Fight Aging! Newsletter, November 14th 2016

Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more.

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  • Reduced ATF4 Slows the Progression of Vascular Calcification in Mice
  • Electrical Properties as the Basis for a Better Biomarker of Cellular Senescence
  • The Decomposition of Alzheimer's Disease
  • Rabep2 Variants Reduce the Harm of Stroke through Increased Alternative Vasculature
  • The Work of the Aoki Foundation to Support SENS Rejuvenation Research
  • Latest Headlines from Fight Aging!
    • The Long Term Wager on Living to 150
    • Propaganda for Death and Aging is Everywhere
    • Mitochondrial Function and the Earliest Stages of Alzheimer's Disease
    • Transplanted Embryonic Nerve Cells can Integrate with the Adult Brain
    • The Abolition of Aging
    • A Review of Progress Towards Artificial Blood
    • The State of the Mainstream of Dementia Research
    • Small Steps Towards Tissue Engineered Lungs
    • More Evidence for a Common Genetic Contribution to Both Education and Longevity
    • Do Cloned Animals Age Normally?

Reduced ATF4 Slows the Progression of Vascular Calcification in Mice

Today I'll point out an open access paper on calcification of blood vessels in which the authors show that genetic engineering to alter levels of ATF4 in mice also alters the pace of the calcification process. Calcification of tissues, especially blood vessel walls, is an important component of the blood vessel stiffening that occurs with age. This stiffness causes raised blood pressure, or hypertension, as well as detrimental remodeling of heart tissue. Higher blood pressure in turn causes damage to important but comparatively delicate tissue structures such as those of the kidney and brain, as well as greater rates of structural failure in small blood vessels. It also sets the stage for larger and usually fatal ruptures that occur in blood vessels weakened by atherosclerosis. That the heart changes its structure over time in response to blood vessel stiffness paves the way towards the numerous varieties of heart failure. So, on the whole, we'd all be a lot better off without calcification, or more to the point with therapies that can get rid of it.

There is some debate over where blood vessel calcification sits in the chain of cause and effect that leads from the starting point of cell and tissue damage that occurs as a side-effect of the normal operation of cellular metabolism to the end point of aging, dysfunction, medical conditions, and death. Is it in and of itself a primary cause of aging that would occur even in absence of the others? Or is it secondary to one or more other known age-associated forms of damage, and if so which ones? Since at the present time the research community has only just found out how to safely remove one of the seven classes of fundamental damage that cause aging, which is to say the accumulation of senescent cells, it is still the case that it is very hard to produce good answers to the question of whether A causes B or B causes A (and how this is influenced by C, D, and E) once you are down at the detail level of molecular machinery inside a cell. Everything in living biochemistry is interconnected, and picking apart the connections is a slow and expensive job. That said, on the matter of calcification I'll point you to a great review paper on the topic, as well as results from another line of research that suggest a specific cellular dysfunction causes calcification, both of which imply that this is not a primary cause of aging. It still leaves open the question of which of the fundamental forms of damage are the significant causes of calcification, however. Good candidates include the cross-linking that is itself thought to be very important in blood vessel stiffening, and the accumulation of hardy waste compounds that clog cellular recycling mechanisms, and anything else that involves generation of chronic inflammation.

One interesting point to think about in connection with the research presented here is that it is a global reduction in ATF4 levels that produces benefits in the form of slower calcification. The authors are largely focused on the kidney, as that is one of the organs most damaged by the high blood pressure produced by calcification and stiffened blood vessels. Yet if you look back in the Fight Aging! archives, you'll find that many of the commonly studied methods of slowing aging in mice are characterized by increased levels of ATF4 in the liver - and it is certainly the case that of these methods, some are known to slow the process of vascular stiffening and calcification. Never let it be said that the molecular biology of living beings is anything other than very complicated. Every organ and tissue is its own special case, and most interventions will result in more or less of a specific protein produced in one organ versus another. This is yet another reason why the metabolic tinkering approach to aging, attempting to adjust levels of specific proteins to a more youthful configuration in order to produce benefits, is an enormous undertaking, far greater in scope and difficulty than the alternative approach of repairing the damage found in old tissues.

Activating transcription factor-4 promotes mineralization in vascular smooth muscle cells

Evidence is emerging that endoplasmic reticulum (ER) stress contributes to the pathogenesis of vascular calcification. The ER is a major site for the regulation of calcium and lipid homeostasis. ER stress is an integrated signal transduction pathway involved in the localization and folding of secreted and transmembrane proteins. Vascular calcification is an independent predictor for the mortality and morbidity of patients with chronic kidney disease (CKD). Vascular calcification is classified into two major types, atherosclerotic and medial, both of which are frequently and simultaneously observed in CKD patients. Vascular calcification is a highly regulated process that resembles skeletal bone formation. Many key transcriptional regulators involved in skeletal osteogenesis are expressed in both calcified medial arterial layers and atherosclerotic plaques. We recently reported that these factors induce ATF4 activation through the ER stress response, resulting in osteogenic differentiation and mineralization of vascular smooth muscle cells (VSMCs) in vitro. However, whether in vivo ATF4 activation causes vascular osteogenesis and the molecular mechanism by which ATF4 induces mineralization of VSMCs have not been determined. In this context, we determined the in vivo role of ATF4 in VSMCs in both atherosclerotic and medial calcification and its mechanisms by using several murine models with global ATF4 deficiency, smooth muscle cell-specific (SMC-specific) ATF4 deficiency, and SMC-specific ATF4 overexpression.

ATF4 is known to be a critical transcription factor that regulates skeletal osteogenesis and bone formation. We and other investigators previously reported that ER stress induces expression of aortic ATF4 in a number of in vitro and in vivo models of vascular calcification. In particular, CKD strongly activates the aortic ER stress response, resulting in a significant induction of aortic ATF4. In this study, we demonstrate that ATF4 expression in VSMCs plays a causative role in the pathogenesis of vascular calcification using a series of mouse models. As an initial model, we used global ATF4-haploinsufficient mice, which showed significantly smaller aortic medial calcified lesions under both CKD and normal kidney condition (NKD) conditions. We also used an SMC-specific ATF4-deficient model, in which both medial and atherosclerotic calcifications under NKD and CKD conditions were attenuated. Finally, we generated a mouse model that overexpresses ATF4 only in SMCs, in which severe medial and atherosclerotic calcification developed even under NKD. These findings strongly suggest that the induction of ATF4 in VSMCs through ER stress is a pivotal event in the development of vascular calcification and osteogenesis.

CHOP is a major target of ATF4, and it is a transcription factor that promotes apoptosis contributing to vascular calcification. We previously reported that global CHOP deficiency attenuated CKD-dependent vascular apoptosis and atherosclerotic calcification in ApoE-/- mice. In this study, SMC-ATF4 deficiency reduced aortic CHOP expression and CKD-dependent apoptosis accompanied by a marked attenuation of vascular calcification, whereas SMC-ATF4 overexpression induced CHOP expression and apoptosis. These results suggest that ATF4 mediates vascular calcification through the induction of phosphate uptake in VSMCs through CHOP-dependent and -independent mechanisms.

Electrical Properties as the Basis for a Better Biomarker of Cellular Senescence

Today, I'll point out a speculative line of research on the detection of senescent cells. It is in an early enough stage to make it hard to say whether or not it will go anywhere in the years ahead. The authors of the open access paper linked below propose that the electrical properties of senescent and normal cells are sufficiently different to be used to build an assay for cellular senescence. Even if useful, this may not take off because the present molecular biomarkers for cellular senescence are generally agreed to be good enough for a first pass at the job at hand, meaning efforts to destroy these cells while having a fair idea after the fact as to how many succumbed to the therapy. Since the set of present biomarkers are soon going to used much more widely, given the rapid growth of the senescent cell research field, an entirely different approach to assays will face an uphill battle to gain adoption, whether or not it is better. And electrical measurement is indeed an entirely different approach when compared to the established methods of detecting the levels of a senescence-associated protein such as β-galactosidase, one requiring entirely different tools.

Why do we care about the number of senescent cells found in tissues? Well, to start with these cells are killing you. Ordinary cells become senescent when they reach their evolved replication limit, or in response to damage, or a toxic environment, or as a part of the wound healing process. Most such cells self-destruct or are destroyed by the immune system fairly rapidly. This serves to remove those cells most at risk of developing cancer. Some linger, however, and in growing numbers over the years. These cells secrete a mix of harmful signals that produce chronic inflammation, destroy fine tissue structure, and alter the behavior of surrounding cells for the worse. If just 1% of the cells in a tissue become senescent, and that happens to all of us eventually, they collectively cause significant dysfunction and contribute to the development of ultimately fatal age-related conditions. This is I'm very enthused by progress towards therapies capable of selectively destroying these cells. Senescent cell clearance treatments will be the first legitimate, actual, working rejuvenation therapies: limited in scope, but capable of reverting one cause of aging and all of its immediate consequences on the state of health.

To develop new senescent cell clearance therapies cost-effectively and rapidly, however, it is important to be able to determine how well the prototypes work. A field with a body of reliable, agreed upon tests to determine the quality of therapeutic outcomes is a field that can forge ahead and experiment at low cost. The field of senescent cell clearance is already well equipped on that front. Researchers can make a fair determination of degree of clearance, and have been doing just that. The standard assays have been used in one form or another for the past fifteen years or so. They are simple, but well proven. The need and market for new assays will, I think, be driven by uncertainties over whether or not the established assays are actually finding all of the senescent cells of interest, and whether or not the differences between classes of senescent cell are important in the grand scheme of things. For example, in the past couple of years researchers have started to distinguish senescent immune cells and senescent foam cells in atherosclerosis from the bulk of senescent cells, arguing that these have significantly different characteristics. Fortunately it so far appears that all of the potential senescent cell destruction therapies under development are fairly indiscriminate when it comes to the varieties of cellular senescence. Still, after the first generation of therapies there will be a second and a third, and we want those future treatments to be much improved over those presently in development. That will require a greater understanding of the varieties of senescence, as well as better assays for quantifying the results produced by potential therapies. Whether that will turn out to involve measurement of electrochemical properties of individual cells is an open question, but the prototyping of such an approach makes for interesting reading:

Cell Electrical Impedance as a Novel Approach for Studies on Senescence Not Based on Biomarkers

Senescence and disease are the two main contributing factors for the termination of life. Although senescence is one of the major causative factors of disease, senescence can be controlled to extend lifespan. In this context, various biomarkers have been used to measure and analyze senescence. In particular, research on senescence is especially important in cardiovascular research because cardiac myocytes are long-lived postmitotic cells, which need renewal of cellular components as a major ability for lifespan, unlike other short-lived cell types. In general, senescent cells have reduced autophagic activity, reduced telomerase activity, altered contents in mitochondrial phospholipid, increased oxidative stress due to reactive oxygen species (ROS), and increased levels of senescence associated β-galactosidase activity. Additionally, senescence associated changes at various levels of gene transcription and protein translation have also been reported. In all of the aforementioned studies, specific biomarkers have been used to evaluate the potential alterations in cell structure and function. However, such analyses involve complex procedures including chemical modification or tagging. In addition, the acquired data provide only comparative (not absolute) values. Further, given that senescence is a highly complex biological process, it is difficult to assess cellular aging based on the limited number of available biomarkers.

Electrochemical impedance spectroscopy has been utilized to indicate the electrical characteristics of different types of tissues. Even though the measurement of electrical impedance of tissues can provide beneficial information, this method is inconsistent and imprecise owing to the complex structure and composition of tissues. Recently, microelectrochemical impedance spectroscopy has been developed to characterize the electrical properties of cells at the single-cell level owing to the advances in lab on a chip and microfabrication technologies. The electrical impedance measurement at the single-cell level can afford more precise information than that of measurements at the tissue level. This technique contributed to acquire the quantitative information of cells, such as resistance, reactance, capacitance, and conductance, because the electric properties of cells are connected with their physiological states. Therefore, microelectrochemical impedance spectroscopy has been suggested to be a simple, fast, and cost effective diagnostic tool that does not require biomarkers.

Recently, changes in cellular components during senescence were quantitatively analyzed using a new methodology called microelectrochemical impedance spectroscopy for diagnosis of senescence (MEDoS), which involves measurement of electrical impedance of a cell. Since electrical properties of a cell gradually change with changes in the cellular components during senescence, cell impedance can be used to analyze senescence. In addition, cell impedance data can provide quantitative characteristic values for individuals with a higher efficiency than biomarkers. MEDoS was designed to ensure that a captured single cell remains steadily at a certain position during measurement. The MEDoS comprises a microfluidic channel for cell flow, a flexible polymer membrane actuator that functions as a cell trap for capturing, a pair of barriers, and sensing electrodes.

In this study, we investigated age-related changes in cell impedance in cardiac myocytes of zebrafish. MEDoS performed in this study exhibited a high cell-capture rate (90%) for cardiac myocytes from zebrafish hearts. The sequence of cell trapping is as follows. (1) Three groups (3, 6, or 18 months old) of cardiac myocytes in 1% fetal bovine serum solution are injected into the fluidic channel. (2) The membrane actuator is inflated by pneumatic pressure to block the cell flow until a single cell stops in front of the trap. (3) The pressure is reduced so that a single cell can enter the trap in a squeezed state. (4) When a single cell is positioned at the center of the sensing electrodes, the pneumatic pressure is increased again to fix the cell on the central surface of the electrodes. For minimization of cell damage, cardiac myocytes were maintained at 4°C during the experiment, and all experiments were completed within 1 hour.

The resistance of the cytoplasm gradually decreased from the 3-month-old cell group to the 18-month-old cell group. Considering that resistance is inversely proportional to conductance, we reviewed previous aging studies that evaluated changes in cellular components that could affect conductance during senescence. Autophagic activity is especially important in cardiac myocytes, a long-lived postmitotic cell, to maintain homeostasis and longevity. Autophagic activity decreases with senescence, and, accordingly, various reactive oxygen species (ROS) accumulate in the cytoplasm of cardiac myocytes. Thus, accumulated ROS could cause changes in cellular components as well as in electrical impedance. In several studies, an increase in the conductance of induced hypoxic alveolar epithelial cells due to an increase in the ROS level was found. In addition, an increase in the conductivity of hemoglobin caused by high oxidative stress was addressed. In other words, accumulated ROS can increase the conductance of the cytoplasm because of their free-radical characteristics. Therefore, our results could suggest that ROS that accumulate during senescence decrease the resistance of the cytoplasm.

Meanwhile, capacitance, which refers to the cell membrane in the electrical circuit model, gradually increased from the 3-month-old cell group to the 18-month-old cell group. A cell membrane has a phospholipid bilayer, which is composed of different types of molecules such as fatty acids and various proteins. During cell senescence, the level of ROS gradually increases with decreasing autophagic activity. ROS are more soluble in the fluid lipid bilayer than in aqueous solution; thus, the membrane phospholipids and polyunsaturated fatty acids, one of the phospholipid acyl chains, are susceptible to oxidative damage. Peroxidation of polyunsaturated fatty acids in the membrane has been shown to be a cause of senescence. Based on the aforementioned studies, the peroxidizability index (PI) was used to measure the relative age-related susceptibility of fatty acid composition to peroxidative damage in the cell membrane. A high PI value implies that the membrane bilayer is easily affected by lipid peroxidation. Many investigators have found that the PI value and lipoxidation-derived molecular damage increase with aging. In addition, the oxide composition amount increases during the process of lipid peroxidation. These phenomena can be explained by the fact that high PI values are obtained as the oxide composition amount increases. The capacitance of the cell membrane also increases as the oxide composition amount increases in the membrane. Therefore, we hypothesize that the increase in PI values reflects an increase in the capacitance of the cell membrane.

The Decomposition of Alzheimer's Disease

The biochemistry of Alzheimer's disease is complex and varied, still incompletely mapped at the detail level. At the edges it merges into grey areas shared with other forms of neurodegeneration - a large number of Alzheimer's patients are diagnosed with other forms of dementia or cognitive impairment. That Alzheimer's is one item in the official list of diseases, that the borders between various forms of neurodegeneration are drawn as they are, is a historical accident carried across more than a century of the taxonomy of disease, not a reflection of current opinions. The age-related dysfunction of the brain is driven by numerous pathological processes. Differences of relative degree between these progresses, and in the locations in the brain that are worst affected, mix and match to produce the various named age-related conditions, collections of different symptoms. The classification of those symptoms into the buckets called diseases happened in most cases long before modern investigations of neural biochemistry. So we have the country of Alzheimer's disease, whose borders as drawn by symptoms and present fairly crude methods of diagnosis encompass what will probably come to be understood as several distinct conditions. They also likely enclose portions of other known conditions, such as vascular dementia, and this muddies the waters in many ways.

In the years ahead, as the first therapies arrive to effectively address the underlying processes that produce neurodegeneration, there will be a redrawing of borders in the matter of brain aging. Some named conditions will vanish, others will split into categories, and entirely new named diseases will arise. In this way taxonomy loosely reflects progress. Being able to remove one cause in a condition that has several causes is one of the most effective ways to figure out how everything fits together, and what the true classification should look like. For Alzheimer's, this phase of research and development is almost upon us. The condition is characterized by harmful accumulations of amyloid-β and tau, to different degrees in different patients, and in different parts of the brain. It is both an amyloidosis and a tauopathy, but without removing one or the other, it is hard to determine the relative importance of these forms of metabolic waste. Even if both are dealt with, there is still the matter of other conditions such as vascular dementia: if a therapy produces little improvement, is it because the target isn't causing significant pathology, or is it because other, untargeted processes are also causing significant pathology? To complicate matters further, the halo of biochemistry surrounding both amyloid and tau aggregates varies considerably by location within the brain and by the form of the aggregate - not all amyloid and not all tau is the same. They are categories, not single items.

Still, not so long ago, researchers finally demonstrated clearance of amyloid-β in the human brain, and in a way that appears to result in decreased symptoms of cognitive decline. Tau should follow in the years ahead. Over the next few years, the understanding of Alzheimer's will greatly increase, as the fastest way to pin down the roles and relative importance of the contributing processes is exactly this, to remove them and see what happens. Beyond the gains in understanding, it has the added bonus of being the most plausible road towards effective therapies, those that can do more than merely gently slow the progression of neurodegeneration. Exciting times lie ahead, and there will be many more papers like this one, in which the existing borders between diseases are questioned in light of new knowledge:

Primary age-related tauopathy and the amyloid cascade hypothesis: the exception that proves the rule?

Extensive data supports the amyloid cascade hypothesis, which states that Alzheimer's disease (AD) stems from neurotoxic forms of the amyloid-beta (Aβ) peptide. Applying the framework provided by the amyloid cascade hypothesis to diagnosing and treating AD has proven problematic. Early neuropathological criteria for diagnosing AD focused on Aβ burden, but this strategy was not optimal given that total Aβ plaques correlate poorly with cognitive impairment and neuronal loss. Several large phase III clinical trials of therapeutics targeting Aβ have failed due to lack of efficacy, prompting reflection as to whether the amyloid cascade hypothesis is invalid. The reason for these failures remain unclear, but some investigators have cited these failed trials as evidence refuting the amyloid cascade hypothesis. Other investigators and pharmaceutical companies have concluded that the design of the trials, which failed to confirm target engagement, were the reason. Another possibility is that Aβ triggers a complex neurodegenerative cascade with a late amyloid-independent phase. The future success of an Aβ-targeting agent is required for final validation of the amyloid cascade hypothesis.

While the heterogeneity of dementing illnesses has complicated efforts to understand the relationship between Aβ and cognitive failure, recent progress in understanding non-AD dementias has put AD into sharper focus. Some of pathologies are more readily differentiated from AD neuropathologically, such as vascular dementia, but this can be difficult to quantify. The TDP-43 proteinopathies (e.g. amyotrophic lateral sclerosis) are largely devoid of Aβ and tau pathology. The more closely overlapping "plaque-only dementia" cases were found to largely represent an α-synucleinopathy (i.e., diffuse Lewy body disease). Another pattern of degeneration, however, which has been variably called tangle-only dementia (TOD), neurofibrillary tangle predominant senile dementia, tangle-dominant dementia, among many other monikers, has received far less attention. Large dementia autopsy series designed to advance our understanding of AD have allowed TOD to come into sharper focus and culminated in the development of a new diagnostic category termed primary age-related tauopathy (PART). New consensus criteria place TOD on a continuum with age-related tangles, that are universally observed in aged brains. Considerable evidence indicates that subjects with PART have a distinct constellation of features that sets them apart from classical "plaque and tangle" AD and other tauopathies. Studying these differences may provide clues to the pathogenesis of tauopathies and refine the amyloid cascade hypothesis.

The neurofibrillary tangles (NFT) in PART are essentially identical to those observed in AD. They are composed of similar tau isoforms, form paired-helical filaments, and are concentrated within neurons. The NFT in PART are localized to the medial temporal lobe. NFT in this distribution can be observed in subjects with normal cognition, mild cognitive impairment and dementia. In cognitively normal elderly subjects, autopsy studies have demonstrated that medial temporal lobe NFT are essentially universal and in a more limited distribution in many younger individuals. In demented subjects, approximately 2-10% of subjects display such tangles without significant amyloid deposition. The proportion of subjects with age-associated memory impairment or mild-cognitive impairment in association with PART might be high. Finally, given that Aβ-deposition is commonly encountered in cognitively normal subjects, "benign Aβ" deposits might be masking an underlying tauopathy in some patients leading to reduced prevalence estimates. Methods for differentiating PART tangles and AD tangles (e.g., biochemical or immunohistochemical markers) would be extremely helpful for answering this question. Tangle-only dementia (TOD) was first described in a series of patients with clinical features that were very similar to those of classical AD. While this category likely included some subjects with other dementing tauopathies, a large proportion have PART as a primary pathological dementing process.

What exactly PART represents has been the matter of debate, with various investigators considering it an AD variant, a frontotemporal dementia variant, or normal (or "pathological") aging. Toxins and infectious causes are also possible, but less likely. Currently, the evidence fails to support a role for Aβ toxicity in PART. Subjects with PART have no Aβ deposition. The possibility that PART is a form of pathological brain aging deserves attention. Mechanical injury in the form of mild yet repetitive traumatic brain injury (TBI) is an established trigger for tauopathy in chronic traumatic encephalopathy (CTE) in elite athletes and boxers. While subjects develop PART in the absence of documented TBI, the hypothesis that these tangles are caused by very mild repetitive "wear and tear" type injury can be supported by three arguments. First, the geometry of the human central nervous system is such that foci of mechanical stress concentration are predicted to include the medial temporal lobe and basal forebrain. Second, the presence of an uncal notch in the medial temporal lobe that overlies the transentorhinal cortex is very common even in the absence of cerebral edema, providing direct physical evidence that this site is a focus of stress concentration. Third, patients with known repetitive mechanical brain injury (i.e., CTE) develop tangles in an overlapping distribution, however more widespread and of greater magnitude. Thus, it is reasonable to hypothesize that the cause of PART is a very mild repetitive mechanical "wear and tear" type of age-related injury.

Rabep2 Variants Reduce the Harm of Stroke through Increased Alternative Vasculature

The research I'll point out today examines one of the mechanisms by which the damage caused by similar strokes can vary from individual to individual. The researchers focus on the degree to which the vascular network of the brain grows to contain alternative routes to the same destination tissues, and identify a gene in mice that accounts for a fair amount of this difference between individuals. A stroke is the outcome of structural failure in a blood vessel in the brain, weakened by the molecular damage of aging, leading to loss of elasticity, and put under stress by the increased blood pressure of hypertension. The result is either blockage or rupture, disrupting the flow of blood to where it is needed. The largest effects result from the downstream loss of blood flow to a region of brain tissue, ischemia, followed by its sudden return. Most cells survive a short loss of oxygenation and nutrients, but then die in the reaction to a renewed influx of oxygenated blood, an effect known as reperfusion injury. The effects of similar strokes vary from individual to individual for many reasons. To pick one example among many, differences in the cellular reaction to reperfusion can be quite influential, and thus genetically engineered mice lacking the oxygen sensor PHD1 have been demonstrated to experience greatly reduced cell death following a stroke.

The vascular network incorporates some redundancy throughout the body, though nowhere near as much as one would like. Blockage of larger vessels is going to cause trauma: there is a given amount of blood flowing through that channel and it can't all fit through the alternative paths. In many cases enough can get by to keep tissues alive, however, and thus reduce the degree of ischemia. Some people have more of those additional redundant blood vessels than others, and thus suffer less in the event of stroke. Being more resistant to damage is better than being less resistant to damage if that is the only game in town, but aiming higher certainly should be the goal. No-one wants to be put in the position of suffering a stroke in the first place. Prevention is far better than cleaning up after the fact, especially given the high risk of death and permanent disability that accompanies stroke.

Thus consider the forms of rejuvenation therapy that can address the root causes of hypertension, blood vessel stiffness, and damage to blood vessel walls, such as that caused by atherosclerosis - these are the goals to work towards. Of the SENS rejuvenation research portfolio, breaking cross-links will most likely do the most address loss of elasticity, but if you look at the evidence almost all of the fundamental forms of cell and tissue damage that cause aging have some contribution to make. So mitochondrial repair of one form or another will reduce the flux of damaged lipids that contribute to atherosclerosis. Cleaning up the related metabolic waste such as 7-ketocholesterol found in atherosclerotic lesions will no doubt also help. From recent work there are hints that senescent cell clearance will also assist in turning back loss of tissue elasticity, and any approach that reduces chronic inflammation will also slow the decline of the vascular system.

Scientists identify "collateral vessel" gene that protects against stroke damage

Scientists have known that when an artery is blocked, the damage to tissues downstream is often limited because these tissues continue to be nourished by special "collateral" vessels that connect the tissue to other arteries. However, for reasons that haven't been understood, the number and size of these collateral vessels - and thus the protection they afford - can vary greatly from one individual to the next. Scientists have now implicated the Rabep2 gene as a major contributor to this variation in collateral vessel formation. Variants of this gene account for most of the differences in collateral vasculature among laboratory mice. Since humans and mice are more than 90 percent genetically similar, the human version of Rabep2 is likely to have a comparable function.

Through a series of experiments, researchers replaced a defective variant of the gene in a mouse strain with poor collaterals with a normal copy of the gene, resulting in the formation of abundant collateral vessels during embryonic development and much greater resistance to tissue injury and cell death when the mice were subjected to experimental stroke as adults. The scientists hope that one day doctors will be able to use a simple blood test to detect variants of the human form of the gene. This would help doctors quickly gauge the extent of collateral vessels in patients who experience heart attacks, strokes, peripheral artery disease, and occlusive disorders in other tissues. In principle the findings also could help lead to therapies that stimulate the formation of more collateral vessels in healthy people to reduce the severity of tissue injury in the event of a future arterial blockage, as well as in people who already have occlusions, thereby reducing damage and improving their recovery.

This comes nine years after researchers first observed that the extent of the collateral vasculature - and thus the damage after arterial occlusion - can differ greatly between different strains of lab mice, even though no differences in the rest of the circulatory systems were evident. They focused on collateral vessels in the brain, which are easier to image than in other tissues, and undertook experiments involving thousands of mice. By 2014, the group had narrowed the search to a small region on mouse chromosome 7. In the new study, the researchers set out to identify the particular gene in this region that might explain the differences in collateral vessel development. From the 28 protein-coding genes in the region, the scientists were able to exclude 13, after determining that mice lacking any of those genes didn't have more or fewer collaterals. Of the 15 remaining genes under suspicion, the team decided to focus on their top suspect, Rabep2. Little was known about this gene, but the scientists had previously found a Rabep2 variant in mouse strains with low collateral extent, whereas high-collateral strains had the normal version of the gene. The variant differs from the normal gene in only a single DNA "letter," but that change - because of its location - is predicted to impair the function of the resulting protein.

Using new CRISPR gene-editing technology, the team was able to test the effect of this Rabep2 variant. They replaced the DNA letter in normal Rabep2 that is present in the genomes of high-collateral mice with the suspect variant. The result: the mice formed many fewer collaterals during development and had much greater stroke damage as adults. And this shift was even greater when the gene was deleted entirely. Conversely, in mice from the low-collateral strain, replacing the variant gene with the normal one induced the animals to develop the abundant collateral vasculature present in the high-collateral strain. These beneficially "edited" mice were thus far more resistant to damage from stroke.

Variants of Rab GTPase-Effector Binding Protein-2 Cause Variation in the Collateral Circulation and Severity of Stroke

The extent (number and diameter) of collateral vessels varies widely and is a major determinant, along with arteriogenesis (collateral remodeling), of variation in severity of tissue injury after large artery occlusion. Differences in genetic background underlie the majority of the variation in collateral extent in mice, through alterations in collaterogenesis (embryonic collateral formation). In brain and other tissues, ≈80% of the variation in collateral extent among different mouse strains has been linked to a region on chromosome 7. We used additional CNG mapping and knockout mice to narrow the number of candidate genes. Subsequent inspection identified a nonsynonymous single nucleotide polymorphism between B6 and BC within Rabep2 (rs33080487). We then created B6 mice with the BC single nucleotide polymorphism at this locus plus 3 other lines for predicted alteration or knockout of Rabep2 using gene editing. The single amino acid change caused by rs33080487 accounted for the difference in collateral extent and infarct volume between B6 and BC mice. Mechanistically, variants of Rabep2 altered collaterogenesis during embryogenesis but had no effect on angiogenesis examined in vivo and in vitro. Rabep2 deficiency altered endosome trafficking known to be involved in VEGF-A / VEGFR2 signaling required for collaterogenesis.

The Work of the Aoki Foundation to Support SENS Rejuvenation Research

Music business entrepreneur Steve Aoki has been a supporter of the SENS rejuvenation research programs for a while now. I'm always pleased to see successful people being vocal about their support for SENS, putting it front and center when talking to their audiences. Placing this important scientific work - as well as the prospects for near future therapies, and the need for philanthropic funding - in front of a bigger audience is vital to the continued growth of our community and progress towards the medical control of aging. We need to reach out to entirely new networks of people, those who would never seek out the longevity science community on their own, as among their numbers are many who will be turn out to be interested, pleasantly surprised, and enthusiastic. Today, I'd wager, a large fraction of those people who will go on to be significant advocates and philanthropic donors of the late 2020s have no idea that we even exist, or that bringing an end to age-related disease, frailty, and suffering is possible outside the realm of science fiction.

Bootstrapping a cause never stops being hard. It was hard when small groups were striving to raise a few thousand in funding for SENS advocacy here and there, when having regular research programs and fund of millions looked to be an impossible distance away. It is hard today, when the SENS Research Foundation is trying to make the leap from a few million in yearly research budgets to something ten times that size. Building greater public awareness and enthusiasm for the medical science of human rejuvenation is a very necessary part of that work. The sooner we collectively manage to change the zeitgeist to one in which charitable support for rejuvenation research is just as normal and lauded as support for cancer research, the better off we all are, and the more money that can be raised for scientific projects. So thanks are due to Steve Aoki for stepping up to the plate and taking a swing at this. He is helping with the present year end SENS Research Foundation fundraiser, with the SENS rejuvenation research programs being one part of his broader interest in neuroscience as it can be applied to the long-term health of the brain:

Steve Aoki Throws a Party For Science

Hang with DJ Steve Aoki at a nightclub and you can expect an earful of his electronic bangers and confetti in your hair. Cozy up to Steve Aoki at Brooklyn Bowl on November 15 and you'll get to hit pins alongside neuroscientists, bid on one-of-a-kind experiences in live and silent auctions (think jumping into the foam pit at Aoki's Las Vegas "playhouse") and catch him outside the booth as he hosts the Aoki Foundation's Bowling for Brains fundraiser. The inaugural event supports the Buck Institute on Aging, SENS Research Foundation and Las Vegas' own Lou Ruvo Center for Brain Health, continuing the foundation's ongoing support of regenerative science.

"Anyone who's willing to help out toward brain research and organizations that are focused on cutting-edge research on degenerative brain diseases - I want to meet these people. I want to be in the same room with them and create more collaborations. That's really cool to me. I don't get the opportunity to do that very often because usually when I do events, I'm just DJing. At this one, I get to hang out. It's more of an intimate thing. Anyone who enters can have conversations about brain health and what we can do to raise more money and awareness of these organizations that are doing incredible work. After my father passed away in 2008, I started doing a lot of research on cancer and understanding what killed him. That led to researching general health and nutrition and understanding the body, the brain, then science and technology, seeing how far we've advanced and what kind of trajectories we're heading toward. A lot of it has to do with understanding our brain. It's the single most important phenomenon in civilization - the human brain. Yet we really don't know much about it. At the end of the day, if we don't die from something like cancer, we will have some kind of degenerative issues that will affect us and the people that we love."

"We're going down a path that, at one point, was considered science fiction. There are a lot of things happening in science that you wouldn't even believe. These radical technological advances are something I'm excited about. You don't really hear about it because the science community is so small. In a way, I use this platform to say, hey, the science community is pretty small, but the music community is pretty large. I would love to use this platform to bounce all of these amazing advances off to a community that would never hear about it and let them know, hey, you can help out. We can get there faster, and we can get there more efficiently. We're working toward a world where degenerative brain diseases do not exist. Imagine if we could eradicate that like we eradicated tuberculosis or polio, then we wouldn't ever have to worry about it again. If we don't have a brain that's working, we're not ourselves."

Aoki Foundation

The AOKI FOUNDATION has a primary goal of supporting organizations in the brain science and research areas with a specific focus on regenerative medicine and brain preservation. Our vision is to one day see a world where degenerative brain diseases do not exist and science and technology play a direct role in extending the healthy lives of ourselves and our loved ones. Steve believes strongly that greater research in brain science can lead to healthier and longer lives. He supports various organizations in the neuroscience field, specifically focused on doing research on regenerative medicine, brain health and preservation. He hopes to use his global influence to raise money for organizations conducting research in important brain health areas. Through the AOKI FOUNDATION, he will take issues into his own hands by directly supporting those affecting change when needs arise, in addition to hosting fundraising events and campaigns for specific charitable organizations throughout the year. The human brain is the most complicated biological structure in the known universe. We've only just scratched the surface in understanding how it works and more importantly how it doesn't work when disorders and disease happen.

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The Long Term Wager on Living to 150

There is a long-standing bet between scientists Steven Austad and S. Jay Olshansky on whether or not someone alive when the bet was made will survive to reach the age of 150. In essence this is a bet on the timing of the process of actuarial escape velocity that has been described by Aubrey de Grey: how soon will new medical technologies, those capable of addressing the root causes of aging to produce rejuvenation, start to extend remaining life span at a faster rate than people age? At some point more than a year of additional life will be added with each year of passing time, but even before then incremental gains in the field will provide enough additional time for older people to be able to survive to benefit from the better technologies ahead. If a partial rejuvenation therapy adds ten years to life expectancy, that is ten extra years of life in which further improvements and other partial rejuvenation therapies can be brought to the clinic. The wager was in the news again recently, following a rather controversial and much misinterpreted paper on observed limits to life:

Two US researchers have doubled their 16-year-old wager on whether anyone born before 2001 will reach the age of 150. The scientists have now staked 600 on the question - but, if the fund in which the cash is deposited keeps growing at its current rate, the descendants of the victor could net hundreds of millions in 2150. The friendly rivalry began in 2000, when Steven Austad, a biologist who studies ageing, was quoted in an article with the provocative statement: "The first 150-year old person is probably alive right now." Jay Olshansky, another expert on ageing, didn't think so - and the scientists agreed to stake cash on the debate. On 15 September 2000, the two put 150 each into an investment fund, and signed a contract stating that the money and any returns would be paid to the winner (or his descendants) in 2150. The bet also stipulates that Austad will only win if the 150-year-old is of sound mind.

Then last week, a paper suggested - from an analysis of global demographic data - that there may be a natural limit to human lifespan of about 115 years. Olshansky wrote an accompanying commentary which argues that fixed genetic programs stand in the way of significant human life extension. He says he believes a major breakthrough that will significantly extend human lifespan will occur within his lifetime, but that it will come too late to help those born before 2001 to reach their 150th birthday. But Austad disagrees. "I'm more convinced than ever that I was correct in our original bet," he says. He cites recent studies showing that a number of drugs, such as the immune-system suppressor rapamycin, can significantly extend lifespan in animals. And he points to the imminent start of a clinical trial called Targeting Aging with Metformin, or TAME, which hopes to show that a well-known diabetes drug can slow ageing. Austad and Olshansky have now agreed to stake another 150 each. In 16 years, their original 300 stake has already grown to 1,275 (increasing by around 9.5% per year). If the topped-up fund maintains this average annual return, the winning pot could top 200 million by 1 January 2150. On that date, three scientists chosen by the president of the American Association for the Advancement of Science will determine the winner - although neither Austad nor Olshansky expects to be alive to find out.

Propaganda for Death and Aging is Everywhere

We all live in societies in which near every formative story and teaching glorifies the process of aging to death. The foundations of our myths paint death through aging as an essential, good thing. This is the natural outcome of thousands of years of creative human culture in which nothing could be done about aging. People came to terms with it by building tools - stories, myths, coping mechanisms - to enable psychological comfort in the face of the horrible and the inevitable. The best of these tools prospered because they allowed the societies that used them to prosper, and so we have today what has been termed the "pro-aging trance". We are now entering a new era, however, and in an age of biotechnology and medicine capable of addressing the causes of aging, these lies that we tell to ourselves about aging and death have outlived their usefulness. They have become a dead weight dragging us down, slowing the growth of support for rejuvenation research that can bring an end to the pain and suffering of aging and age-related disease.

Two clichés really ruined a recent moviegoing experience for me: the implied, groundless cliché that 'living forever is not as nice as you think, it's something only bad guys would want and it comes at a high price' creeping up throughout the entire movie, and the inevitable 'death gives life its meaning' cliché. I am really tired of hearing this false mantra being mindlessly repeated over and over. Books, movies, newspaper articles, people - everyone seems to be persuaded that without death, life would have no meaning. No one, though, bothers explaining why this depressing claim would hold true, and if they do, their arguments boil down to unconvincing, carelessly generalised hand-waving about how you couldn't properly appreciate a good thing without its opposite. That's like saying that in order to appreciate not having cancer, you need to have had cancer first. I appreciate how being mortal may make you see things differently from how an immortal being might see them, but that is not the same as death being mandatory to appreciate life.

So, please, stop. Stop repeating this dangerous and foolish mantra. Don't let movies, books, or anyone tell you that death gives life its meaning. Don't let anyone decide for you what is the meaning of life, or what gives meaning to it, because in general, there is no such thing. Meaning is relative, not absolute, and you get to decide for yourself what gives meaning to your life, not an age-old piece of nonsense people perpetuate merely to sugarcoat death. Death is nothing special. It is not a monster. It is not a foe, no more than the status of 'broken' is for an inanimate object. Death is the name we give to the status of a biological creature whose body is too damaged to keep functioning. That's all it is. I don't know what gives meaning to your life, but I can tell you what gives meaning to mine. People I love. Things I like doing. Music I like listening to. Playing piano. Drawing. Writing. Learning new things. Having fun with friends. Discussing science. Enjoying a beautiful landscape. Wondering about the countless mysteries of nature we haven't solved yet - and many, many other things.

We have hospitals to cure sick people. We have international organisations trying to save people in poor countries from starvation, to put an end to war and help its victims. Why all these initiatives aimed at preserving our lives, if death is what gives it meaning? If you are struck by a fatal illness, why turn to doctors to save your life? Perhaps the time has come for death to give it meaning. Do you see the nonsense yet? The very idea that death gives meaning to life, when we've tried so very hard from time immemorial to stave off death for as long as possible, is absurd-or perhaps, a hint that we don't care that much for our lives to have a meaning after all. Does all that you do, feel, and care for, magically become worthless if you don't die? Are the people you love dear to you only because one day you won't have them any more? What about the things they have done for you, or the fact they understand you like no one else does?

No, I don't think death gives meaning to life. Things I fill my life with give it meaning, and all my death is going to accomplish is taking those things away from me. (Or rather, it's going to take me away from those things.) Ageing is the worst example of this: It gradually makes you more and more unable to dedicate yourself to the things that give your life meaning, thus making your life more and more meaningless. Eventually, it deprives you of life entirely. So please, stop repeating the death mantra. Stop believing in this crazy nonsense. I understand where it comes from, and I understand our need to rationalise death, but it is time to move on. It is time to look at death for what it is and keep on refining our tools to stave it off indefinitely, so that people can live in perfect health for as long as they wish.

Mitochondrial Function and the Earliest Stages of Alzheimer's Disease

All age-related disease is built upon a foundation of damage and dysfunction that stretches as far back as decades prior to the evident manifestation of pathology. The normal operation of cellular metabolism produces forms of molecular damage that take a long time - most of a lifetime - to become prevalent enough to produce obvious change and harm. Researchers here examine the development of Alzheimer's disease from this perspective, with a focus on mitochondrial function, something known to be important in the processes of aging:

Alzheimer's disease (AD) - the most common form of dementia - is a progressive, degenerative disease of the brain. While commonly associated with elderly individuals, this devastating illness is now believed to have its origins much earlier, infiltrating the nervous system decades before the onset of clinical symptoms. Indeed, the greatest obstacle to successful treatment of Alzheimer's is the fact that the disease is typically not recognized until its progress has irreparably ravaged the brain. "Although amyloid plaques and tau neurofibrillary tangles remain as the definitive neuropathological hallmark of the disease, plaques do not correlate at all with degree of cognitive impairment in AD and tangles correlate only slightly. We further know that plaques and tangles are late comers in the cascade of events that cause the dementia of AD."

Mitochondria - membrane-bound organelles found in all eukaryotic organisms - are often called the powerhouses of the cell. Through a process known as oxidative phosphorylation, they produce most of the cell's chemical energy in the form of adenosine triphosphate or ATP. In addition to supplying cellular energy, mitochondria are involved in cell signaling, cellular differentiation, and cell death, as well as in cellular growth and the maintenance of the cell cycle. Because mitochondria play such an important role in the cell, mitochondrial dysfunction has been implicated in a broad range of illness. Unsurprisingly, defects in mitochondrial function more severely affect energy hungry organ systems in the body, particularly muscles, the gastrointestinal tract and the brain. In addition to the role of mitochondrial dysfunction in disease, the gradual degradation of mitochondrial integrity is believed to play a central role in the normal process of aging.

The current study examines tissue from the hippocampus, a structure critical for memory and one severely impacted by the advance of Alzheimer's. Using microarray technology, the authors examined hippocampal tissue from an aging cohort - 44 normal brains from 29-99 years of age, 10 with mild cognitive impairment and 18 with Alzheimer's disease. Gene expression was examined for two sets of genes, 1 encoding mitochondrial DNA and the other, in the nuclear DNA. The two sets of genes both coded for proteins associated with a mitochondrial complex essential for oxidative phosphorylation (OXPHOS), producing energy in the form of ATP for the cell. Intriguingly, while the mitochondrial genes themselves were largely unaffected, the nuclear genes associated with the OXPHOS complex underwent significant modification, depending on the tissues examined. The microarray data revealed substantial down-regulation of nuclear-encoded OXPHOS genes in Alzheimer's tissue, a finding also found in normally aging brains. The same genes, however, were up-regulated in the case of mild cognitive impairment, a precursor to Alzheimer's disease. The authors suggest this effect may be due to a compensatory mechanism in the brain in response to early pathology.

The findings are consistent with earlier work establishing that accumulations of amyloid beta (Aβ) in neurons, a hallmark of Alzheimer's, are directly implicated in mitochondrial dysfunction. The pronounced effect on nuclear-encoded but not mitochondrial-encoded OXPHOS genes may point to dysfunctions in the transport of molecules from the cell nucleus to the mitochondria. "Our work on mitochondria offers the promise of a reliable marker appearing earlier in the course of the disease - one which more closely correlates with the degree of dementia than the current diagnostic of plaques and tangles."

Transplanted Embryonic Nerve Cells can Integrate with the Adult Brain

In what seems like an important proof of concept, researchers here demonstrate that transplanted embryonic neurons can integrate fully into an adult brain, and carry out the same functions as existing adult cells. This means that suitable forms of reprogrammed neural cells, such as those derived from induced pluripotent stem cells, should be just as capable. This sort of result reinforces the need to continue the development of cell therapies for the aging brain, intended to replace lost cells and reinforce failing functionality. Lost cells are only one part of the overall problem, as there is the age-damaged cellular environment to repair as well, but in a number of neurodegenerative conditions cell loss is a very significant proximate cause of pathology. Parkinson's disease, for example, involves the loss of the small population of neurons that produce dopamine.

When it comes to recovering from insult, the adult human brain has very little ability to compensate for nerve-cell loss. Biomedical researchers and clinicians are therefore exploring the possibility of using transplanted nerve cells to replace neurons that have been irreparably damaged as a result of trauma or disease. Previous studies have suggested there is potential to remedy at least some of the clinical symptoms resulting from acquired brain disease through the transplantation of fetal nerve cells into damaged neuronal networks. However, it is not clear whether transplanted intact neurons can be sufficiently integrated to result in restored function of the lesioned network. Now researchers have demonstrated that, in mice, transplanted embryonic nerve cells can indeed be incorporated into an existing network in such a way that they correctly carry out the tasks performed by the damaged cells originally found in that position. Such work is of importance in the potential treatment of all acquired brain disease including neurodegenerative illnesses such as Alzheimer's or Parkinson's disease, as well as strokes and trauma, given each disease state leads to the large-scale, irreversible loss of nerve cells and the acquisition of a what is usually a lifelong neurological deficit for the affected person.

The researchers specifically asked whether transplanted embryonic nerve cells can functionally integrate into the visual cortex of adult mice. "This region of the brain is ideal for such experiments. We know so much about the functions of the nerve cells in this region and the connections between them that we can readily assess whether the implanted nerve cells actually perform the tasks normally carried out by the network." In their experiments, the team transplanted embryonic nerve cells from the cerebral cortex into lesioned areas of the visual cortex of adult mice. Over the course of the following weeks and months, they monitored the behavior of the implanted, immature neurons by means of two-photon microscopy to ascertain whether they differentiated into so-called pyramidal cells, a cell type normally found in the area of interest. "The very fact that the cells survived and continued to develop was very encouraging. But things got really exciting when we took a closer look at the electrical activity of the transplanted cells." The researchers were able to show that the new cells formed the synaptic connections that neurons in their position in the network would normally make, and that they responded to visual stimuli. The team then went on to characterize, for the first time, the broader pattern of connections made by the transplanted neurons. They found that pyramidal cells derived from the transplanted immature neurons formed functional connections with the appropriate nerve cells all over the brain. In other words, they received precisely the same inputs as their predecessors in the network. In addition, they were able to process that information and pass it on to the downstream neurons which had also differentiated in the correct manner.

The Abolition of Aging

The Abolition of Aging was pointed out to me a little while ago as a more populist companion to Ending Aging. It offers less of a detailed introduction to the relevant areas of rejuvenation biotechnology, and more of an argument for the manifest destiny of radical life extension, a goal for our species that in this age of biotechnology should be both inevitable and desirable. I'm all for more people putting forward strong moral arguments for the work needed to bring an end to aging. There is no such thing as too much advocacy for this cause; helping to alleviate the vast and ongoing suffering and death produced by degenerative aging is the greatest good that anyone can achieve, and yet so very many people remain to be persuaded.

We live in an era of sweeping change. Every day brings a fresh wave of news reports about apparent breakthroughs by scientists and engineers. As a futurist, when I talk to audiences about the implications of accelerating technology, I'm used to witnessing some powerful reactions. Our untutored gut reactions to hearing about an unexpected future scenario are liable to lead us astray - badly astray. The evaluative principles which served us well in the past may lose their applicability in the very different circumstances that could exist in the future. Therefore, let's try to calmly assess this possibility: practical therapies for the comprehensive reversal of biological aging may be just around the corner. It's my own carefully considered view that, within 25 years - that is, by around the year 2040 - science may have placed into our hands the means to radically extend human longevity. A suite of rejuvenation treatments, administered regularly, could periodically undo the accumulated damage of aging in both body and brain. As a result, life expectancy will shoot upwards. Not long afterward, more and more people will start sailing past the current world record for the longest verified human lifespan.

But when I mention this viewpoint to people that I meet I frequently encounter one of two adverse reactions. First, people tell me that it's not possible that such treatments are going to exist in any meaningful timescale any time soon. In other words, they insist that human rejuvenation can't be done. It's wishful thinking to suppose otherwise, they say. It's bad science. It's naively over-optimistic. It's ignorant of the long history of failures in this field. The technical challenges remain overwhelmingly difficult. Second, people tell me that any such treatments would be socially destructive and morally indefensible. In other words, they insist that human rejuvenation shouldn't be done. It's essentially a selfish idea, they say - an idea with all kinds of undesirable consequences for societal harmony or planetary well-being. It's an arrogant idea, from immature minds. It's an idea that deserves to be strangled. Can't be done; shouldn't be done - in this book, I will argue that both these objections are profoundly wrong. I'll argue instead that rejuvenation is a noble, highly desirable, eminently practical destiny for our species - a "Humanity+" destiny that could be achieved within just one human generation from now. As I see it, the abolition of aging is set to take its place on the upward arc of human social progress, echoing developments such as the abolition of slavery, the abolition of racism, and the abolition of poverty.

A Review of Progress Towards Artificial Blood

In the long run it should be possible to produce safe forms of artificial or augmented blood with superior characteristics to the real thing, whether built on a largely biological or largely non-biological foundation. A fair amount of theorizing and some practical work has gone into ways to enormously increase oxygenation, to the point of not needing to breathe for ten to twenty times longer, for example. There are also lines of research that might improve clotting or reduce side-effects of blood oxygenation, as well as other lines of augmentation. However, meaningful progress past the trial stage has yet to occur. Meanwhile, the ever greater ability to generate large amounts of patient-matched cells of any desired type makes it likely that production of real blood in cell factories will dominate this niche in the near future. True artificial blood still lies some way beyond that.

Understanding the blood behavior at the microcirculation level where blood and tissues come into contact is a key step in the development and application of blood substitutes. Development of an agent properly mimicking the oxygen-carrying capability of blood among its various functions has been of great interest, and many products have been established based on this property. Red blood cells (RBCs) isolated from donated blood are an important component widely used to save patients' lives via oxygen-carrying capacity owing to hemoglobin (Hb). However, there are complications associated with transfusion of RBCs to patients, such as risk of infection. These complications are the most important concerns for the application of RBCs. Furthermore, crossmatch and blood group typing are needed before transfusion, which is challenging in case of emergencies and when rare blood group types are needed. Hence, it is essential to develop efficient RBC substitutes capable of active oxygen and carbon dioxide transfer. RBC substitutes or synthetic oxygen transporters studied so far are of mainly two types: perfluorocarbon and Hb-based substitutes.

Perfluorochemicals (PFCs) are colorless, inert, and apparently nontoxic liquids with low boiling point temperatures and are insoluble in water and alcohol. The level of oxygen dissolved in PFCs has a direct linear relationship with oxygen pressure, and therefore, high oxygen pressure is necessary for maximum oxygen-carrying capacity. Since hydrogen atoms are replaced by fluorine atoms in PFCs, these compounds are not metabolized due to the strong bond between carbon and fluorine atoms. PFCs are insoluble in aqueous phase, and in case of their clinical application, they are solubilized using an emulsifying agent. Oxygen is dissolved in PFCs at a concentration of about 40%-50%, which is 20 times higher than the capacity of water and 2 times higher than plasma. PFCs are heat resistant and can withstand 300°C and higher temperatures without any change, which makes them easily amenable to heat sterilization. Their small sizes enable them to easily pass through the vessels occluded in some diseases, where RBCs cannot pass; hence, their application helps improving the oxygenation rate. An in vitro study showed that use of PFCs as artificial blood is considerably advantageous in occluded coronary artery to maintain myocardial function.

Human hemoglobin (Hb) derived from expired RBC bags is the main source of Hb for the production of Hb-based RBC substitutes. The half-life of Hb is equal inside and outside the RBCs; however, outside the RBCs, the natural tetramer molecule of Hb rapidly converts to dimer and monomer Hb species, which cause severe complications such as kidney damage. On the other hand, it has been shown that Hb scavenges the existing nitrous oxide (NO) molecules by its heme groups. NO is also involved in relaxation of smooth muscles of blood vessels, and this property is responsible for the vasoactivity of Hb-based products. Overall, this type of Hb must be modified before its application as an oxygen carrier. The Hb-based oxygen carriers (HBOCs) are divided into the following two groups: acellular and cellular HBOCs. Acellular HBOCs have been developed to increase Hb performance and decrease its side effects. These are now in various phases of clinical trials and belong to three categories including cross-linked HBOC, polymerized HBOC, and conjugated HBOC. However, among different modifications of Hb, only nanotechnology-based polyhemoglobin (PolyHb) and conjugated Hb are effective. However, due to their short blood half-lives and side effects, a majority of these products did not achieve required criteria in clinical trials.

Cellular HBOCs are those in which Hb is encapsulated in a cell-like structure. In this way, some products with highest similarity to RBCs were produced, which do not cause vasoactivation due to scavenging of NO. Encapsulation of Hb by a phospholipid layer prolonged its half-life and shelf-life comparing to acellular products. These particles are much smaller than RBCs. This small size enables their entry into areas of body that are not accessible for RBCs. Hence, they can pass through clots and blockages causing more oxygenation during stroke. However, this product has a short circulation half-life, which can be solved by a number of approaches for example by PEGylation of the particles' surface. Another series of products used as RBC imitators are biodegradable Hb-loaded polymeric nanoparticle (HbPNP). However, the most important problem with their application is rapid clearance by phagocytes. Other cellular-based biocompatible Hb products with repetitively branched molecular structures are dendrimers. The shape and size of these products are similar to Hb, and they are able to bind and release oxygen. However, their production is time consuming and costly. Therefore, a kind of dendrimer known as hyperbranched polymer has been developed, with reduced problems, which can be used as oxygen carrier by some adaptations. Dendrimers are also used for encapsulation in drug delivery. Therefore, it has been suggested that dendrimers could be used as artificial oxygen carriers by encapsulating Hb.

Due to the increased demand for blood transfusion and concerns about blood-borne pathogens, development of artificial blood substitutes, especially HBOCs, is under intensive focus. However, although many important steps have been taken to date, no oxygen-carrying blood substitutes are approved for use by the US FDA. Side effects and short half-life are the two main reasons that they did not met criteria for being approved. The fact of having no approved product in this field shows that there is an important challenge against formulation and application of promising and effective blood substitutes. In addition, it indicates the immense potential that exists in this field. However, being optimistic, it seems that science and technology would facilitate developing real blood substitutes, at least oxygen-carrying blood substitutes, whose production will substantially alleviate the worldwide shortage of blood needed for transfusion. It seems that future studies on artificial blood substitutes would focus on real blood substitutes, ie, RBCs obtained through differentiation of stem cells, however.

The State of the Mainstream of Dementia Research

This recent popular science article looks at the state of research into Alzheimer's disease and other forms of dementia. There is, so far, little tangible progress in the clinic resulting from the past twenty years of efforts in the laboratory. This is the result of a combination of factors, including a doubling of the imposed costs of medical regulation in those countries with the greatest investment in research, a poor high level strategy on the part of many research and development groups, in that they seek to patch over proximate causes and tinker with the late stage disease state rather than address causes, and the fact that dementia is a hard problem to start with. Much of what is funded as dementia research is in fact fundamental science intended to build a better understanding of the biochemistry of the brain and brain aging, a process of establishing a foundation for future work. That in and of itself is an enormous project, and will probably continue well past the point at which the first effective therapies for Alzheimer's disease arrive. That said, the Alzheimer's research community is one of the few in which sizable efforts are being made to address a root cause of aging, the accumulation of forms of metabolic waste such as amyloid-β and tau, by removing it. This is the right direction to take, and it is a pity that it has so far proved to be much harder than hoped.

By 2050, current predictions suggest, incidence of dementia worldwide could reach more than 130 million, at which point the cost to US health care alone from diseases such as Alzheimer's will probably hit 1 trillion per year. Funding has not kept pace with the scale of the problem; targets for treatments are thin on the ground and poorly understood; and more than 200 clinical trials for Alzheimer's therapies have been terminated because the treatments were ineffective. Of the few treatments available, none addresses the underlying disease process. But this message has begun to reverberate around the world, which gives hope to the clinicians and scientists. Experts say that the coming wave can be calmed with the help of just three things: more money for research, better diagnostics and drugs, and a victory - however small - that would boost morale. "What we really need is a success. After so many failures, one clinical win would galvanize people's interest that this isn't a hopeless disorder."

The NIH's annual budget for Alzheimer's and other dementias jumped in the past year to around 1 billion, and there is support for a target to double that figure in the next few years - even in the fractious US political landscape. Now, he adds, the research community just needs to work out "what are we going to do with it if in fact we get it?". The answer could depend in large part on the fate of a drug called solanezumab. This antibody-based treatment removes the protein amyloid-β, which clumps together to form sticky plaques in the brains of people with Alzheimer's. By the end of this year, researchers are expected to announce the results of a 2,100-person clinical trial testing whether the drug can slow cognitive decline in people with mild Alzheimer's. It showed preliminary signs of cognitive benefit in this patient population in earlier trials, but the benefits could disappear in this final stage of testing, as has happened for practically every other promising compound. No one is expecting a cure. If solanezumab does delay brain degradation, at best it might help people to perform 30-40% better on cognitive tests than those on a placebo. But even such a marginal gain would be a triumph. It would show scientists and the drug industry that a disease-modifying therapy is at least possible.

On a scientific level, success for solanezumab could lend credence to the much-debated amyloid hypothesis, which posits that the build-up of amyloid-β in the brain is one of the triggers of Alzheimer's disease. The previous failure of amyloid-clearing agents led many to conclude that plaques were a consequence of a process in the disease, rather than the cause of it. But those in favour of the amyloid hypothesis say that the failed drugs were given too late, or to people with no amyloid build-up - possibly those with a different form of dementia. For its latest solanezumab trial, researchers sought out participants with mild cognitive impairment, and used brain scans and spinal-fluid analyses to confirm the presence of amyloid-β in their brains. Another group took the same approach to screening participants in a trial of its amyloid-targeting drug aducanumab. Earlier this year, a 165-person study reported early signs that successfully clearing amyloid-β with that therapy correlated with slower cognitive decline.

Small Steps Towards Tissue Engineered Lungs

From a starting point of a few cells, researchers can at present build small amounts of at least partially functional tissue for a range of organs, including lungs. These are known as organoids, limited in size because reliable methods of generating the blood vessel networks needed to support larger tissues have yet to be developed. For some organs, those that largely act as filters or chemical factories, it is possible that organoids alone can have significant therapeutic value: transplant many of them at once and let them integrate into a damaged organ to augment its function, for example. For organs like the lung, however, where overall structure is important, there is further to go. The leap must be made from organoids to, at minimum, large and properly structured tissue sections. Meanwhile, the existence of organoids does allow researchers to gain valuable experience in tissue engineering, and to refine the outcomes achieved to date. That is important. This is a journey of many small steps:

Researchers have transplanted lab-grown mini lungs into immunosuppressed mice where the structures were able to survive, grow and mature. "In many ways, the transplanted mini lungs were indistinguishable from human adult tissue." Respiratory diseases account for nearly 1 in 5 deaths worldwide, and lung cancer survival rates remain poor despite numerous therapeutic advances during the past 30 years. The numbers highlight the need for new, physiologically relevant models for translational lung research. Lab-grown lungs can help because they provide a human model to screen drugs, understand gene function, generate transplantable tissue and study complex human diseases, such as asthma.

Researchers used numerous signaling pathways involved with cell growth and organ formation to coax stem cells - the body's master cells - to make the miniature lungs. The researchers' previous study showed mini lungs grown in a dish consisted of structures that exemplified both the airways that move air in and out of the body, known as bronchi, and the small lung sacs called alveoli, which are critical to gas exchange during breathing. But to overcome the immature and disorganized structure, the researchers attempted to transplant the miniature lungs into mice, an approach that has been widely adopted in the stem cell field. Several initial strategies to transplant the mini lungs into mice were unsuccessful.

The team used a biodegradable scaffold, which had been developed for transplanting tissue into animals, to achieve successful transplantation of the mini lungs into mice. The scaffold provided a stiff structure to help the airway reach maturity. "In just eight weeks, the resulting transplanted tissue had impressive tube-shaped airway structures similar to the adult lung airways." Researchers characterized the transplanted mini lungs as well-developed tissue that possessed a highly organized epithelial layer lining the lungs. One drawback was that the alveolar cell types did not grow in the transplants. Still, several specialized lung cell types were present, including mucus-producing cells, multiciliated cells and stem cells found in the adult lung.

More Evidence for a Common Genetic Contribution to Both Education and Longevity

A web of correlations exist in human data between social status, wealth, education, intelligence, and natural variations in longevity. One can propose possible mechanisms, such as better access to medical technology and greater willingness to use it well, and better care of the health basics such as diet, exercise, and weight. Intriguingly there are some signs that genetics may have some influence over this picture, with studies suggesting that more intelligent individuals tend to also be more robust and longer-lived. This remains far less convincing than the hypothesis that more intelligent people tend to take better care of their long-term health, however, going simply by weight of evidence. Still, here is another paper that runs along these lines:

Individual differences in educational attainment have been linked to variation in life chances and longevity: those with more education tend to be healthier, richer in adulthood, more upwardly socially mobile, and longer-lived. Because education influences - and is influenced by - various personal characteristics and social factors, it has been difficult to disentangle the precise reasons for its prediction of key life outcomes. Despite it being widely used in studies as a social-environmental variable, differences in education are under substantial genetic influence, with heritability frequently estimated at 60% and above in family studies, and 20-30% in molecular genetic studies. Some specific education-associated genetic variants have also been uncovered in genome-wide association studies (GWAS). The present study uses previously-discovered genetic correlates of education to predict variation in arguably the most important life outcome of all: longevity.

The association of educational outcomes-measured either by attained qualifications or by duration of full-time education - with longevity is well established in the scientific literature. The high value placed upon educational qualifications in society and in the labor market forms one possible explanation for this link: the higher-level occupations and socioeconomic positions afforded by better education allow greater access to health-improving resources and surroundings. However, education also acts as a signal for personal characteristics with which it is phenotypically correlated, such as general cognitive ability, motivation, and health, in addition to aspects of a person's socio-economic background. Thus, according to two nonmutually exclusive views, educational attainment might cause improvements in longevity via social mechanisms, or might itself be caused by preexisting - partly heritable - factors that also increase longevity.

Some evidence for the latter view - that some of the variance in educational attainment and longevity is caused by preexisting factors - comes from the pervasive genetic correlations of education with many other longevity-linked traits, indicating that these traits are substantially associated with the same genetic variants. For example, one study used linkage-disequilibrium (LD) regression analysis to show that educational attainment was significantly genetically correlated with lifespan-limiting conditions like cardiovascular disease and stroke. In addition, educational attainment is strongly genetically correlated with general cognitive ability, itself a well-replicated phenotypic and genetic correlate of longevity.

In this study, we tested whether the genetic variants associated with educational attainment are associated with longevity. We thus assessed the extent to which the genetic contributions to educational outcomes, which are preexisting and nonsocial, are related to a key health outcome. To do so, we used the established technique of testing for associations between genotyped subjects and their phenotyped relatives (in this case, the lifespan of parents). Here, we used summary data from an independent GWAS of educational attainment to create polygenic profile scores. These scores quantify the extent to which each participant carried the genetic variants known to be associated with higher educational attainment (in the GWAS, education was measured as the number of years of education). We then linked these polygenic profile scores to data on the participants' parents' age at death. Our hypothesis was that offspring with polygenic profiles for higher educational attainment would have longer-living parents.

This study found that offspring polygenic profiles for education were robustly associated with parental longevity: those with more genetic variants related to better educational qualifications had longer-living parents. We tested the study's principal hypothesis across three large cohorts, totaling over 130,000 participants. The associations were of broadly similar effect size in all three cohorts. Parents with offspring in the upper third of the polygenic score distribution lived an average of 0.55 years longer than those in the lower third. The results - which were comparable to the effect sizes from other known predictors of mortality, such as cardiovascular disease and smoking, and which were bolstered by the finding of a moderate-sized genetic correlation between the two variables - suggest the hypothesis that the ultimate reason education predicts mortality is, in part, because of an underlying, quantifiable, genetic propensity.

Do Cloned Animals Age Normally?

From the perspective of understanding how cloning affects aging, the field of somatic cell nuclear transfer is still young. Only recently has there been enough data for the longer-lived mammals to draw initial conclusions, and even then much more health and mortality data would be needed to go beyond the simple statistic of maximum observed life span. This is an area of interest to those researchers involved in mapping the detailed relationship between the operation of metabolism and the progression of degenerative aging. If it turns out that individuals of some species do not age normally as a result of being cloned, that may point to specific mechanisms in cellular biochemistry that merit a deeper investigation, especially those involved in the sweeping process of damage repair that occurs early in embryonic development, turning aged parental cells into youthful child cells.

It is a basic, yet still quite mysterious fact that at fertilization the aging clock in metazoans is "reset to zero." While every individual "ages" over time, and consequently dies at some point, the cells in the germline seem completely resistant to age-related changes - otherwise a species would age as quickly as the individual itself. While individual germ cells do age along with its organism, various control and selection mechanisms assure that the next generation starts relatively "unchanged" and healthy. It is, for example, now known that both nuclear and mitochondrial genomes are likely to acquire a small number of mutations between parents and offspring. We regard this minimal change that occurs during natural reproduction, within the physiological reproductive lifespan of the parents, as the ideal 'reset to zero' of the aging clock, against which the aging of cloned animals has to be compared.

In somatic cell nuclear transfer (SCNT), the nucleus of an adult cell is transferred to an enucleated oocyte, and is thought to not only regain pluripotency, but is also "rejuvenated" by factors in the ooplasm. Starting with works based on frogs, SCNT fully took off with the birth of Dolly the sheep. Since then, SCNT has been applied successfully in numerous species. There are relatively high losses of individuals derived from SCNT during their perinatal and early postnatal development, but they are thought to be indistinguishable from controls once they reach higher age. In fact, they are reported to have comparable performance on traits like beef and milk production. While there are clearly factors that limit the efficiency of cloning, at least some nuclei seem to be completely reprogrammed and rejuvenated to result in a completely "normal" adult individual. However, is it possible with a nucleus derived from a somatic cell, to completely start at time point zero, like gametes after a conventional fertilization? One of the biggest concerns regarding aging of cloned animals is the age of the nuclear donor cell. It was argued that if this cell is old, and consequently has shortened telomeres, the clone would already start at the age of the donor cell. However, the telomere length turned out to be at least partly restored during SCNT.

The ultimate outcome of aging is death, and therefore life expectancy is perhaps the most easily measurable parameter of aging (the question of aging can of course not be reduced to life expectancy alone). The time since several species were first cloned outdates, or is at least close to, the life expectancy of the respective species by now: goat, cattle, dog, sheep, mouse, cat, and pig. Therefore, we should be able to finally answer the question of whether at least some cloned animals can reach a life expectancy similar to that of the control animals. In several species, cloned animals reach indeed the expected lifespan. Cloned dogs seem to reach a high age. Snuppy, an Afghan hound and the first cloned dog, was 10 in 2015; and cloned female dogs of the same breed were 9. Also 3 cloned dairy goats lived to a normal age of 15 years, and Yang Yang, China's first cloned goat turned 15 in 2015. Also for cloned mice, several studies report a normal lifespan. While Dolly, the first cloned sheep, only reached 6 years, very recently, important further work on the aging of cloned sheep has been published. Thirteen aged (7-9 years old) cloned sheep, with 4 of them derived from the cell line that gave rise to Dolly, were analyzed. Detailed measurements of blood pressure and metabolism, as well as musculoskeletal tests showed no significant differences from age matched controls. Notably, these cloned sheep are already close to their typical natural lifespan. Copycat, the first cloned cat turned 10 in 2011, which is at least respectable for a cat, if still several years from the maximum lifespan. Pigs were first cloned in 2000, but the highest age reported to the best of our knowledge was 6 years.

Our own data of 33 SCNT-cloned dairy cattle show a maximum age of 14.4 years, with an average lifespan of 7.5 years. The cattle lines were discontinued in 2014 due to the end of the project. Death reasons were qualitatively not different from conventional kept cattle. This mostly anecdotal evidence shows that the aging of cloned animals seems to be qualitatively very similar or even the same as that of normal animals. Once the cloned animal has reached adulthood, most problems of the rather unspecific condition "reprogramming failure of the donor nucleus" seem to be overcome. Unfortunately, there are by far too little data available to measure possible, or even probable quantitative differences.

While the question which age cloned animals can reach is asked very often, it is surprising that actual data in the scientific literature are scarce, even about the "celebrated" first cloned animals of several species. Therefore, we had to resort to own data, personal communication and even newsletters. Nevertheless, including the very recent report about the aging of cloned sheep, it is now possible to say that at least for those species where the question of longevity of cloned animals was addressed (mouse, goat, sheep), a normal lifespan is possible. It would be interesting to find out what proportion of cloned animals indeed reaches old age, but with the current amount data it is impossible to do so. Unfortunately, research on aged cloned animals seems almost non-existent despite the public interest in various "safety" questions of SCNT. This might partly be explained by the fact that SCNT is still a very recent technique when compared to the life expectancy of most cloned species. Moreover, cloned farm animals are unlikely to be kept longer than their productive phase. Cloned sport and companion animals are mainly being kept in private care, and thus are less accessible for scientific studies. Based on the literature available so far, and also in our experience, the aging of cloned animals seems to proceed very similar to control animals. However, a thorough clinical study with a sufficient number of cloned animals, together with control animals over their entire lifespan is clearly needed for every species.


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