinopathies; these are neurodegenerative conditions characterized by the misfolding and consequent aggregation of α-synuclein. This is one of a handful of proteins in the body that can misfold in a way that encourages other molecules to also misfold, forming structures and then solid deposits that cause considerable harm as they spread throughout the aging brain. The best form of therapy would be some form of periodic clearance of these errant molecules, but, absent that, a way to interfere in the processes of misfolding and aggregation would be a step forward.

The over-expression and aggregation of α-synuclein (αSyn) are linked to the onset and pathology of Parkinson's disease. Native monomeric αSyn exists in an intrinsically disordered ensemble of interconverting conformations, which has made its therapeutic targeting by small molecules highly challenging. Nonetheless, here we successfully target the monomeric structural ensemble of αSyn and thereby identify novel drug-like small molecules that impact multiple pathogenic processes.

Using a surface plasmon resonance high-throughput screen, in which monomeric αSyn is incubated with microchips arrayed with tethered compounds, we identified novel αSyn interacting drug-like compounds. Because these small molecules could impact a variety of αSyn forms present in the ensemble, we tested representative hits for impact on multiple αSyn malfunctions in vitro and in cells including aggregation and perturbation of vesicular dynamics. We thereby identified a compound that inhibits αSyn misfolding and is neuroprotective, multiple compounds that restore phagocytosis impaired by αSyn overexpression, and a compound blocking cellular transmission of αSyn.

Our studies demonstrate that drug-like small molecules that interact with native αSyn can impact a variety of its pathological processes. Thus, targeting the intrinsically disordered ensemble of αSyn offers a unique approach to the development of small molecule research tools and therapeutics for Parkinson's disease.

SHMT2 in the Age-Related Decline of Mitochondrial Function

Mitochondria are the descendants of ancient symbiotic bacteria, several hundred of them in every cell. Their primary task is to produce the chemical energy store molecule adenosine triphosphate (ATP) to power cellular operations. With aging, mitochondria throughout the body decline in function. They change their morphology, the balance between fission and fusion shifts, the ability of the cell to remove worn and damaged mitochondria is impaired. Researchers have made some inroads into the proximate causes of these global changes, meaning upregulation or downregulation of specific proteins, but the connection to the root causes of aging remains unclear. The research noted here is an example of continued efforts in this direction, and in this specific case offers a hint that mitochondrial decline with aging may be a part of the evolved trade-off between (a) cancer risk due to active cells in a damaged environment and (b) functional decline due to inactive cells that fail to maintain an increasingly damaged environment.

In a previous study, we proposed that age-related mitochondrial respiration defects observed in elderly subjects are partially due to age-associated downregulation of nuclear-encoded genes, including serine hydroxymethyltransferase 2 (SHMT2), which is involved in mitochondrial one-carbon (1C) metabolism. This assertion is supported by evidence that the disruption of mouse Shmt2 induces mitochondrial respiration defects in mouse embryonic fibroblasts generated from Shmt2-knockout E13.5 embryos experiencing anaemia and lethality.

Here, we elucidated the potential mechanisms by which the disruption of this gene induces mitochondrial respiration defects and embryonic anaemia using Shmt2-knockout E13.5 embryos. The livers but not the brains of Shmt2-knockout E13.5 embryos presented mitochondrial respiration defects and growth retardation. Metabolomic profiling revealed that Shmt2 deficiency induced foetal liver-specific downregulation of 1C-metabolic pathways that create taurine and nucleotides required for mitochondrial respiratory function and cell division, respectively, resulting in the manifestation of mitochondrial respiration defects and growth retardation.

The results in this study also suggest that age-associated downregulation of SHMT2 would furthermore control age-related growth retardations, as well as mitochondrial respiration defects, in human fibroblasts from elderly subjects. Therefore, activation of SHMT2 or uptake of certain supplementary 1C sources, such as formate and glycine, might thwart the manifestation of age-related disorders. By contrast, activation of SHMT2 or intake of these supplements might enhance tumour growth due to the fact that SHMT2 is activated in certain human tumour cells, and that its disruption suppresses tumour growth, as well as respiratory function. Therefore, it appears to be controversial whether the activation of SHMT2 or intake of these supplements extends lifespan by restoring mitochondrial respiratory function and cell division or shortens lifespan by the activation of tumour growth and tumour progression. To resolve this controversial issue, further investigation is required.

Reporting on the Aging Research and Drug Discovery Meeting Held at BASAL Life 2019

Earlier this year the Aging Research and Drug Discovery meeting was organized as a part of the broader BASAL LIFE scientific conference. As is traditional for such events, the organizers put together a paper reviewing the proceedings. A few of the early highlights are noted below, but many more presentations are briefly discussed in the open access paper. It is a representative selection of the present distribution of projects and research goals in the scientific community focused on intervention in the aging process.

Aging poses profound health-related challenges that need to be tackled to reduce the social and economic burden on our aging society. Multidisciplinary perspectives will be of tremendous importance to understand the underlying molecular processes of aging and to accelerate the discovery and development of effective aging interventions. It is therefore indispensable that industry and academia develop deeper cooperation and greater interchange of knowledge and technology. For this purpose, world leading experts from diverse research fields and various sectors came together at the 6th installment of the Aging, Drug Discovery and Artificial Intelligence conference, which was held from the 10th to the 12th September 2019 in Basel as part of the Basel Life Science Week.

Although great progress has been made towards the understanding of aging mechanisms, effective drug interventions are still missing for most age-related disorders. Targeting the aging process contrasts the traditional approach of "one disease-one drug"; thus, multiple challenges need to be overcome, as discussed by Nir Barzilai from the Albert Einstein College of Medicine, NY, USA. In particular, the political attention needs to be further strengthened by highlighting the clinical and economic benefits of aging interventions. However, no party will cover intervention costs without an indication for which simple and reliable biomarkers are still lacking. Towards a resolution of this issue, the Targeting Aging with Metformin (TAME) study driven by Nir Barzilai may represent a proof-of-concept that could pave the way to clinical trials leading to healthy aging.

How can we fill the gap between lab animal research, which has traditionally stopped at murine studies, and human clinical trials? Matt Kaeberlein from the University of Washington, Seattle, USA, and colleagues several years ago initialized the dog aging project to overcome this barrier. Companion animals like dogs as model organisms provide multifarious advantages including a faster aging pace than humans, high genetic diversity, and a shared environment with humans. The dog aging project aims to investigate the influence of genetic and environmental determinants on the life- and healthspan of domestic dogs based on survey, sequencing, blood biochemistry and -omics data collection. Further, the project provides the opportunity to test aging interventions, as already initiated for the mammalian Target Of Rapamycin (mTOR) inhibitor rapamycin. Notably, the completed phase 1 for the rapamycin intervention trial revealed no-side effects and improved cardiac function in treated dogs

Aubrey de Grey from the SENS Research Foundation, Mountain View, California, USA, emphasized that placing the focus on healthspan and not on lifespan will help to rebut societal concerns for longevity investigations. Further, he discussed that human diseases with a higher prevalence at older ages should be treated and explored differentially than communicable diseases. In this regard, he introduced the SENS Research Foundation (SRF) and their concept of maintenance by targeting mechanisms that mitigate cellular damage accumulating during aging. Notably, treatments of age-related diseases directed by spinouts of SRF aim to increase the healthspan of elderly - increased longevity is considered as a positive side-effect.

Exercise Reduces Inflammatory Leukocyte Production, Slowing Development of Atherosclerosis

Researchers here report on the investigation of a lesser known mechanism by which exercise lowers risk of cardiovascular mortality. It alters cell signaling that drives the creation of inflammatory immune cells, and in turn thus accelerates the development of atherosclerosis. Atherosclerosis is the buildup of fatty deposits called plaques that narrow and weaken blood vessels, leading to heart attack and stroke. It is a condition resulting from dysfunction in the innate immune cells called macrophages that are responsible for clearing out fats from blood vessel walls. Once atherosclerosis has started, chronic inflammation from any source will accelerate its progression, by making it even harder for macrophages in an atherosclerotic plaque to adopt the set of behaviors required to help clear the damage.

Researchers examined how physical activity affects the activity of bone marrow, specifically hematopoietic stem and progenitor cells (HSPCs). HSPCs can turn into any type of blood cell, including white blood cells called leukocytes, which promote inflammation. The body needs leukocytes to defend against infection and remove foreign bodies. But when these cells become overzealous, they start inflammation in places where they shouldn't, including the walls of arteries.

Researchers studied a group of laboratory mice who were housed in cages with treadmills. Some of the mice ran as much as six miles a night on the spinning wheels. Mice in a second group were housed in cages without treadmills. After six weeks, the running mice had significantly reduced HSPC activity and lower levels of inflammatory leukocytes than other mice who simply sat around their cages all day. Exercising caused the mice to produce less leptin, a hormone made by fat tissue that helps control appetite, but also signals HSPCs to become more active and increase production of leukocytes. In two large studies, the team detected high levels of leptin and leukocytes in sedentary humans who have cardiovascular disease linked to chronic inflammation.

Reassuringly, the study found that lowering leukocyte production levels by exercising didn't make the running mice vulnerable to infection. This study underscores the importance of regular physical activity, but further focuses on how mechanisms by which exercise dampens inflammation could lead to novel strategies for preventing heart attacks and strokes.

View the full article at FightAging

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