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Fight Aging! Newsletter, October 5th 2020
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter,
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The Old are Becoming Functionally Younger
The Aging of Chimpanzees versus that of Humans
A Research Agenda for Aging in China
On the Aging of the Germline and Rejuvenation in Embryos
Building the Glucosepane Research Toolkit Continues with the Creation of Anti-Glucosepane Antibodies
Upregulation of Mitophagy as an Approach to Treat Age-Related Disease
Injection of Metformin Improves Cognitive Function in Old Mice to a Greater Degree than Oral Administration
Parkinson's Disease is Two Distinct Conditions with a Similar Outcome
Exosome Therapy Appears as Effective as Cell Therapy for Cardiac Regeneration
Learning is Damaged Before Memory in the Progression to Clinical Alzheimer's
Cellular Senescence as a Mediator of Age-Related COVID-19 Severity
Ketone Body β-hydroxybutyrate Inhibits Inflammation to Reduce Alzheimer's Pathology in a Mouse Model
Visceral Fat Tissue is the Major Determinant of Mortality Due to Excess Body Weight
Insight into How Loss of Functional TDP-43 Contributes to ALS and Frontotemporal Dementia
Fructose Metabolism in Alzheimer's Disease
https://www.fightaging.org/archives/2020/09/the-old-are-becoming-functionally-younger/
Today's research materials cover one of a number of studies to suggest that older people are becoming functionally younger over time, comparing the capabilities of age-matched cohorts of old people in past decades with old people of the same age today. Being 70 or 80 in 1990 was accompanied by greater loss of physical capabilities, such as walking speed or grip strength, than is the case at those ages today. This is what one would expect given the slow upward trend in life expectancy that has continued year after year for more than a century now, driven by a shifting combination of better lifestyle choices, greater control over medical issues throughout life, and slow improvements in treating age-related disease.
It is interesting to see just how much has been achieved without undertaking direct efforts to target the mechanisms of aging. While the reasons for a lesser burden of frailty and mortality in late life have changed over time, from a reduction in the burden of infectious disease across the 20th century to a lessening of cardiovascular disease over the last few decades, the theme remains an incidental reduction in the level of accumulated damage and dysfunction at a given age. Now that we are moving into an era in which the research and development community is actively and deliberately targeting underlying causes of aging, we might expect to see a considerable increase in the upward trend of vigor, health, and longevity in old age.
Older people have become younger: physical and cognitive function have improved meaningfully in 30 years
Among men and women between the ages of 75 and 80, muscle strength, walking speed, reaction speed, verbal fluency, reasoning and working memory are nowadays significantly better than they were in people at the same age born earlier. In lung function tests, however, differences between cohorts were not observed. "The cohort of 75- and 80-year-olds born later has grown up and lived in a different world than did their counterparts born three decades ago. There have been many favourable changes. These include better nutrition and hygiene, improvements in health care and the school system, better accessibility to education and improved working life."
The results suggest that increased life expectancy is accompanied by an increased number of years lived with good functional ability in later life. The observation can be explained by slower rate-of-change with increasing age, a higher lifetime maximum in physical performance, or a combination of the two. "The results suggest that our understanding of older age is old-fashioned. From an aging researcher's point of view, more years are added to midlife, and not so much to the utmost end of life. Increased life expectancy provides us with more non-disabled years, but at the same time, the last years of life comes at higher and higher ages, increasing the need for care. Among the ageing population, two simultaneous changes are happening: continuation of healthy years to higher ages and an increased number of very old people who need external care."
Cohort differences in maximal physical performance: a comparison of 75- and 80-year-old men and women born 28 years apart
Whether increased life expectancy is accompanied by increased functional capacity in older people at specific ages is unclear. We compared similar validated measures of maximal physical performance in two population-based older cohorts born and assessed 28 years apart. Participants in the first cohort were born in 1910 and 1914 and were assessed at age 75 and 80 years, respectively (N=500, participation rate 77%). Participants in the second cohort were born in 1938 or 1939 and 1942 or 1943 and were assessed at age 75 and 80 years, respectively (N=726, participation rate 40%). Maximal walking speed, maximal isometric grip strength and knee extension strength, lung function measurements; forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were assessed. Data on non-participation were systematically collected.
Walking speed was on average 0.2-0.4 m/s faster in the later than earlier cohort. In grip strength, the improvements were 5-25%, and in knee extension strength 20-47%. In FVC, the improvements were 14-21% and in FEV1 0-14%. The later cohort showed markedly and meaningfully higher results in the maximal functional capacity tests, suggesting that currently 75- and 80-year old people are living to older ages nowadays with better physical functioning.
https://www.fightaging.org/archives/2020/09/the-aging-of-chimpanzees-versus-that-of-humans/
We humans are unusually long-lived in comparison to our near primate cousins, and also compared to other mammals of similar body mass. We also exhibit menopause, an end to reproductive capability well before the end of life, which occurs in only a small number of other mammalian species. With a few noteworthy exceptions, such as naked mole-rats, some bats, and we humans, mammalian lifespan correlates quite well with some combination of body mass and resting metabolic rate. So why are the outliers long-lived?
Evolutionary theorists consider longer human life spans to be a consequence of our intelligence and culture. Once it became possible for grandparents to meaningfully contribute to the fitness of their grandchildren, a selection pressure for longer lives came into being. Unfortunately that selection pressure was not necessarily for anything other than an extended decline, given that the role of grandparents in the success of grandchildren is more intellectual and cultural than physical. At that point, we diverge from other primate species over time by gaining a much longer life span.
Today's research materials are an interesting look at some of the differences between humans and chimpanzees, the latter living a little more than half as long as we do. The effects of a sedentary lifestyle are clearly quite similar at the end of the day, despite the faster process of aging that occurs in our primate relatives. The pace of aging can be measured by an epigenetic clock that assesses characteristic changes in DNA methylation that take place with age, and researchers have recently extended that line of work into a number of species, chimpanzees the latest addition.
Evolution of the primate ageing process
The world's population is ageing rapidly, presenting an urgency to address the health problems of the aged. Critical insights on these problems can be gained by examining how the ageing process has been shaped over evolutionary time, and how it is influenced by different environments and lifestyles. In this issue, we feature research conducted on humans in small-scale societies and on our closest primate relatives to ask how bodies, minds, and behaviour age outside of the usual research settings. These contributions shed light on the complex relationship between ageing and disease and offer clues to the social and ecological predictors of successful ageing.
Researchers find cardiovascular health similarities between chimpanzees, humans
Researchers examined cardiovascular profiles in chimpanzees living in African sanctuaries. These chimpanzees occupy large rainforest enclosures, consume a diet of fruits and vegetables, and generally experience conditions more similar to a wild chimpanzee lifestyle. They measured blood lipids, body weight and body fat in 75 sanctuary chimpanzees during annual veterinary health check-ups, and then compared them to published data from laboratory-living chimpanzees. Free-ranging chimpanzees in sanctuaries exhibited lower body weight and lower levels of lipids, both risk factors for human cardiovascular disease. Some of these disparities increased with age, indicating that the free-ranging chimpanzees stayed healthy as they got older.
Prior work suggested that chimpanzees have very high levels of blood lipids that are cardiovascular risk factors – higher than humans in post-industrial societies in some cases. The work also showed that chimpanzees living a naturalistic life have much lower levels even as they age, providing a new reference for understanding human health. In biomedical research labs, chimpanzees have more limited space and often consume a processed diet (food such as primate chow), unlike wild chimpanzees.
Your Cells Look Young for Their Age, Compared to a Chimp's
Many humans live to see their 70s and 80s, some even reach 100 years old. But life is much shorter for our closest animal relatives. Chimpanzees, for example, rarely make it past age 50, despite sharing almost 99% of our genetic code. While advances in medicine and nutrition in the last 200 years have added years to human lifespans, a new study suggests there could be a more ancient explanation why humans are the long-lived primate.
Studies have shown that certain sites along our DNA gain or lose chemical tags called methyl groups in a way that marks time, like a metronome. The changes are so consistent that they can be used as an "aging clock" to tell a person's age to within less than four years. The new study marks the first time such age-related changes have been analyzed in chimpanzees. Researchers analyzed some 850,000 of these sites in blood from 83 chimpanzees aged 1 to 59. Sure enough, they found that aging leaves its mark on the chimpanzee genome, just as it does in humans. More than 65,000 of the DNA sites the scientists scrutinized changed in a clock-like way across the lifespan, with some gaining methylation and others losing it.
The pattern was so reliable that the researchers were able to use DNA methylation levels to tell a chimpanzee's age to within 2.5 years, which is much more accurate than current methods for estimating a wild animal's age by the amount of wear on their molars. When the researchers compared the rates of change they found in chimps with published data for humans, the epigenetic aging clock ticked faster for chimpanzees.
https://www.fightaging.org/archives/2020/09/a-research-agenda-for-aging-in-china/
Today's review paper is a look at views on aging on the other side of the world, a counterpoint to commentaries from US and European sources. It is interesting to compare the intersection between science and policy in different regions of the world, when it comes to perspectives on degenerative aging, the enormous costs of age-related disease, and what is to be done about it. It is only comparatively recently that scientific advances have offered the potential for aging to become anything other than an inevitable, enormous cost to be suffered. Governments with entrenched and growing entitlement programs (such as the US Social Security) or command and control health systems (such as the UK NHS) – both transfers of wealth to the old – face insolvency and collapse as the fraction of the population that is old and expecting not to work expands over time.
Regardless of entitlement programs, everyone in every country faces a future of personal decline, pain, loss, and death. While much of the literature is focused on funding and the collapse of government programs, the real reason to make progress is this point about individual suffering. A world in which people did not decline with age would be a world in which people can support themselves through multiple careers and a life worth living. It is a goal to aim for, step by step, via the development of new medical technologies.
Still, few government bodies have waded in to talk in earnest about funding research to prevent and reverse degenerative aging. Where discussion takes place, it is largely focused on approaches such as calorie restriction mimetic drugs, unlikely to do much more than very modestly slow aging in humans. Policy is stuck in the era of aging as a costly inevitability, and the cause of a future collapse due to unsustainable entitlements. There is always considerable lag between an expansion of the bounds of the possible, driven by new technology, and policy white papers, of course. But still, the first rejuvenation therapies exist, in the form of first generation senolytic drugs, and it won't be too many years before their use becomes widespread. The world at large has a great deal of catching up to do in present thinking on the future of aging and its treatment.
A research agenda for ageing in China in the 21st century (2nd edition): Focusing on basic and translational research, long-term care, policy and social networks
One of the key issues facing public healthcare is the global trend of an increasingly ageing society which continues to present policy makers and caregivers with formidable healthcare and socio-economic challenges. Ageing is the primary contributor to a broad spectrum of chronic disorders all associated with a lower quality of life in the elderly. In 2019, the Chinese population constituted 18% of the world population, with 164.5 million Chinese citizens aged 65 and above (65+), and 26 million aged 80 or above (80+). China has become an ageing society, and as it continues to age it will continue to exacerbate the burden borne by current family and public healthcare systems.
Europe is characterized by three types of care provision: 1) 'crowding out', whereby the state largely replaces family care; 2) 'crowding in', whereby the state promotes family care; 3) 'mixed responsibility', whereby both the state and the family take a joint responsibility for care, yet have separate functions. In China, family is still the traditional provider for elderly care. In order to deal with the ongoing boom in the elderly population, the Chinese government has put more effort into funding research on ageing and its related diseases in recent decades. More attention has been placed on the development of pharmacological strategies against ageing, organ degeneration and major ageing-related diseases.
Targeting classic longevity pathways
Calorie restriction (CR) was first demonstrated as an effective way to extend lifespan in rodents, however the physiological mechanisms behind its anti-ageing effectiveness were not fully understood at the time, and remain uncertain. Later studies have suggested that CR might extend lifespan by regulating insulin-like growth factor (IGF) and mammalian target of rapamycin (mTOR) pathways. Metformin is primarily known for treating type 2 diabetes, with its underlying molecular mechanisms leading to the to down-regulation of IGF-1 signaling, and the inhibition of cellular proliferation, mitochondrial biogenesis, reactive oxygen species (ROS) production, DNA damage, activity of the mTOR pathway, etc. Acarbose has been shown to partially mimic the effects of CR and extend lifespan in mice by controlling blood sugar and slowing carbohydrate digestion. Rapamycin, a well-known inhibitor of mTOR, has shown life-extending effects in all model organisms and postpones the onset of age-associated diseases.
NAD+ boosters
Nicotinamide adenine dinucleotide (NAD+) is a fundamental molecule in human life and health; while there is an age-dependent reduction of NAD+, NAD+ augmentation extends lifespan and improves healthspan in different animal models as well as shows potential to treat different neurodegenerative diseases based on phase I clinical trials. NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) have emerged as promising approaches for intervention against ageing phenotypes and age-related diseases. Supplementation via these precursors can elevate NAD+ level in vivo and improve glucose metabolism, mitochondria biogenesis, DNA repair, neovascularization, and neuroprotection.
Senolytics
Senescent cells accumulate in aged tissues and this accumulation is considered one of the driving forces of ageing. Senolytics are a class of molecules specifically designed to induce apoptosis of these senescent cells. Clearing senescent cells in mice has been shown to substantially alleviate ageing phenotypes, producing potent therapeutic effects in ageing-related diseases such as Alzheimer's disease, atherosclerosis, and osteoarthritis. The senolytic cocktail of dasatinib plus quercetin (DQ) decreased naturally occurring senescent cells, improved mobility, and reduced the risk of mortality. While clinical trials on senolytic drugs are mainly conducted in the USA, the concept of reducing senescent cells to delay the ageing progress has attracted interest from all over the world. Since 2016, the National Natural Science Foundation of China (NSFC) has set up special programs, providing millions to support research on cellular senescence and organ degeneration.
https://www.fightaging.org/archives/2020/10/on-the-aging-of-the-germline-and-rejuvenation-in-embryos/
It is clearly the case that cells and tissues are in principle capable of rejuvenation. Individuals age, but their offspring are born young. The germline in adults is protected in comparison to other cell populations, but it nonetheless accumulates forms of stochastic damage over time. Yet that damage is not apparent by the time later stage embryonic development takes place. Somewhere between conception and that later stage of embryonic development, a form of rejuvenation takes place.
The authors of today's open access paper consider this topic in some detail, and the relevance it might have to future efforts to produce rejuvenation therapies. In recent years, scientists have become interested how and why reprogramming cells into induced pluripotent stem cells turns out to mirror much of what takes place in the developing embryo. Many of the marks of age are removed, and cells are rejuvenated.
An unexpected development in this field of research is that reprogramming cells in vivo appears to be beneficial, rather than very disruptive to tissue structure and function, and this approach is consequently now under development as a form of rejuvenation therapy. This makes it much more interesting to better understand exactly what is going on in the developing embryo.
The Ground Zero of Organismal Life and Aging
One of most profound revelations of recent advances in science is that biological systems can be completely rejuvenated. Indeed, just a few years ago, reversing the deleterious changes that accumulate with age in their entirety was simply unimaginable. Yet, we now know that this is possible, whether we consider the conversion of somatic cells to induced pluripotent stem cells (iPSCs) or the natural reversal of age of the germline with each generation. These two processes converge somewhere during early development at the point here proposed to be termed the 'ground zero.' It is here that both organismal life and aging begin.
It is often discussed that, because the germline is immortal, it does not age; this notion dates to the 19th century, when August Weismann proposed the separation of ageless germline and aging body. However, at the time of conception, the contributing human germline has typically been maintained in a metabolically active state for two or more decades and must have accumulated damage, such as metabolic by-products, epimutations, and modified irreplaceable proteins. In other words, it has become biologically older than its earlier, embryonic state.
Although the germline biological age at the time of conception is expected to be much younger than that of somatic tissues of the same organism, and although some of the accumulated damage may be removed by designated molecular systems, rejuvenation in the prezygotic state could only be partial because, in the absence of cell division (as in the oocyte), there are always more damage forms than the means of protecting against them. Also, although some germ cells may accumulate more damage than others and therefore may lead to early mortality and abnormalities in the offspring (this damage will also increase with the age of the host), all germ cells unavoidably accumulate some damage. Thus, for the new life to begin in the same young state as in the previous generation, the zygote must somehow remove this damage and decrease its biological age to the level of the germline age in the previous generation. In other words, it appears that the germline ages during development and adult life, and then it is rejuvenated in the offspring after conception.
All this leads to a model wherein early embryos are gradually rejuvenated, for example, by extending their telomeres, erasing epigenetic marks, and clearing up and diluting molecular damage, and this continues up to a particular time during early development. Conception represents a starting point for this process, culminating in the state of the lowest biological age, the ground zero of organismal life and aging. In effect, the period from conception to this stage may be viewed as a preparatory stage, which is associated with damage clearance and rejuvenation, for subsequent development of the organism.
The ground zero model extends and modifies Weismann's notion of heritable immortal germline and noninheritable aging body by positing that (i) both body and germline can age; (ii) both body and germline can be rejuvenated; (iii) body and germline can be brought to a common state characterized by the lowest biological age, ground zero; and (iv) age can be reversed without the need to have a separate body and germline. The proposed model is currently based on in vitro experiments and application of epigenetic and other clocks to assess biological age and should be extended to experimental organismal biology. Understanding the nature and mechanisms of rejuvenation, defining the exact point of ground zero, and discovering ways to manipulate the lowest age may provide opportunities for dramatic advances in human biology and medicine
https://www.fightaging.org/archives/2020/10/building-the-glucosepane-research-toolkit-continues-with-the-creation-of-anti-glucosepane-antibodies/
Glucosepane is likely the most important form of persistent cross-linking in aging human tissue. There is some remaining uncertainty, but it appears that the vast majority of cross-links in old tissues are based on glucosepane. Cross-links are the consequence of advanced glycation end-products (AGEs), sugary metabolic waste that can bond with the structural molecules of the extracellular matrix. Where two such molecules are linked together by a single AGE (a "cross-link"), it reduces their ability to move relative to one another. The presence of many persistent cross-links thus degrades the structural properties of that tissue. This is particularly true of elasticity, vital to the correct function of skin and, more importantly, blood vessels. Cross-linking is likely an important contribution to arterial stiffening, and the hypertension and cardiovascular disease that follows as a consequence.
The solution to this aspect of aging is to find a way to periodically remove cross-links. That effort has been hampered by the fact that the important cross-links in humans and laboratory species such as mice are completely different. That was well demonstrated by the high profile failure of the cross-link breaker compound alagebrium to perform in humans in the same way that it does in rats. Further, the tools required to work with important human AGEs such as glucosepane have been lacking. Without necessary line items such as animal models, a cheap method of synthesizing glucosepane, and antibodies specific to glucosepane, scientists avoided this part of the field in favor of easier programs of research. Fortunately the SENS Research Foundation started to fund efforts to solve this tooling problem some years ago, and, once started and shown to be productive, that line of work has continued.
Today's paper reports on the development of specific antibodies for glucosepane by the same group that first produced a robust, low-cost method of glucosepane synthesis. Antibodies that are highly specific to the molecules under study are needed for any rigorous program of development, as without them many assays of cells and tissues become questionable or impossible. This paper is an important step forward, just as much so as the synthesis of glucosepane. This part of the field of cross-link study is being opened up, and the more researchers to participate, the sooner we'll see successful trials of cross-link breaking drugs capable of removing glucosepane from the human body. There is at present one startup biotech company working towards that goal, and in a better world there would be a dozen, a mirror of the developing senolytics industry.
Generation and Characterization of Anti-Glucosepane Antibodies Enabling Direct Detection of Glucosepane in Retinal Tissue
Glucosepane is among the most abundant AGEs found in human tissues. It is formed from lysine, arginine, and glucose, and it is over an order of magnitude more abundant than any other AGE crosslink in extracellular matrix (ECM). Notably, glucosepane levels have been shown to correlate with various disease states, including diabetic retinopathy, microalbuminuria, and neuropathy. While the exact mechanisms behind glucosepane-mediated dysfunction remain unclear, it is believed to impair the functional and mechanical properties of proteins in the ECM and interfere with proteolytic degradation of collagen.
To date, the primary method for identifying glucosepane in tissues has required exhaustive enzymatic degradation followed by high pressure liquid chromatography-mass spectrometry (LC/MS). Although these protocols have proven effective in quantifying glucosepane in bulk tissue extracts, they are labor-intensive and the degradation process destroys the tissue architecture, making it difficult to examine the localization of glucosepane.
In recent years, anti-AGE antibodies have emerged as useful tools for studying AGEs and have the advantage of being compatible with the evaluation of intact tissues, enabling immunohistochemical staining and imaging procedures. Several anti-AGE antibodies have been produced by immunization of animals with AGEs generated either from total synthesis or through in vitro glycation methods. Such methods involve the incubation of an immunogenic carrier protein, such as BSA, with glucose or other reactive sugar metabolites. Reaction conditions that generate glucosepane are known also to generate a range of AGE by-products, including carboxymethyllysine. These in vitro preparation methods are unlikely to produce antibodies that are specific for glucosepane, although no such studies have been reported.
To avoid this expected complication, we decided to synthesize homogeneous, synthetic glucosepane immunogens. Herein, we describe the development and characterization of the first antibodies known to selectively recognize glucosepane. To this end, we have created a synthetic glucosepane immunogen that closely resembles glucosepane found in vivo and used it to generate a polyclonal antibody serum that recognizes glucosepane both in vitro and in ex vivo tissue samples. We have demonstrated that the antibodies can bind to glucosepane with high degrees of specificity and sensitivity through ELISA studies and have employed these antibodies in immunohistochemical experiments.
Interestingly, these latter studies demonstrate that glucosepane accumulates within sub-components of the retina, specifically the retinal pigment epithelium (RPE), Bruch's membrane, and choroid, which are anatomic areas highly affected by AMD and diabetic retinopathy.
https://www.fightaging.org/archives/2020/09/upregulation-of-mitophagy-as-an-approach-to-treat-age-related-disease/
Mitophagy is a cellular housekeeping process that removes damaged mitochondria. Mitochondria are the power plants of the cell, crucial in all tissues, but particularly so in the energy-hungry brain and muscles. Mitochondrial function declines with age throughout the body, and failing mitophagy is a proximate contributing cause of this issue, allowing dysfunctional mitochondria to accumulate in cells. Why this happens is a topic for study; various important genes relating to mitochondrial structure and mitophagy have alterations in expression levels, a maladaptive reaction to the damaged environment of aged tissues, perhaps. But it is not well understood. Boosting the operation of mitophagy in old tissues may be a useful approach to therapy for age-related conditions, and may also be an important mechanism by which exercise can improve health and reduce mortality older individuals.
Macroautophagy, hereafter referred to as "autophagy," is an evolutionarily conserved pathway involving the engulfment of cytosolic contents by a lipid membrane for recycling of nutrients or removal of harmful aggregates, microbes, and organelles. Mitophagy is one form of macroautophagy that involves selectively targeting and engulfing mitochondria for removal through lysosomal degradation. Activation of this pathway is a result of mitochondria being damaged beyond the capabilities of other quality control methods or in instances in which the cell needs to get rid of mitochondria for metabolic or developmental purposes.
Mitophagy is important for any cell that contains mitochondria. When moving from this idea of a nondescript eukaryotic cell to differentiated, specific cells that make up our body's organs, certain tissues become focal points for discussion. These include muscle cells and neurons because of their specific functions, metabolism, and energy requirements. These cells make up organs with high energy consumption and vulnerability, and slight perturbations in homeostasis can lead to pronounced effects. Although we focus on these two cell types, mitophagy is important in all organs where mitochondria play important roles.
The deep molecular understanding of mitophagy we have stems from the thorough investigation into PINK1 and Parkin, which are both major recessive risk factors for developing early onset Parkinson's disease (PD). The unique structure of the neuron creates an environment where not only does the mitochondrial pool have to be healthy, but it also must be properly transported down the axon to quite distant sites where ATP production and calcium buffering are its two most important functions. An aged nervous system coupled with a decline in mitophagy leads to accumulation of bad mitochondria and is a hallmark of neurodegeneration.
Until recently, surprisingly little evidence directly linked mitophagy to the most common neurodegenerative disease, Alzheimer's disease (AD). Historically, PD etiology was more focused on defective mitophagy, whereas investigation of AD has focused on accumulation of amyloid-β (Aβ) plaques and phospho-tau neurofibrillary tangles. Recent studies have shown that mitophagy is, in fact, affected in AD and, more important, that inducing mitophagy could benefit the pathological and cognitive outcomes. Models of toxic Aβ and tau were shown to impair mitophagy, and increasing mitophagy helped to reduce the plaque and neurofibrillary tangle burden in Caenorhabditis elegans and mouse models.
As with most therapeutics that control a biological process, increasing levels of mitophagy must be carefully controlled because passing an upper limit would induce cell death, so careful modulation rather than constitutive activation would be ideal for this style of treatment. Physiologically relevant stimulation through NAD+ supplementation has been effective in mouse and C. elegans studies in AD. By supplementing with a molecule that is already present in the body, the safety concerns are greatly reduced. Alternatively, by removing the brakes on the mitophagy system, such as the deubiquitinating enzymes, we would also increase levels of basal mitophagy. Regardless of the treatment approach, the ideal therapy will be targeted to the dysfunctional organ because affecting the balance of mitophagy in off-target organs that do not have mitochondrial dysfunction will create additional problems.
https://www.fightaging.org/archives/2020/09/injection-of-metformin-improves-cognitive-function-in-old-mice-to-a-greater-degree-than-oral-administration/
Researchers here note that delivering metformin via injection rather than the usual oral administration removes unwanted side-effects and better improves cognitive function in old mice. Near all testing of metformin has used oral administration, and the effects on pace of aging and life span are, frankly, too unreliable and too small to justify the present level of interest in the drug on the part of the longevity community. Administration by injection might be a different story, but waiting on further research and confirming data would be a wiser course of action than immediate excitement. Even then, this is tinkering with the damaged state of metabolism, not a form of repair. The upside is always going to be more limited than that of approaches that address underlying causes of aging.
Many studies have shown that in patients with type 2 diabetes, chronic administration of metformin causes side effects such as abdominal or stomach pain, diarrhea, early satiety, decreased appetite, risk of vitamin B-12 deficiency, and lactic acidosis. In the current study, we treated non-diabetic mice with metformin for 10 months. Unequivocally, our results show that chronic metformin treatment may lead to severe disabilities, including cancer, cataracts, and dermatitis. Studies in nematodes and other smaller organisms suggest that the side effects of chronic metformin treatment may be caused by changes in the gut microbiome.
To avoid the side effects of metformin, we treated mice with metformin by tail vein injection, which is believed to have little effect on the composition of gut microbes. Interestingly, it appears that metformin treatment by tail vein injection results in better cognitive function performance than oral administration. Consequently, we speculate that gut microbes may play an important role in mediating the side effects of metformin, and this potential role needs to be further explored. The beneficial effects of metformin on cognitive function are associated with the restoration of vascular integrity, producing a richer cerebral blood flow, as well as activation of neurogenesis in the subventricular zone. The mechanism of metformin administration enhanced glycolysis through increased mRNA expression of GAPDH, which ultimately increased angiogenesis and neurogenic potential of neural stem cells.
To avoid the side effects of metformin, our study proposes careful reconsideration of lower doses of metformin treatment by tail vein injection for translational research. Altogether, our study shows an improved method for metformin treatment, which might contribute to a reduction in the side effects of metformin and lead to better therapeutic value for anti-aging in humans.
https://www.fightaging.org/archives/2020/09/parkinsons-disease-is-two-distinct-conditions-with-a-similar-outcome/
Some age-related and other diseases with formal definitions based on symptoms and late stage mechanisms are likely several distinct conditions that happen to converge on a similar end result. This is particularly true of conditions of the brain and the immune system, where there is a great deal of biochemistry yet to map and fully understand. While Parkinson's disease in the late stages uniformly involves α-synuclein aggregation and loss of dopaminergenic neurons, the research community has in recent years gathered the data needed to make a clear distinction between cases that start in the brain and cases that start in the intestines. Thus Parkinson's disease is in fact two distinct diseases that will likely require different approaches to prevention and early stage diagnosis and treatment.
Researchers around the world have been puzzled by the different symptoms and varied disease pathways of Parkinson's patients. A major study has now identified that there are actually two types of the disease. Although the name may suggest otherwise, Parkinson's disease is not one but two diseases, starting either in the brain or in the intestines, which explains why patients with Parkinson's describe widely differing symptoms. "With the help of advanced scanning techniques, we've shown that Parkinson's disease can be divided into two variants, which start in different places in the body. For some patients, the disease starts in the intestines and spreads from there to the brain through neural connections. For others, the disease starts in the brain and spreads to the intestines and other organs such as the heart."
Parkinson's disease is characterised by slow deterioration of the brain due to accumulated alpha-synuclein, a protein that damages nerve cells. This leads to the slow, stiff movements which many people associate with the disease. In the study, the researchers have used advanced PET and MRI imaging techniques to examine people with Parkinson's disease. People who have not yet been diagnosed but have a high risk of developing the disease are also included in the study. The study showed that some patients had damage to the brain's dopamine system before damage in the intestines and heart occurred. In other patients, scans revealed damage to the nervous systems of the intestines and heart before the damage in the brain's dopamine system was visible.
"It has long since been demonstrated that Parkinson's patients have a different microbiome in the intestines than healthy people, without us truly understanding the significance of this. Now that we're able to identify the two types of Parkinson's disease, we can examine the risk factors and possible genetic factors that may be different for the two types. The next step is to examine whether, for example, body-first Parkinson's disease can be treated by treating the intestines with fecal microbiota transplantation or in other ways that affect the microbiome. The discovery of brain-first Parkinson's is a bigger challenge. This variant of the disease is probably relatively symptom-free until the movement disorder symptoms appear and the patient is diagnosed with Parkinson's. By then the patient has already lost more than half of the dopamine system, and it will therefore be more difficult to find patients early enough to be able to slow the disease."
https://www.fightaging.org/archives/2020/09/exosome-therapy-appears-as-effective-as-cell-therapy-for-cardiac-regeneration/
Cells are logistically challenging and more expensive to work with in comparison to components of cell signaling such as proteins or extracellular vesicles. In cell therapies wherein the bulk of the benefit is due to signaling by the transplanted cells – which is the case for near all first generation stem cell therapies, in which the newly introduced cells have a very low survival rate – it makes a lot of sense to isolate the relevant signals and deliver those instead of cells. Since a majority of signaling is transported via classes of extracellular vesicle, such as exosomes, many development programs now focus on the delivery of harvested exosomes rather than cultured cells, well in advance of a full understanding of the beneficial signals involved.
Cell transplant has been an attractive potential therapy for cardiovascular disease; however, poor cell engraftment limits efficacy of the approach. We here compared transplanting a mixture of human induced pluripotent stem cell-derived cardiomyocytes, endothelial cells, and smooth muscle cells to transplant of exosomes produced by these cells in a pig model of myocardial infarction. They saw similar improvements in cardiac function in cell, cell fragment, and exosome transplant groups without evidence of increased arrhythmogenicity.
We compared the efficacy of treatment with a mixture of cardiomyocytes (CMs; 10 million), endothelial cells (ECs; 5 million), and smooth muscle cells (SMCs; 5 million) derived from human induced pluripotent stem cells (hiPSCs), or with exosomes extracted from the three cell types, in pigs after myocardial infarction (MI). Female pigs received sham surgery; infarction without treatment (MI group); or infarction and treatment with hiPSC-CMs, hiPSC-ECs, and hiPSC-SMCs (MI + Cell group); with homogenized fragments from the same dose of cells administered to the MI + Cell group (MI + Fra group); or with exosomes (7.5 mg) extracted from a 2:1:1 mixture of hiPSC-CMs:hiPSC-ECs:hiPSC-SMCs (MI + Exo group). Cells and exosomes were injected into the injured myocardium.
In vitro, exosomes promoted EC tube formation and microvessel sprouting from mouse aortic rings and protected hiPSC-CMs by reducing apoptosis, maintaining intracellular calcium homeostasis, and increasing adenosine 5′-triphosphate. In vivo, measurements of left ventricular ejection fraction, wall stress, myocardial bioenergetics, cardiac hypertrophy, scar size, cell apoptosis, and angiogenesis in the infarcted region were better in the MI + Cell, MI + Fra, and MI + Exo groups than in the MI group 4 weeks after infarction. The frequencies of arrhythmic events in animals from the MI, MI + Cell, and MI + Exo groups were similar. Thus, exosomes secreted by hiPSC-derived cardiac cells improved myocardial recovery without increasing the frequency of arrhythmogenic complications and may provide an acellular therapeutic option for myocardial injury.
https://www.fightaging.org/archives/2020/09/learning-is-damaged-before-memory-in-the-progression-to-clinical-alzheimers/
Researchers searching for better ways to assess the early progression towards clinical Alzheimer's disease have established what looks like a decent way to measure loss of learning capability, a decline that occurs well before loss of memory function. This sort of approach compares poorly with a hypothetical blood biomarker or other non-invasive, low-cost assay, but while there are a few promising inroads towards the development of such a test, none have yet emerged into clinical practice.
As amyloid-β (Aβ) accumulates in a person's brain during the long preclinical stage of Alzheimer's disease, deficits in learning emerge prior to impairments in episodic memory, according to a new study. Cognitively normal people who tested positive for brain amyloid learned fewer Chinese characters over a six-day period than their amyloid-negative peers. Their learning deficit was more pronounced than any form of memory impairment, and it correlated with smaller hippocampi.
In public parlance, memory loss has become almost synonymous with AD. Alas, during the disease's preclinical stage-which scientists are trying to target for intervention – memory loss creeps up slowly and varies from person to person. Hence trials enrolling people at those stages struggle to assess clinical efficacy of the drug under investigation. New tests are sorely needed.
The new study tested 80 cognitively normal participants – 42 amyloid-negative, 38 amyloid-positive – and included other cognitive and neuroimaging measures. As had been seen in the previous cohort, amyloid-negative participants learned the meaning of Chinese characters faster, with accuracy differences between the groups emerging on day one and growing in each session. The two groups' average rate of learning over the entire six days differed by more than two standard deviations. In contrast, the groups barely differed on their most recent scores on any test of episodic memory. Among Aβ-positive participants only, those who learned the Chinese characters more slowly had smaller hippocampi and larger brain ventricles, suggesting less gray-matter volume.
https://www.fightaging.org/archives/2020/09/cellular-senescence-as-a-mediator-of-age-related-covid-19-severity/
Wherever we find the intersection of inflammation and aging, important in many age-related conditions, it has become the case that attention is drawn to the role of senescent cells. Senescent cells cease replication, grow in size, and secrete a potent mix of inflammatory signals. Usually they self-destruct or are destroyed by the immune system shortly after entering a senescent state. Cells become senescent constantly throughout life, and for a variety of reasons, but only with advancing age do these cells linger and build up in number. Senescent cells serve a number of useful purposes when present in the short term, assisting in cancer suppression and wound healing, for example. When senescent cell signaling continues unabated, however, it disrupts tissue structure and function, and rouses the immune system to a state of chronic inflammation. This is an important contributing cause of degenerative aging.
SARS-CoV-2 is a novel betacoronavirus which infects the lower respiratory tract and can cause coronavirus disease 2019 (COVID-19), a complex respiratory distress syndrome. Epidemiological data show that COVID-19 has a rising mortality particularly in individuals with advanced age. Identifying a functional association between SARS-CoV-2 infection and the process of biological aging may provide a tractable avenue for therapy to prevent acute and long-term disease.
Here, we discuss how cellular senescence – a state of stable growth arrest characterized by pro-inflammatory and pro-disease functions – can hypothetically be a contributor to COVID-19 pathogenesis, and a potential pharmaceutical target to alleviate disease severity. First, we define why older COVID-19 patients are more likely to accumulate high levels of cellular senescence. Second, we describe how senescent cells can contribute to an uncontrolled SARS-CoV-2-mediated cytokine storm and an excessive inflammatory reaction during the early phase of the disease. Third, we discuss the various mechanisms by which senescent cells promote tissue damage leading to lung failure and multi-tissue dysfunctions. Fourth, we argue that a high senescence burst might negatively impact on vaccine efficacy.
Measuring the burst of cellular senescence could hypothetically serve as a predictor of COVID-19 severity, and targeting senescence-associated mechanisms prior and after SARS-CoV-2 infection might have the potential to limit a number of severe damages and to improve the efficacy of vaccinations.
https://www.fightaging.org/archives/2020/10/ketone-body-%ce%b2-hydroxybutyrate-inhibits-inflammation-to-reduce-alzheimers-pathology-in-a-mouse-model/
Ketosis is a response to low dietary intake of carbohydrates, and one of the mechanisms by which calorie restriction produces benefits to health and longevity. A ketogenic diet attempts to capture that part of the process by reducing carbohydrate intake without reducing calorie intake. Ketosis results in the production of ketone bodies, metabolites that change cellular behavior for the better throughout the body. One beneficial effect is a reduction in chronic inflammation, via inhibition of the inflammasome as shown here. The sustained inflammation of aging is important in the progression of neurodegenerative conditions such as Alzheimer's disease, and, as demonstrated here, suppression of inflammation improves matters in a mouse model of the condition.
Alzheimer's disease (AD) is a progressive, late-onset dementia with no effective treatment available. Recent studies suggest that AD pathology is driven by age-related changes in metabolism. Alterations in metabolism, such as placing patients on a ketogenic diet, can alter cognition by an unknown mechanism. One of the ketone bodies produced as a result of ketogenesis, β-hydroxybutyrate (BHB), is known to inhibit NLRP3 inflammasome activation. Therefore, we tested if BHB inhibition of the NLRP3 inflammasome reduces overall AD pathology in the 5XFAD mouse model of AD.
Here, we find BHB levels are lower in red blood cells and brain parenchyma of AD patients when compared with non-AD controls. Furthermore, exogenous BHB administration reduced plaque formation, microgliosis, PYCARD speck formation, and caspase-1 activation in the 5XFAD mouse model of AD. Taken together, our findings demonstrate that BHB reduces AD pathology by inhibiting NLRP3 inflammasome activation. Additionally, our data suggest dietary or pharmacological approaches to increase BHB levels as promising therapeutic strategies for AD.
https://www.fightaging.org/archives/2020/10/visceral-fat-tissue-is-the-major-determinant-of-mortality-due-to-excess-body-weight/
It is the metabolic activity of visceral fat packed around abdominal organs that determines most of the harmful consequences of being overweight, not the subcutaneous fat deposits elsewhere in the body. Excess visceral fat produces chronic inflammation through a variety of mechanisms, such as increased burden of senescent cells, cell signaling that mimics the signals of infected cells, and more cell debris that triggers the immune system into overactivity. That chronic inflammation in turn disrupts normal tissue maintenance and cell behavior, and drives the onset and progression of all of the common age-related conditions. It is fair to say that being overweight literally accelerates aging, and the more visceral fat, the larger the effect.
Two recent comprehensive meta-analyses assessed the association of general adiposity, represented by body mass index, with the risk of all cause mortality in the general population. The results indicated that a U shaped and a J shaped association existed between body mass index and the risk of all cause mortality in the general population. The lowest risk was observed for a body mass index of 22-23 in healthy never smokers. Body mass index is easy to obtain and so is the most frequent anthropometric measure used to investigate obesity-mortality and obesity-morbidity associations.
The validity of body mass index as an appropriate indicator of obesity has been questioned. Research suggests that body mass index does not differentiate between lean body mass and fat mass; therefore, when using body mass index as a measure, inaccurate assessment of adiposity could occur. Additionally, the most important limitation of body mass index is that it does not reflect regional body fat distribution. Existing evidence suggests that central obesity and abdominal deposition of fat is more strongly associated with cardiometabolic risk factors and chronic disease risk than overall obesity.
Taking this evidence into account, indices of central obesity might be more accurate than body mass index when estimating adiposity, and therefore could be more closely and strongly associated with the risk of mortality. We aimed to perform a systematic review and dose-response meta-analysis of prospective cohort studies to investigate the association of indices of central fatness with the risk of all cause mortality in the general population, in never smokers, and in healthy never smokers. The indices of central fatness were waist circumference, hip circumference, thigh circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index.
Indices of central fatness including waist circumference, waist-to-hip ratio, waist-to-height ratio, waist-to-thigh ratio, body adiposity index, and A body shape index, independent of overall adiposity, were positively and significantly associated with a higher all cause mortality risk. Larger hip circumference and thigh circumference were associated with a lower risk. The results suggest that measures of central adiposity could be used with body mass index as a supplementary approach to determine the risk of premature death.
https://www.fightaging.org/archives/2020/10/insight-into-how-loss-of-functional-tdp-43-contributes-to-als-and-frontotemporal-dementia/
TDP-43 is one of a number of proteins that can misfold in ways that cause neurodegeneration, either via aggregation into solid deposits, or via a diminished amount of functional protein in critical cells in the brain. Research into TDP-43 is at an earlier stage than is the case for amyloid-β, α-synuclein, or other better known proteins that exhibit these problems. Important and quite fundamental discoveries related to the way in which TDP-43 causes pathology are still being made, as is the case in this recently announced paper.
Two common neurodegenerative diseases – ALS and frontotemporal lobar degeneration, or FTLD – result from reduced transportation of RNA by the protein TDP-43, which ultimately disrupts neuron function. Because one of the biggest physiological changes in both ALS and FTLD is the disappearance of TDP-43 from the nucleoli of neurons, the team focused their research on finding out what TDP-43 normally does. TDP-43 is known to bind to RNA, and the team's first experiment showed that in neurons, TDP-43 attaches to RNA that codes for pieces of ribosomes, which are necessary for making proteins from RNA code.
"We discovered TDP-43 in axons and that it binds to ribosomal protein messenger RNA. That was strong support for the idea that TDP-43 carries the RNA to the axon where it can be used to make ribosomal proteins. This would allow local synthesis of proteins at ribosomes built in axons." Indeed, further experiments confirmed that hypothesis and showed that when TDP-43 was missing, the RNA in question could not be transported to the axon.
But what happens if the RNA cannot be transported? The researchers examined axon growth in culture as well as in mouse embryos. They found that in both cases, axon extension and outgrowth were stunted when TDP-43 was missing. However, outgrowth could be restored by forcing the neurons to overproduce ribosomal proteins. "Now that we understand TDP-43's role in transporting the ribosomal protein messenger RNA, it should help us develop new strategies and new targets for ALS and FTLD treatments. Our results in reversing stunted axon extension in mouse embryos is promising, but is just a first step."
https://www.fightaging.org/archives/2020/10/fructose-metabolism-in-alzheimers-disease/
The degree to which Alzheimer's disease is a lifestyle condition is an interesting question. A good deal of research points to insulin resistance in the brain as important in the progression of Alzheimer's disease, to the point at which one group declared Alzheimer's to be a type 3 diabetes, a condition that should be thought of as primarily metabolic in origin. That idea gained enough traction that when a definitively new type of diabetes was discovered, it had to be named type 4 diabetes to avoid confusion.
Insulin resistance and type 2 diabetes are a consequence of being overweight in the vast majority of patients, but Alzheimer's disease isn't as obviously directly a consequence of excess fat as is the case for type 2 diabetes. Fewer overweight people develop Alzheimer's disease than develop type 2 diabetes – it isn't the same picture at all as the comparatively reliable progression to metabolic syndrome, insulin resistance, and then type 2 diabetes that happens as a result of excessive weight gain. Nonetheless, the disrupted metabolism of overweight people does look compelling as a contributing cause of this form of neurodegenerative condition.
The loss of cognitive function in Alzheimer's disease is pathologically linked with neurofibrillary tangles, amyloid deposition, and loss of neuronal communication. Cerebral insulin resistance and mitochondrial dysfunction have emerged as important contributors to pathogenesis supporting our hypothesis that cerebral fructose metabolism is a key initiating pathway for Alzheimer's disease.
Fructose is unique among nutrients because it activates a survival pathway to protect animals from starvation by lowering energy in cells in association with adenosine monophosphate degradation to uric acid. The fall in energy from fructose metabolism stimulates foraging and food intake while reducing energy and oxygen needs by decreasing mitochondrial function, stimulating glycolysis, and inducing insulin resistance. When fructose metabolism is overactivated systemically, such as from excessive fructose intake, this can lead to obesity and diabetes.
Herein, we present evidence that Alzheimer's disease may be driven by overactivation of cerebral fructose metabolism, in which the source of fructose is largely from endogenous production in the brain. Thus, the reduction in mitochondrial energy production is hampered by neuronal glycolysis that is inadequate, resulting in progressive loss of cerebral energy levels required for neurons to remain functional and viable. In essence, we propose that Alzheimer's disease is a modern disease driven by changes in dietary lifestyle in which fructose can disrupt cerebral metabolism and neuronal function. Inhibition of intracerebral fructose metabolism could provide a novel way to prevent and treat this disease.
Fight Aging! Newsletter, October 19th 2020
Fight Aging! Newsletter, July 6th 2020
Fight Aging! Newsletter, July 20th 2020

redpajama_set_name: RedPajamaCommonCrawl


text:
O vinho Dom Pérignon é produzido pela casa francesa Moët et Chandon.  O nome vem do monge beneditino Dom Pérignon que desenvolveu o método de vinificação da bebida chamado "método champenoise".

Dom Pérignon foi o primeiro champanhe cuvée ("safrado"), o que lhe deu enorme prestígio.  A primeira vintage de Dom Pérignon foi a de 1921 e somente colocada à venda em 1936, depois da Grande Depressão de 1929.   O champanhe cuvée ou vintage significa que ele foi produzido com as melhores uvas de um ano (safra) especialmente bom o que lhe dá uma característica especial sobre os demais champanhes: a estampa do ano (safra) no rótulo.   Por essa razão é que não existem champagnes vintage todos os anos como acontece com os vinhos não efervescentes.   A maioria dos champanhes, por outro lado, são produzidos por uma mistura de uvas colhidas em anos diferentes.

Desde 1990, Richard Geoffroy é o enólogo responsável pela produção de Dom Pérignon.

Produção

São produzidas cerca de 5 milhões de garrafas de cada vintage. Ele é feito com a mistura de 55% de uvas chardonnay e 40% pinot noir, com dosagem de 7 g/l açúcar.

Ligações externas

Vinhos da França
Vinhos espumantes

redpajama_set_name: RedPajamaWikipedia


Central Astoria is proud to bring The Devotions, a group of Doo Wop musical wonders that has thrilled six decades of listeners, to Astoria Park for a free concert.
This free concert is open to the public and no RSVP or tickets are required. Just show up! We look forward to seeing you there!
Central Astoria Local Development Coalition Inc.


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MA provides audit and validation services and business advice to assist owners, shareholders and managers in making sound business decisions to meet their objectives. This is conducted by auditing the financial statements of a company, government, individual, or any other legal entity which is independent of the entity being audited.
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text:
Q: is currentUser logged in different device This is a simple question, is there a Parse format for checking if the user is already logged in, in a different device?
I'm aware I can manually do this, updating objects, registering devices and using pointers etc etc, just wondering if there is a simple API workaround or an easier alternative someone has creatively utilized?

A: Yes there is. They announced sessions in the latest Facebook conference. You need a basic find or count query in Session class:
var query = PFSession.query()!
query.findObjectsInBackgroundWithBlock{ (objects: [AnyObject]?, error: NSError?) -> Void in
    if error != nil {
        println(error!)
    } else {
        if let sessions = objects {
            println(sessions)
        }
    }
}

Note that you don't need to add query.whereKey("user", equalTo: currentUser). Because the query will only return the sessions of the current user due to the ACL set on the session object. The session object is something like:
createdWith =     {
    action = signup;
    authProvider = anonymous;
};
expiresAt = "2016-04-14 13:43:53 +0000";
installationId = "...";
restricted = 0;
sessionToken = "...";
user = "<PFUser: 0x7fc990681120, objectId: yoELURj4i8>";

redpajama_set_name: RedPajamaStackExchange


text:
Hellental ist ein Ortsteil von Heinade, einer Gemeinde in der Samtgemeinde Eschershausen-Stadtoldendorf im Landkreis Holzminden in Niedersachsen.

Geographie
Das Dorf liegt an einem Hang im Tal der Helle. Durch den Ort führt keine Durchgangsstraße.

Geschichte
In diesem Tal gab es bereits im Hochmittelalter Waldglashütten. Es handelte sich um mehrere zeitweilige Hütten, die wegen der darauf folgenden Wüstungsperiode zu keiner dauerhaften Ansiedlung führte.

In der Frühen Neuzeit ist für die Jahre 1624/25 die Waldglashütte Am Lummenborn belegt. Von dieser sind erhalten die zugehörige Lummenbornquelle und der dortige Standort der Hütte, heute als Weide genutzt. Von einer weiteren Hütte, die in die Jahre nach 1617 datiert wird, sind weiter oben in demselben Tal Überreste des Ofens als Bodenwelle sichtbar. Zudem wurde dort ein Stempel zur Erzeugung von Nuppen gefunden, der im örtlichen Museum ausgestellt ist. Die Lage dieser Hüttenplätze ergab sich aus dem verfügbaren Rohstoffvorkommen sowie durch die Lage an der Alten Einbecker Straße als Handelsroute bis zum Tiedexer Tor des dortigen Marktortes.

Der Nordrand des Sollings war Teil des Fürstentum Braunschweig-Wolfenbüttel, als August Wilhelm im Jahr 1716 einem Glasmacher die Errichtung dieser Glashütte im Tal der Helle erlaubte. Diese Steinbeker Glashütte war in Betrieb von 1717 bis 1744. Sie wurde gegründet von einem Glasmacher aus der Familie Gundlach, der 1735 von Ferdinand Albrecht II. zum Amtmann im Amt Lichtenberg ernannt wurde. Dadurch siedelten sich auch Familienangehörige und Personal hier an. Daraus entwickelte sich dann das Dorf Hellental. Sie wurde 1743 aufgekauft von Karl I. und nach Schorborn verlegt, so dass die hiesige Glashütte wegen der konkurrierenden und als Nachfolge angelegten Glasmanufaktur Schorborn aufgegeben wurde.

In den Jahren des Königreiches Westphalen gehörte das Dorf anfangs zum Kanton Stadtoldendorf, danach zum Kanton Dassel.

Am 1. Januar 1973 wurde Hellental in die Gemeinde Heinade eingegliedert.

Kultur

Sehenswürdigkeiten
 Museum im Backhaus: Ausstellungsschwerpunkte sind das Herstellen von Waldglas mittels Glashafen im Solling sowie das Backen von Brot mittels Backofen des 19. Jahrhunderts.
 Naturschutzgebiet Hellental
 Graslandpfad

Vereine
 Tischtennisverein Hellental von 1969 e.V.
 Heimat- und Geschichtsverein e.V.
 Solling- und Verkehrsverein e.V.

Literatur
 Achim Schoppe: Die Entstehung Hellentals. In: Sollinger Heimatblätter 2/89, S. 1–5

Weblinks
 Hellental auf eschershausen-stadtoldendorf.de
 Solling- und Verkehrsverein e. V.

Einzelnachweise

Ort im Landkreis Holzminden
Heinade
Ehemalige Gemeinde (Landkreis Holzminden)
Gemeindeauflösung 1973


text:
ML-Algorithms-Matlab
====================

Implementing ML Algorithms from scratch while referring to Bishop's book & Publications

redpajama_set_name: RedPajamaGithub


text:
Public Release: 5-Jan-2010
In all the universe, just 10 percent of solar systems are like ours
Washington, DC -- In their quest to find solar systems analogous to ours, astronomers have determined how common our solar system is.
They've concluded that about 10 percent of stars in the universe host systems of planets like our own, with several gas giant planets in the outer part of the solar system.
"Now we know our place in the universe," said Ohio State University astronomer Scott Gaudi. "Solar systems like our own are not rare, but we're not in the majority, either."
Gaudi will report the results of the new study on Tuesday, January 5 at the American Astronomical Society Meeting in Washington, DC, when he accepts the Helen B. Warner Prize for Astronomy.
The find comes from a worldwide collaboration headquartered at Ohio State called the Microlensing Follow-Up Network (MicroFUN), which searches the sky for extrasolar planets.
MicroFUN astronomers use a method called gravitational microlensing, which occurs when one star happens to cross in front of another as seen from Earth. The nearer star magnifies the light from the more distant star like a lens. If planets are orbiting the lens star, they boost the magnification briefly as they pass by.
This method is especially good at detecting giant planets in the outer reaches of solar systems -- planets analogous to our own Jupiter.
This latest MicroFUN result is the culmination of 10 years' work -- and one sudden epiphany, explained Gaudi and Andrew Gould, professor of astronomy at Ohio State.
Ten years ago, Gaudi wrote his doctoral thesis on a method for calculating the likelihood that extrasolar planets exist. At the time, he concluded that less than 45 percent of stars could harbor a configuration similar to our own solar system.
Then, in December of 2009, Gould was examining a newly discovered planet with Cheongho Han of the Institute for Astrophysics at Chungbuk National University in Korea. The two were reviewing the range of properties among extrasolar planets discovered so far, when Gould saw a pattern.
"Basically, I realized that the answer was in Scott's thesis from 10 years ago," Gould said. "Using the last four years of MicroFUN data, we could add a few robust assumptions to his calculations, and we could now say how common planet systems are in the universe."
The find boils down to a statistical analysis: in the last four years, the MicroFUN survey has discovered only one solar system like our own -- a system with two gas giants resembling Jupiter and Saturn, which astronomers discovered in 2006 and reported in the journal Science in 2008.
"We've only found this one system, and we should have found about eight by now -- if every star had a solar system like Earth's," Gaudi said.
The slow rate of discovery makes sense if only a small number of systems -- around 10 percent -- are like ours, they determined.
"While it is true that this initial determination is based on just one solar system and our final number could change a lot, this study shows that we can begin to make this measurement with the experiments we are doing today," Gaudi added.
As to the possibility of life as we know it existing elsewhere in the universe, scientists will now be able to make a rough guess based on how many solar systems are like our own.
Our solar system may be a minority, but Gould said that the outcome of the study is actually positive.
"With billions of stars out there, even narrowing the odds to 10 percent leaves a few hundred million systems that might be like ours," he said.
This research was partly funded by the National Science Foundation.
Contact: Scott Gaudi, (614) 292-1914; Gaudi.1@osu.edu
Andrew Gould, (614) 292-1892; Gould.34@osu.edu
Written by Pam Frost Gorder, (614) 292-9475; Gorder.1@osu.edu
Scott Gaudi
Gaudi.1@osu.edu
@osuresearch
http://news.osu.edu
AAS 215th Meeting
PLANETS/MOONS
STARS/THE SUN
http://researchnews.osu.edu/archive/planetrare.htm


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Assume that you are a lender attempting to foreclose on a relatively small commercial asset (i.e., a hotel or gas station) in a judicial foreclosure state (like Kentucky or Indiana). After fighting for months and months to get to judgment and schedule a sale date, at the eleventh hour your borrower files a Chapter 11, which stays your foreclosure sale and portends even more delay. Assume this case is designated a "small business" case, under which the Debtor has non-insider debt totaling less than $2,490,925 (as of 2013). After litigating inside of the Chapter 11 for several additional months, the Bankruptcy Court ultimately dismisses the case. Happily, you now are ready to head back to state court to complete the foreclosure sale. Nothing could possibly interfere with that sale now, right?
Not so fast! 48 hours before the foreclosure sale, you learn that your borrower has hired new counsel and filed another Chapter 11 case. You call your lawyer and ask how this could possibly be permissible. There has to be something in the Bankruptcy Code that prohibits a debtor from filing a bankruptcy right after the first one was dismissed, right? Unfortunately, there is no easy answer to that question. You might be able to move to dismiss the second case as a bad faith filing, but resolution of that motion itself will interpose significant delay. How can you keep your sale date?
(D) is an entity that has acquired substantially all of the assets or business of a small business debtor described in subparagraphs (A), (B), or (C), unless such entity establishes by a preponderance of the evidence that such entity acquired substantially all of the assets or business of such small business debtor in good faith and not for the purpose of evading this paragraph.
There are two exceptions, set forth in Setion 362(n)(2). First, if the second case is an involuntary bankruptcy involving no collusion with the debtor, Section 362(n)(1) does not apply. Second, if the debtor can prove that the filing of the second case "resulted from circumstances beyond the control of the debtor," and that it is more likely than not that the debtor will confirm a feasible plan within a reasonable period of time, Section 362(n)(1) also does not apply.
Assuming those exceptions do not apply, there simply is no automatic stay to prevent your foreclosure sale. However, it may be advisable to request that the Bankruptcy Court issue an order determining that the automatic stay does not apply. As a practical matter, it may be difficult to effectively explain to state court judges and personnel that despite the second case, there is no automatic stay. This kind of "comfort order" may prove useful in keeping your sale on track.


ROTT: Segal points to the fact that carbon emissions from power plants have already been decreasing because of the energy market. Natural gas is cheaper than coal, and renewable energy is booming. That, Segal says, may have a bigger impact on greenhouse gas emissions than any regulation. The proposal will be up for public comment and is likely to face legal opposition of its own. Nathan Rott, NPR News. Transcript provided by NPR, Copyright NPR.


text:
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YPFS Team
Andrew Metrick
Program Director and Janet L. Yellen Professor of Finance and Management
Metrick's current research and teaching is focused on financial stability, including the regulation of systemic risk, the activities of complex financial institutions, and the causes and consequences of the financial crisis of 2007-2009. From August 2009 to July 2010, he served on the staff of the Council of Economic Advisers and as the financial economist staffing the President's Economic Recovery Board, where he worked extensively on what became the Dodd-Frank Act, and on many areas relating to the ongoing crisis.
Vincient Arnold
Vincient Arnold joined the YPFS New Bagehot Project as a Research Associate in August 2022. He spent two years working for an international law firm with the antitrust and national security teams. He received a BS in Foreign Affairs with minors in Statistics and East Asian Studies from the University of Virginia. He is originally from Roanoke, Virginia.
Shavonda Brandon
Research Support Assistant
Shavonda Brandon joined the YPFS team as a Research Support Assistant in July 2019. She is originally from Bridgeport, CT. She graduated from the University of Connecticut in 2014 with a B.A. in Economics and a minor in English. Shavonda supports the implementation of several YPFS strategic projects.
Bailey Decker
Bailey joined the YPFS team as a Research Associate in 2022. She graduated with a BSPA in Public Policy from Indiana University-Bloomington and an MA in French Studies from New York University. Her other research interests include demography, identity, and employment in francophone society.
Jaan Elias
Director, Case Research and Development
In 2006, Jaan Elias became the Yale School of Management's first Director of Case Study Research. In his time at Yale, Elias and his team developed the "raw" case study format that draw together Internet links, interactive exhibits, text and video on a multimedia, web platform. These cases have been widely used not only at Yale, but in management curriculum through the world. Elias received a Ph.D. in Organizational Behavior (a joint degree program between the Harvard Sociology Department and the Harvard Business School).
William B. English
Professor in the practice of Finance
Bill English joined Yale University from the Board of Governors of the Federal Reserve System, where he was the Senior Special Advisor to the Board for monetary policy. Over more than 20 years at the Board of Governors, he has held a range of positions, including, from 2010 to 2015, Director of the Division of Monetary Affairs and Secretary to the Federal Open Market Committee. In that position, Bill oversaw the development of monetary policy, working extensively on issues related to asset purchases, policy normalization, and policy communication. Prior to joining the Federal Reserve, Bill taught at the University of Pennsylvania and the University of Chicago. He received a PhD in economics from the Massachusetts Institute of Technology in 1986 and a BA in economics and mathematics from Yale University in 1982.
Greg Feldberg
Research Scholar and Director of Research
Greg Feldberg is a Research Scholar at the Yale School of Management and Director of Research for the Yale Program on Financial Stability. Prior to joining the YPFS, Feldberg spent six years at the Office of Financial Research, where he helmed the Office's annual Financial Stability Report and other publications. In 2010, he was the Director of Research at the Financial Crisis Inquiry Commission, which was established by Congress to investigate the causes of the global financial crisis. Feldberg spent 10 years at the Federal Reserve Board as a researcher and financial analyst. He has also worked in the financial industry, heading technology research teams at two investment banks. His research focuses on financial stability, macroprudential policy, and financial crisis management.
Deborah Felstehausen
Deborah Felstehausen (formerly McClellan) joined the Yale Program on Financial Stability after serving as editorial director and project manager for Ben Bernanke, Tim Geithner, and Hank Paulson in their examination of the Global Financial Crisis. That project resulted in two books—First Responders: Inside the U.S. Strategy for Fighting the Global Financial Crisis (Yale University Press, 2020) and Firefighting: The Financial Crisis and Its Lessons (Penguin Books, 2019)—and a collection of charts telling the crisis story graphically. Previously, she worked with Paulson as editorial project manager on his memoirs and oversaw editorial production for Institutional Investor magazine.
Jack French
Jack French joined the YPFS team as a Research Associate in June 2022. He graduated from Quinnipiac University with a BS in Economics and previously worked as a Research Associate in the Client Service department of Bridgewater Associates.
Ayodeji George
Ayodeji George joined the YPFS team as a Research Associate in July 2022. He received a BA in political science with minors in French and linguistics from Swarthmore College. Alongside his work at YPFS, he is part of the leadership team of Design Football Club, a nonprofit after-school program based in Chester, PA. He is originally from Cranston, RI.
Gary Gorton
Co-Director of the Systemic Risk Institute and Frederick Frank Gary Gorton, Class of 1954 Professor of Management and Finance
Gorton has done research in many areas of finance and economics, including both theoretical and empirical work. His recent work on the financial crisis, particularly the role of the repo market and the shadow banking system, has been influential in shaping how the events of 2007-2008 are understood. He is the author of Slapped by the Invisible Hand: The Panic of 2007 (Oxford University Press) and Misunderstanding Financial Crises (Oxford University Press).
Salil Gupta
Salil joined YPFS as a Research Associate in 2022 after completing a master's in Systemic Risk from Yale SOM. Before that, he spent six years in Mumbai at the principal investing arm of the Enam group. He was responsible for macro research at the firm, working on both private and public market transactions, while keenly observing global markets and central banks. He has also worked in financial market roles in New York and Hong Kong. Salil has bachelor's degrees in Systems Engineering and Finance from the Wharton School as a part of the University of Pennsylvania's M&T program.
Ben Hoffner
Ben Hoffner joined the YPFS team as a Research Associate in August 2021. He received a B.S. in International Economics with minors in Italian and Philosophy from Georgetown University's School of Foreign Service. He is originally from San Francisco, CA.
Alex Hoglen
Associate Director for Yale Program on Financial Stability and Master of Management Studies
Alex joined the Yale School of Management in 2018 and joined the YPFS team in 2019. Alex serves as the primary faculty support for Andrew Metrick and Gary Gorton.
Steven Kelly
Steven is an alumnus of the University of Wisconsin and the Yale School of Management. His work focuses on financial crises and systemic risk in the United States. He can be reached at steven.kelly@yale.edu.
Anmol Makhija
Anmol Makhija joined the YPFS team as a Research Associate in July 2022. He majored in Mathematics, Economics, and Finance at the University of Massachusetts Amherst. He is originally from Hyderabad, India, and loves playing table tennis.
Christian McNamara
Director, New Bagehot Project
Prior to joining the staff of the YPFS, McNamara spent several years as an associate at a law firm in New Haven where his practice focused on M&A, private equity and venture capital transactions, as well as the preparation of securities filings. McNamara has also worked as a strategic consultant for a consulting firm focused on the social sector. McNamara received a BBA from the University of Notre Dame and a JD from Harvard Law School.
Carey Mott
Carey Mott joined the YPFS team in August 2021. Previously, he was an associate at the Federal Reserve Bank of New York. Carey started his career at the Federal Reserve Bank of Boston and graduated from the University of Colorado Boulder with a B.A. in Economics.
June Rhee
Director, Master of Management Studies in Systemic Risk
Prior to joining the YPFS, Rhee was a fellow at the Harvard Law School's Program on Corporate Governance and served as an editor for the Harvard Law School Forum on Corporate Governance and Financial Regulation. During her fellowship, Rhee focused on corporate governance problems within U.S. public companies. Rhee also spent several years as an associate at a law firm in New York where her practice focused on securities regulation and structured finance, and a general counsel for Samsung Corporation where she managed compliance and governance issues. Rhee received a JD from Harvard Law School.
Stella Schaefer-Brown
Stella Schaefer-Brown joined the YPFS team as a Research Associate in August 2022. She is from Minneapolis, Minnesota. She earned her bachelor's degree from Grinnell College in Iowa, majoring in Political Science and Economics with a minor in Statistics.
Lakshimi Swaminathan
Lakshimi Swaminathan joined the YPFS team as a Research Associate in July 2022. She received an MA in Economics from Yale University, where she wrote her thesis on diversity in the US venture capital industry. She graduated from Delhi University with a BA in Economics in 2021. She is originally from Kerala, India.
Roz Wiggins
Director, Global Financial Crisis Project
Wiggins joined the YPFS with over two decades of experience in securities disclosure, corporate governance, Sarbanes-Oxley compliance, and business law from her years as in-house counsel at Pitney Bowes and Equifax. Wiggins was also previously an adjunct professor at the University of Connecticut Law School where she co-taught a course on Tax-Exempt organizations. She is particularly interested in the corporate governance aspects of decisions made during the crisis and teaches a version of Professor Metrick's Global Financial Crisis class in the MBA for Executives program. Wiggins began her career at the law firm of Day, Berry and Howard. She received a BA from Yale and a JD from Stanford Law School.
Research Associate Alumni
Julia Arnous
Alec Buchholtz
Mallory Dreyer
Lily Engbith
Sean Fulmer
Ben Henken
Manuel León Hoyos
Devyn Jeffereis
Adam Kulam
Aidan Lawson
Natalie Leonard
Riki Matsumoto
Sharon Nunn
Alexander Nye
Kaleb Nygaard
Junko Oguri
Corey Runkel
Keni Sabath
Priya Sankar
Claire Simon
Ariel Smith
David Tam
Pascal Ungersboeck
Vaasavi Unnava
Ezekiel Vergara