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Fight Aging! Newsletter, September 27th 2021


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#1 reason

  • Guardian Reason
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Posted 26 September 2021 - 02:36 PM


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

Longevity Industry Consulting Services

Reason, the founder of Fight Aging! and Repair Biotechnologies, offers strategic consulting services to investors, entrepreneurs, and others interested in the longevity industry and its complexities. To find out more: https://www.fightaging.org/services/

Contents

  • Hyperbaric Oxygen Treatment Improves Cerebral Blood Flow and Cognitive Function in Old People
  • Reviewing What is Known of the Biochemistry of Blood-Brain Barrier Dysfunction in Aging
  • A Small Change in the Ribosome Reduces Protein Synthesis Errors and Modestly Extends Lifespan in Short-Lived Species
  • Proposing a Liver Amyloid Hypothesis of Alzheimer's Disease
  • The Staggering Ongoing Cost of Failing to Aggressively Pursue the Development of Rejuvenation Therapies
  • A Trend Towards Increased Proteostasis in Longer-Lived Mammalian Species
  • Are Gene Variant Interactions a Better Approach to Determining the Contribution of Genetics to Longevity?
  • A Demonstration of Artificial Mitochondria Capable of Generating Adenosine Triphosphate to Support Cell Function
  • Identifying Age-Related Epigenetic Changes Related to Reduced Function in Mesenchymal Stem Cells
  • Mitochondrially Targeted Hydrogen Sulfide Delivery Molecules Slow Photoaging
  • Mitochondrial AMPK as a Trigger of Beneficial Mitophagy
  • A Tipping Point for Amyloid Accumulation in the Development of Alzheimer's Disease
  • Working Towards Biomarkers of Aging Based on Analysis of Saliva
  • Bifidobacterium Longum in the Aging Gut Microbiome
  • Exercise Lowers Markers of Inflammation in Older Individuals

Hyperbaric Oxygen Treatment Improves Cerebral Blood Flow and Cognitive Function in Old People
https://www.fightagi...-in-old-people/

In today's open access paper, researchers report a modest improvement in cerebral blood flow and cognitive performance in a small study of older individuals suffering cognitive impairment as a result of sustained hyperbaric oxygen treatment over a period of months. This seems a compensatory approach to therapy, in that improvements in cerebral blood flow should be expected to improve cognitive function at any age. This is the mechanism by which exercise rapidly improves memory function, for example. A direct comparison of hyperbaric oxygen treatment and exercise would be interesting.

This result might help to inform discussions of the degree to which loss of blood supply to the brain contributes to cognitive decline in patients diagnosed with neurodegenerative conditions. Vascular dementia is an acknowledged and well-researched condition, but to what degree is the impairment of Alzheimer's patients at various stages due to vascular aging and consequent reduced blood flow to the brain, versus the harmful protein aggregation and neuroinflammation characteristic of Alzheimer's? Absent a way to remove just one of these pathologies, it is hard to answer that question.

It is worth noting that this study was conducted and published by the same groups who put together the poor study and accompanying overhyped media materials regarding the effects of hyperbaric oxygen treatment on measures of metabolism related to aging. It is most likely a good idea to treat this and any future work conducted by these researchers with an appropriately greater level of scrutiny and skepticism.

Hyperbaric oxygen therapy alleviates vascular dysfunction and amyloid burden in an Alzheimer's disease mouse model and in elderly patients

Vascular dysfunction is entwined with aging and the pathogenesis of Alzheimer's disease (AD), and contributes to reduced cerebral blood flow (CBF) and consequently, hypoxia. Hyperbaric oxygen therapy (HBOT) is in clinical use for a wide range of medical conditions. In the current study, we exposed 5XFAD mice, a well-studied AD model that presents impaired cognitive abilities, to HBOT and then investigated the therapeutical effects. HBOT increased arteriolar luminal diameter and elevated CBF, thus contributing to reduced hypoxia. Furthermore, HBOT reduced amyloid burden by reducing the volume of pre-existing plaques and attenuating the formation of new ones. This was associated with changes in amyloid precursor protein processing, elevated degradation and clearance of amyloid-ß protein and improved behavior of 5XFAD mice. Hence, our findings are consistent with the effects of HBOT being mediated partially through a persistent structural change in blood vessels that reduces brain hypoxia.

To understand whether the ability of HBOT to change CBF and affect cognitive function also applied to elderly people, we performed a human study in which six elderly patients (age 70.00 ± 2.68 years) with significant memory loss at baseline (memory domain score < 100) were treated with HBOT (60 daily HBOT sessions within 3 months). CBF and cognitive function were evaluated before and after HBOT. CBF was measured by MRI, while cognitive functions were evaluated using computerized cognitive tests. Following HBOT, there were significant CBF increases in several brain areas.

At baseline, patients attained a mean global cognitive score (102.4±7.3) similar to the average score in the general population normalized for age and education level (100), while memory scores were significantly lower (86.6 ± 9.2). Cognitive assessment following HBOT revealed a significant increase in the global cognitive score (102.4 ± 7.3 to 109.5 ± 5.8), where memory, attention and information processing speed domain scores were the most ameliorated. Moreover, post-HBOT mean memory scores improved to the mean score (100.9 ± 7.8), normalized per age and education level (100). The improvements in these scores correlate with improved short and working memory, and reduced times of calculation and response, as well as increased capacity to choose and concentrate on a relevant stimulus.

Reviewing What is Known of the Biochemistry of Blood-Brain Barrier Dysfunction in Aging
https://www.fightagi...ction-in-aging/

Blood vessels passing through the central nervous system are sheathed by specialized cells that form the blood-brain barrier. The barrier controls the passage of cells and molecules into the brain. This protection is essential to the normal function of the brain, which operates in a biological environment that is very different to that of the result of the body. Unfortunately, and like all systems in the body, the blood-brain barrier deteriorates with age. This allows harmful molecules and cells to leak into the brain, provoking a damaging state of chronic inflammation in brain tissue. Inflammation is thought to be an important component of age-related neurodegenerative conditions, and to the degree that blood-brain barrier dysfunction contributes to the overall state of inflammation in brain tissue, it can be considered one of the important causes of neurodegeneration.

What to do about this problem? There is the question. The blood-brain barrier is a complex system, and thus its failure is also complex, when considered in detail. As is the case for much of aging, it is presently somewhere between challenging and impossible to accurately assess the relative importance of the many changes, failures, and forms of damage that can be measured in the cells of the blood-brain barrier. Even determining the direction of cause and effect for a few of these line items can be a hard task, an undertaking of years for teams of scientists. This is why the easier path to knowledge is to start with what is known of the root causes of aging, attempt to repair those causes one by one, and then observe the results on the dysfunction of critical biological systems such as the blood-brain barrier.

For example, senescent cells that accumulate in old tissues can now be cleared to a sizable degree via the application of senolytic therapies. Will this help to restore lost blood-brain barrier integrity? If so, it is then possible to look at specific differences before and after treatment in order to ask why this outcome the case. That may then inform researchers about the arrangement and relationships of blood-brain barrier pathologies in a more general sense. A working, narrowly focused rejuvenation therapy is the best of tools with which to explore the details of the aging process.

Blood-Brain Barrier Breakdown: An Emerging Biomarker of Cognitive Impairment in Normal Aging and Dementia

Blood vessels are essential to transport oxygen and nutrients, remove CO2 and other waste products, and, thus, maintain homeostasis in the body. Blood vessels that vascularize the central nervous system (CNS) acquire specific anatomical and functional characteristics that collectively form the blood-brain barrier (BBB). At the cellular level, the BBB is developed by continuous non-fenestrated endothelial cells (ECs) encompassed by pericytes, smooth muscle cells, astrocytes, microglia, oligodendroglia, and neurons that are altogether called the neurovascular unit (NVU). At the molecular level, the BBB ECs are compacted by claudins, occludins, and ZO-1 [tight junction (TJ) proteins] and junction adhesion molecule (JAM) proteins to restrict the paracellular and transcellular diffusion of molecules in the CNS.

In addition, the BBB ECs mediate influx transporters to select metabolite uptake from the blood and efflux transporters to remove toxins and waste products from the brain into the blood. In BBB ECs, leukocyte adhesion molecules (LAMs) express very low to suppress immune surveillance in the brain. Thus, the BBB confines the access of neurotoxic compounds, blood cells, and pathogens to the brain. In addition, the BBB sustains the homeostasis of the brain through tight regulation of the transport of molecules between the brain parenchyma and peripheral circulation.

Hence, the BBB is a fundamental and crucial element of normal and healthy brain function. Any impairment in the cellular or molecular components causes BBB breakdown that results in BBB dysfunction. Aging is one of several factors involved in the breaking of the BBB and was first observed in aged patients reported in the 1970s. In dysfunctional BBBs, the possibility of permeability increases; thus, toxic and blood-borne inflammatory substances that infiltrate the brain could change the biochemical microenvironment of the neurons, thus leading to neurodegenerative diseases and dementia. It has been reported that BBB disruption in aged people is strongly related to Alzheimer's disease (AD) and cognitive impairment.

Although researchers have reported the contributions of BBB disruption to the pathogenesis of cognitive impairment associated with normal aging and dementia, more research is needed to elucidate the precisely causing factors and the cellular and molecular mechanisms of BBB maintenance, breakdown, and repair correlated with neurodegeneration and cognition decline. In the future, how aging and dementia affect BBB function in health and disease state, thus leading to neurodegeneration and cognitive impairment, should be explored in living organisms. Clinical research pertaining to this will boost our knowledge and help us better understand the association between BBB breakdown and cognitive decline. Such studies pave the way for the use of the BBB as a novel biomarker and therapeutic target to treat dementia and other neurological diseases associated with cognitive impairment.

A Small Change in the Ribosome Reduces Protein Synthesis Errors and Modestly Extends Lifespan in Short-Lived Species
https://www.fightagi...-lived-species/

The ribosome is a cellular structure responsible for the translation stage of protein manufacture, in which proteins are assembled from amino acids according to the blueprint provided by a messenger RNA molecule. In today's research materials, scientists report that a small change in a ribosomal protein, found in heat-tolerant organisms, has interesting effects when introduced into short-lived laboratory species via genetic engineering. The outcome is a reduction in the error rate for protein manufacture, an increased heat tolerance, and a modestly extended life span.

It is worth noting that life span increases of this degree in very short-lived species such as yeast, flies, and worms should not be expected to appear in humans when the same approach is taken in our species. Very short-lived species have highly plastic life spans, particularly when it comes to approaches that improve the quality control of proteins in the cell, such as by increasing the efficiency of autophagy or proteasomal function in order to clear damaged proteins. As species life span increases, the effects of such interventions diminish. This is likely because longer-lived species have already evolved mechanisms that compensate in other ways, a necessary precondition for their longer life spans.

Nonetheless, this work on the ribosome, at the other end of the spectrum of protein quality control mechanisms, is interesting when considered in the context of the naked mole-rat, which lives nine times as long as similarly sized mammalian species. The much longer life span of the naked mole-rat is likely a result of the combination of many favorable differences in many areas of metabolism. That said, a few years ago it was found that this species has unusually efficient ribosomes, and therefore a lower rate of errors in protein manufacture. Today's results in flies and worms really only provide a starting point for debate over the degree to which the exceptional life span of the naked mole-rat is dependent on improved protein synthesis. While we should likely be leaning towards a smaller fraction of the overall effect rather than a larger fraction, there is clearly much more work to be accomplished on this topic.

Antiaging advice from single-celled creatures: Build better proteins

Many studies of the causes of aging and disease have focused on the accumulation of mutations in genes - the blueprints for a cell's proteins and other molecules. Far fewer have looked at glitches in how each blueprint gets translated, which can create faulty proteins. Key to translation is the ribosome, the cellular machinery that uses DNA's instructions to assemble amino acids into proteins. When the ribosome makes a mistake, the resulting proteins may fold improperly, stick to other proteins, and sometimes cause damage to cells.

Researchers looked to a part of the ribosome known to be critical for accurate translation: a protein called RPS23. While analyzing genetic data from species across the tree of life-from cows to gut microbes - the researchers found the same amino acid at a key position in this ribosomal protein. But there was an exception: Certain species of single-celled organisms called archaea that thrive in extremely hot and acidic environments had a mutation that replaced this amino acid with another.

Curious about the effects of this mutation, the researchers used the gene editor CRISPR to swap it into RPS23 genes of yeast, fruit flies, and the tiny roundworm Caenorhabditis elegans. Organisms with the mutation had fewer protein synthesis errors than unmodified controls. All three types of organisms could also survive at higher temperatures. Most strikingly, the yeast cells, flies, and worms lived between 9% and 23% longer. The mutants also seemed healthier as they aged: Compared with the control counterparts, older flies with the mutation were better able to climb and older modified worms produced more offspring.

Increased fidelity of protein synthesis extends lifespan

Loss of proteostasis is a fundamental process driving aging. Proteostasis is affected by the accuracy of translation, yet the physiological consequence of having fewer protein synthesis errors during multi-cellular organismal aging is poorly understood. Our phylogenetic analysis of RPS23, a key protein in the ribosomal decoding center, uncovered a lysine residue almost universally conserved across all domains of life, which is replaced by an arginine in a small number of hyperthermophilic archaea. When introduced into eukaryotic RPS23 homologs, this mutation leads to accurate translation, as well as heat shock resistance and longer life, in yeast, worms, and flies. Furthermore, we show that anti-aging drugs such as rapamycin, Torin1, and trametinib reduce translation errors, and that rapamycin extends further organismal longevity in RPS23 hyperaccuracy mutants. This implies a unified mode of action for diverse pharmacological anti-aging therapies. These findings pave the way for identifying novel translation accuracy interventions to improve aging.

Proposing a Liver Amyloid Hypothesis of Alzheimer's Disease
https://www.fightagi...eimers-disease/

The earliest stages of Alzheimer's disease are characterized by increasing aggregation of misfolded amyloid-β, but there is considerable debate over the role played by amyloid-β in the onset and progression of the condition. The failure of amyloid-clearing immunotherapies to improve patient outcomes has spurred a great deal of alternative theorizing, some of which regards amyloid-β aggregation as a side-effect of other, more important processes, and some of which adjusts the details by which amyloid-β produces pathology, but retains it as a central pillar of disease onset.

Unfortunately all animal models of Alzheimer's pathology are highly artificial, as the usual laboratory species do not naturally develop anything resembling the Alzheimer's neurodegenerative processes in humans. Thus the models reflect preconceptions about which processes are important. If a researcher thinks that a specific subset of amyloid-β aggregation is vital to the progression of Alzheimer's disease, then that lab will generate mice that exhibit this specific biochemistry. This strategy is inefficient, to say the least. The hypothesis leads to the mouse model, which leads to therapies that can rescue the mouse model, which leads to treatments that so far don't work well in humans, because the hypothesis is in some way incorrect.

It seems fairly well established that there is a dynamic equilibrium between amyloid-β in the brain and in the rest of the body. Researchers have run human trials based on attempts to clear amyloid-β in the bloodstream, and thus cause amyloid-β to leave the brain via the equilibrium mechanisms. This seems to be working modestly well so far, though it is only slowing progression of Alzheimer's disease. Amyloid-β is created in both the brain and the body, but which of these is the important source when it comes to the onset of Alzheimer's disease? In today's research materials, scientists suggest that Alzheimer's may originate in amyloid-β production in the liver. So of course they engineered a highly artificial mouse model in which that happens, producing neurodegeneration as a consequence. Sadly, this alone should give us little confidence that the liver amyloid hypothesis is a true reflection of what is going on in humans, for the reasons given above.

The concept is interesting, however, given recent work on the origins of α-synuclein aggregates in Parkinson's disease. It appears that in some fraction of Parkinson's patients, the α-synuclein responsible for the onset of the condition originates in the gut and then spreads to the brain. Given that, it isn't outrageous to suggest a bodily origin of the amyloid-β aggregation in Alzheimer's disease. It does, however, need more and better evidence in order to become convincing.

Landmark study presents evidence Alzheimer's disease begins in the liver

For several decades it has been generally accepted that Alzheimer's disease is caused by the accumulation of amyloid proteins in the brain. These proteins form toxic aggregations known as plaques and it is these plaques that damage the brain. Although doubts are growing regarding the veracity of the "amyloid hypothesis," the build up of these plaques is still the most prominent physiological sign of Alzheimer's. And one of the more interesting hypotheses that has been suggested is that these damaging amyloid proteins originate in the liver.

The big challenge in investigating this liver-amyloid hypothesis is that amyloid is also produced in the brain. Most mouse models used in Alzheimer's research involve engineering the animals to overexpress amyloid production in the central nervous system, which only really resembles the minority of humans suffering from hereditary early-onset Alzheimer's. The vast majority of people developing the disease instead experience what is known as sporadic Alzheimer's, where the disease develops in older age, with no familial or genetic history.

The breakthrough in this new research is the development of a new animal model of Alzheimer's disease. Here, the researchers engineered a mouse to produce human amyloid proteins solely in the liver, and this allowed for novel observations into how these proteins can enter the bloodstream and travel to the brain. This new study offers clear evidence of a "blood-to-brain pathway." Using the newly developed mouse model the study shows how amyloid produced in the liver can move to the brain and cause damage leading to pathological signs similar to those seen with Alzheimer's disease.

Synthesis of human amyloid restricted to liver results in an Alzheimer disease-like neurodegenerative phenotype

Several lines of study suggest that peripheral metabolism of amyloid beta (Aß) is associated with risk for Alzheimer disease (AD). In blood, greater than 90% of Aß is complexed as an apolipoprotein, raising the possibility of a lipoprotein-mediated axis for AD risk. In this study, we report that genetic modification of C57BL/6J mice engineered to synthesise human Aß only in liver (hepatocyte-specific human amyloid (HSHA) strain) has marked neurodegeneration concomitant with capillary dysfunction, parenchymal extravasation of lipoprotein-Aß, and neurovascular inflammation. Moreover, the HSHA mice showed impaired performance in the passive avoidance test, suggesting impairment in hippocampal-dependent learning. Transmission electron microscopy shows marked neurovascular disruption in HSHA mice. This study provides causal evidence of a lipoprotein-Aß /capillary axis for onset and progression of a neurodegenerative process.

The Staggering Ongoing Cost of Failing to Aggressively Pursue the Development of Rejuvenation Therapies
https://www.fightagi...tion-therapies/

No feasible amount of funding that could be devoted to the research and development of rejuvenation therapies would be too much. If near all other projects were dropped, and institutions radically retooled on a short term basis, then the world might be able to devote 300 billion per year into medical research and development aimed at aging. That is an unachievable upper bound, of course. Given a few decades in which to train new researchers while rapidly and radically expanding existing institutions, then humanity might start to approach that scale of expenditure. Realistically it will take 20-30 years following the first unarguable successes in human rejuvenation for the economic incentives to meaningful start in on the creation of a suitably vast industry. Progress on this scale takes time.

The cost of the medical conditions, suffering, and mortality caused by aging, meanwhile, is staggeringly large. Researchers have estimated that slowing aging by one year worldwide is worth 38 trillion in productivity gains. Direct and easily measured medical and productivity costs of aging are more than 1 trillion per year in the US alone. Looking at the common estimates of the economic worth of a human life, the cost of the yearly death toll due to aging is well over 100 trillion, a vast destruction of the value of living individuals, their knowledge and capacity to make the world a better place. No feasible amount of funding devoted to achieving medical control over aging could be enough, given these numbers.

Tiday's short article is a fairly standard call for the US government to do more for a favored cause. Its novelty is that the cause is human longevity, the medical control of aging. The various patient advocacy, investor, academic, and biotechnology industry factions interested in the development of the means to treat aging have not yet developed an earnest lobbying arm - and are perhaps not yet large enough to produce more than the few initiatives that have emerged to date, such as the Longevity Dividend. It isn't only governments that fund medical research and development, however. Philanthropy and industry are just as important, and just as capable of contributions at the large scale.

The Case for a Longevity Moonshot

There has been tremendous progress in understanding aging and showing that it is possible to reverse it, and there is a growing longevity industry validating the approach to treat aging directly. Researchers are using a variety of approaches, from drugs that get rid of old cells to gene and stem cell therapies. Institutions researching aging include the nonprofit SENS Research Foundation, David Sinclair's lab at Harvard, and biotech companies including Calico (a sister company of Google), Rejuvenate Bio, BioAge, Cambrian, Unity Biotechnology, Juvenescence, Retro Biosciences, and Oisin Biotechnologies.

Both donors and investors see promise in reversing aging. However, there is research that the private sector will not do on its own because investors seek quick returns and donors have only so much money. It has taken seven years to fundraise for clinical trials to see if metformin slows down aging. And there has been more research in mice than in people, partly because clinical trials for people cost more. Basic research is risky, expensive, and without a certain payoff, so important research goes undone because the private sector is unwilling to fund it. The government needs to fill in the gap.

If we discovered a cure for aging, it would make society much wealthier, and the benefits to mankind would be enormous. Increasing life expectancy by one year alone by slowing down aging is worth 38 trillion, according to a recent study-more than the entire national debt of 29 trillion. Finding a cure for aging would significantly boost GDP by allowing people to work for longer. It would also lower the national debt, because higher GDP would lead to more tax revenue, and less would need to be spent on Medicare and Social Security because people would be healthier for longer.

Unfortunately, aging receives only 6% of government health research funding. There has been far more government spending on treating individual diseases, but as Vijay Pande and Kristen Fortney wrote for Andreessen Horowitz, curing cancer would add only four years to the average lifespan "because another major killer like stroke would be just around the corner. Only by targeting aging itself can we make significant impact on improving quality of life and healthspan." It would be more valuable to find a cure for aging than for individual diseases like cancer because it would stop those diseases from materializing in the first place. You're at much greater risk of cancer and Alzheimer's at age 70 than at age 30, and a cure for aging could fundamentally change that. U.S. life expectancy has been roughly stagnant, rising only 7% since 1980. We should target life expectancy as an important measure of national well-being, in addition to GDP. A cure for aging would boost life expectancy far more than finding a cure for individual diseases because aging increases people's risk of disease.

A Trend Towards Increased Proteostasis in Longer-Lived Mammalian Species
https://www.fightagi...malian-species/

Researchers here report on a broad comparison of protein sequences across many mammalian species, conducted in order to search for small differences between individual proteins that correlate with species life span. They find that humans, as one of the longer-lived mammals, already have most of these differences present across most of the the population. Further, the nature of these differences between proteins, meaning the specific functions of differing proteins in cell metabolism, is argued to support the hypothesis that quality control processes responsible for maintaining protein structure and removing damaged proteins make a sizable contribution to species differences in life span.

A key mechanism that may contribute to differences in lifespan between species is the maintenance of the proteostasis network. Protein stability or proteostasis refers to the capacity to protect protein structures and functions against environmental stressors, including aging. In fact, dysfunction of the protein quality control mechanisms is a hallmark of aging and there is substantial evidence linking proteostasis and longevity. For instance, improved protein stability is determinant for longevity in exceptionally long-lived mollusks and in the naked mole-rat, the longest-living rodent. In addition, interventions that enhance proteome stability can improve health or increase lifespan in model organisms, such as pharmacological chaperones that have been investigated as potential therapeutic targets to reduce the adverse effects of misfolding of aging-related proteins.

A mammalian-wide study of the genomic underpinnings of lifespan has never been carried out with the combined goals of identifying individual mutations linked to longevity; analyzing the functional properties of their genes and the pathways in which they take part; and studying how the stability of proteins coded by these genes may differentiate long- and short-lived species. Here, we performed the largest phylogeny-based genome-phenotype analysis to date, focusing on the detection of individual mutations and genes that underlie the enormous variation of lifespan in mammals. We report the discovery of more than 2,000 longevity-related genes and show that, overall, they present a trend towards increased protein stability in long-lived organisms. In addition, we successfully show that our findings enhance the interpretation of the results of longevity genome-wide association studies that have been carried out in humans.

We discovered a total of 2,737 single amino acid differences (AA) in 2,004 genes that distinguish long- and short-lived mammals, significantly more than expected by chance. These genes belong to pathways involved in regulating lifespan, such as inflammatory response and hemostasis. Among them, a total 1,157 AA showed a significant association with maximum lifespan in a phylogenetic test. Interestingly, most of the detected AA positions do not vary in extant human populations (81.2%) or have allele frequencies below 1% (99.78%). Consequently, almost none of these putatively important variants could have been detected by genome-wide association studies. Additionally, we identified four more genes whose rate of protein evolution correlated with longevity in mammals. Crucially, SNPs located in the detected genes explain a larger fraction of human lifespan heritability than expected, successfully demonstrating for the first time that comparative genomics can be used to enhance interpretation of human genome-wide association studies. Finally, we show that the human longevity-associated proteins are significantly more stable than the orthologous proteins from short-lived mammals, strongly suggesting that general protein stability is linked to increased lifespan.

Are Gene Variant Interactions a Better Approach to Determining the Contribution of Genetics to Longevity?
https://www.fightagi...s-to-longevity/

The analysis of the effects of genetic variants on human life expectancy has employed ever large databases in recent years: more genes, more sequences, more people. As the data grows, the likely size of the effect of genetic variation on human longevity has become smaller. Outside of a few interesting genes, such as those relating to blood cholesterol levels and cardiovascular disease risk, he picture is one of countless variants with small, interacting, environment-dependent effects, different in every study population.

How much of this picture is a true assessment versus a consequence of larger effects being hidden in the interactions between gene variants? Past studies have near all focused on a variant by variant analysis, considering each variant alone - and so this is an interesting question. Interesting or not, it remains the case that there may be no practical application here, however. Old people are still aged, damaged, and increasingly frail, whether or not they carry rare gene variants associated with longevity. Finding ways to emulate survivors to old age is an inherently poor approach to the treatment of aging, at least in comparison to working towards the repair of the underlying molecular damage that causes aging, in order to produce rejuvenation.

A major goal of aging research is identifying genetic targets that could be used to slow or reverse aging - changes in the body and extend limits of human lifespan. However, the majority of genes that showed the anti-aging and pro-survival effects in animal models were not replicated in humans, with few exceptions. Potential reasons for this lack of translation include a highly conditional character of genetic influence on lifespan, and its heterogeneity, meaning that better survival may be result of not only activity of individual genes, but also gene-environment and gene-gene interactions, among other factors.

In this paper, we explored associations of genetic interactions with human lifespan. We selected candidate genes from well-known aging pathways (IGF1/FOXO growth signaling, P53/P16 apoptosis/senescence, and mTOR/SK6 autophagy and survival) that jointly decide on outcomes of cell responses to stress and damage, and so could be prone to interactions. We estimated associations of pairwise statistical epistasis between SNPs in these genes with survival to age 85+ in the Atherosclerosis Risk in Communities study, and found significant effects of interactions between SNPs in IGF1R, TGFBR2, and BCL2 on survival to age 85 and older. We validated these findings in the Cardiovascular Health Study sample, using survival to age 85+, and to the 90th percentile, as outcomes.

Our results show that interactions between SNPs in genes from the aging pathways influence survival more significantly than individual SNPs in the same genes, which may contribute to heterogeneity of lifespan, and to lack of animal to human translation in aging research.

A Demonstration of Artificial Mitochondria Capable of Generating Adenosine Triphosphate to Support Cell Function
https://www.fightagi...-cell-function/

Researchers here demonstrate the creation of artificial pseudo-organelles capable of generating adenosine triphosphate (ATP). ATP is a chemical energy store molecule that is produced by mitochondria. It is vital to cell function. Mitochondrial production of ATP falters with age, as well as in tissues that become poorly supplied with nutrients. Finding a way to provide additional ATP could be quite helpful as a compensatory therapy, though whether or not a constant oversupply of ATP has meaningful negative consequences will have to be explored in greater detail than has been the case to date.

Cells have small compartments known as organelles to perform complex biochemical reactions. These compartments have multiple enzymes that work together to execute important cellular functions. Research have now successfully mimicked these nano spatial compartments to create 'artificial mitochondria'. This was achieved through reprogramming of 'exosomes', which are small vesicles (diameter ~120 nm) that cells use for intercellular signaling. The researchers carried out the experiments using microfluidic droplet reactors, which generated small droplets that were of similar size as typical cells. The researchers first aimed to facilitate controlled fusion of these exosomes within the droplets while preventing unwanted fusions.

These customized exosomes were then preloaded with different reactants and enzymes, which turned them into biomimetic nano factories. The team demonstrated this multienzyme biocatalytic cascade function by encapsulating glucose oxidase (GOx) and horseradish peroxidase (HRP) inside the exosomes. The GOx first converts glucose into gluconic acid and hydrogen peroxide. The HRP in turn uses the hydrogen peroxide generated in the first reaction to oxidize Amplex Red to a fluorescent product, resorufin. Next, the researchers wanted to know exactly how well these mini reactors can be uptaken and internalized by the cells. The cells derived from human breast tissues were fed with fused exosome nanoreactors, and their internalization over the next 48 hours was observed. It was found that cells were able to uptake these customized exosomes primarily through endocytosis, along with multiple other mechanisms.

Armed with this knowledge, the team sought to create functional artificial mitochondria that are capable of producing energy inside the cells. To achieve this, ATP synthase and bo3 oxidase were reconstituted into the earlier exosomes containing GOx and HRP, respectively. These exosomes were in turn fused to create nanoreactors that can produce ATP using glucose and dithiothreitol (DTT). It was found that the fused exosomes were capable of penetrating deep into the core part of a solid spheroid tissue and produce ATP in its hypoxic environment.

Identifying Age-Related Epigenetic Changes Related to Reduced Function in Mesenchymal Stem Cells
https://www.fightagi...mal-stem-cells/

Stem cells maintain tissue by providing a supply of daughter somatic cells to replace losses. This stem cell activity declines with age, and a sizable fraction of that decline in the most studied populations appears to be a reaction to the aged signaling environment rather than intrinsic dysfunction, at least in earlier old age. The behavior of cells lacking damage is controlled by their epigenetic state, alterations to the genomic machinery that governs the production of specific proteins. Could long term health be significantly improved by altering the epigenetic state of old stem cells, overriding their reaction to the aged tissue environment, and maintaining function at youthful levels? The consensus view of stem cell aging is that loss of function is an evolved response that serves to minimize cancer risk, but equally the evidence to date from animal studies suggests that there is considerable room to improve stem cell function and tissue maintenance in later life without greatly raising cancer risk.

Researchers have been looking at epigenetics as a cause of ageing processes for some time. Epigenetics looks at changes in genetic information and chromosomes that do not alter the sequence of the genes themselves, but do affect their activity. One possibility is changes in proteins called histones, which package the DNA in our cells and thus control access to DNA. A research group has now studied the epigenome of mesenchymal stem cells. These stem cells are found in bone marrow and can give rise to different types of cells such as cartilage, bone, and fat cells.

"We wanted to know why these stem cells produce less material for the development and maintenance of bones as we age, causing more and more fat to accumulate in the bone marrow. To do this, we compared the epigenome of stem cells from young and old mice. We could see that the epigenome changes significantly with age. Genes that are important for bone production are particularly affected."

The researchers then investigated whether the epigenome of stem cells could be rejuvenated. To do this, they treated isolated stem cells from mouse bone marrow with a nutrient solution which contained sodium acetate. The cell converts the acetate into a building block that enzymes can attach to histones to increase access to genes, thereby boosting their activity. The treatment caused the epigenome to rejuvenate, improving stem cell activity and leading to higher production of bone cells. To clarify whether this change in the epigenome could also be the cause of the increased risk in old age for bone fractures or osteoporosis in humans, the researchers studied human mesenchymal stem cells from patients after hip surgery. The cells from elderly patients who also suffered from osteoporosis showed the same epigenetic changes as previously observed in the mice.

Mitochondrially Targeted Hydrogen Sulfide Delivery Molecules Slow Photoaging
https://www.fightagi...low-photoaging/

Researchers here demonstrate that molecules designed to supply hydrogen sulfide to mitochondria in skin cells can slow the progression of photoaging, the damage done to skin tissue by UV radiation. This provides some insight into the role of mitochondria in the reaction to UV radiation that produces lasting structural damage in skin. The publicity materials speculate on the ability to reverse existing photoaging damage, but that is unsupported by the work presented in the paper, which only shows the outcome of the topical application of the treatment to skin prior to exposure to ultraviolet radiation.

Two new molecules, AP39 and AP123, that generate minute amounts of the gas hydrogen sulfide have been found to prevent skin from ageing after being exposed to ultraviolet light found in sunlight. Researchers exposed adult human skin cells and the skin of mice to ultraviolet radiation (UVA). UVA is the part of natural sunlight which damages unprotected skin and can penetrate through windows, and even through some clothes. It causes skin to age prematurely by turning on skin digesting enzymes called collagenases. These enzymes eat away at the natural collagen, causing the skin to lose elasticity and sag, resulting in wrinkles

In the experiments, the compounds AP39 and AP123 did not protect the skin in the same way traditional sun creams prevent sunburn, but instead penetrated the skin to correct how skin cells' energy production and usage was turned off by UVA exposure. This then prevented the activation of skin-degrading collagenase enzymes and subsequent skin damage.

The compounds AP39 and AP123 specifically target the energy generating machinery inside our cells, the mitochondria, and supply them with minute quantities of alternative fuel, hydrogen sulfide, to use when skin cells are stressed by UVA. The direct result of this was the activation of two protective mechanisms. One is a protein call PGC-1α, which controls mitochondria number inside cells and regulates energy balance. The other is Nrf2, which turns on a set of protective genes that mitigate UVA damage to skin and turn off the production of collagenase, the main enzyme that breaks down collagen in damaged skin tissue and causes skin to look significantly more "aged".

Mitochondrial AMPK as a Trigger of Beneficial Mitophagy
https://www.fightagi...cial-mitophagy/

Mitophagy is a quality control process that removes damaged and worn mitochondria, sending them to a lysosome for disassembly. Mitochondria are essential to cell function, a herd of hundreds of these bacteria-like organelles present in every cell. Active mitophagy ensures that this population of mitochondria remains usefully functional, providing the cell with a sufficient supply of the energy store molecule adenosine triphosphate (ATP). When mitophagy falters, as occurs throughout the body with age, for reasons that remain incompletely understood, the outcome is that mitochondrial function, cell function, and tissue function are all negatively affected. A better understanding of the triggers of the mitophagy process could lead to the development of compensatory therapies that at least partially restore lost mitochondrial function, and thus improve health and turn back aging in the old.

Mitochondria form a complex, interconnected reticulum that is maintained through orchestrated remodeling processes, such as biogenesis, dynamic fission and fusion, and targeted degradation of damaged/dysfunctional mitochondria, called mitophagy. These remodeling processes are collectively known as mitochondrial quality control and are initiated by various cues to maintain energetic homeostasis, which is particularly important for tissues with high-energy demands (e.g., skeletal muscle and heart). While the reticulum appears to respond to energetic demand uniformly, mitochondrial quality control acts with remarkable subcellular precision. For example, in both skeletal muscle and heart, impaired or damaged regions of mitochondria are separated from the functional reticulum in response to certain cellular signals, setting the stage for their degradation by mitophagy. However, what governs the spatial specificity of this process is poorly understood.

The cellular energy sensor AMPK senses cellular energy status by monitoring AMP and/or ADP levels. AMP and/or ADP bind to the γ subunit of AMPK, resulting in a conformational change. Muscle-specific knockout of both α subunit isoforms impairs exercises capacity and mitochondrial oxidative capacity, clearly linking energy sensing of AMPK to mitochondrial function as well as tissue function. Indeed, AMPK activation promotes mitochondrial fission in vitro through its direct substrate mitochondrial fission factor (Mff). We and others have previously demonstrated that induction of mitophagy in response to energetic stress (e.g., exercise, fasting, etc.) is controlled by AMPK-dependent mechanisms.

To reconcile the subcellular specificity of mitochondrial quality control with the fact that exercise and other energetic stresses increase ADP and AMP, the known activators of AMPK, we hypothesized that a proportion and/or subtype of AMPK is localized at mitochondria. This pool of AMPK may serve as a gauge of energetic cues, particularly when and where ATP production through oxidative phosphorylation becomes limited. Herein, we uncovered that a particular combination of subunits of AMPK are localized to mitochondria in a variety of tissues, including skeletal muscle and heart in both mice and humans, which we term mitoAMPK.

We show that mitoAMPK is localized to the outer mitochondrial membrane and is activated in response to various stimuli of mitochondrial energetic stress. mitoAMPK activity and activation are spatially variable across the mitochondrial reticulum. Finally, we present evidence that suggests activation of mitoAMPK in skeletal muscle is required for mitophagy in vivo. Discovery of a pool of AMPK on mitochondria and its importance for mitochondrial quality control highlights the complexity of energetic monitoring in vivo and could facilitate development of strategies of targeting mitochondrial energetics to treat diseases related to impaired mitochondrial function.

A Tipping Point for Amyloid Accumulation in the Development of Alzheimer's Disease
https://www.fightagi...eimers-disease/

Researchers here report on their view of amyloid accumulation in the brains of older people, as established by PET scans. They suggest that there is a tipping point after which further accumulation and the consequent development of Alzheimer's disease becomes predictable. It is interesting to consider what is going on under the hood to produce this behavior. Most aspects of age-related disease involve mutual interactions between different processes of damage and dysfunction, leading to feedback loops that change behavior at different stages of disease progression. In a system in which there is some capacity for maintenance, there may well be thresholds of damage and dysfunction after which maintenance cannot keep up, and pathology develops more rapidly as a result.

In those who eventually develop Alzheimer's dementia, amyloid silently builds up in the brain for up to two decades before the first signs of confusion and forgetfulness appear. Amyloid PET scans already are used widely in Alzheimer's research, and now an algorithm developed by researchers represents a new way of analyzing such scans to approximate when symptoms will arise. Using a person's age and data from a single amyloid PET scan, the algorithm yields an estimate of how far a person has progressed toward dementia - and how much time is left before cognitive impairment sets in.

Researchers analyzed amyloid PET scans from 236 people participating in Alzheimer's research studies. The participants were an average of 67 years old at the beginning of the study. All participants underwent at least two brain scans an average of 4½ years apart. The researchers applied a widely used metric known as the standard uptake value ratio (SUVR) to the scans to estimate the amount of amyloid in each participant's brain at each time point. The researchers also accessed over 1,300 clinical assessments on 180 of the participants. The assessments typically were performed every one to three years. Most participants were cognitively normal at the start of data collection, so the repeated assessments allowed the researchers to pinpoint when each participant's cognitive skills began to slip.

Researchers spent years trying to figure out how to use the data in amyloid PET scans to estimate the age at which symptoms would appear. The breakthrough came when they realized that amyloid accumulation has a tipping point and that each individual hits that tipping point at a different age. After this tipping point, amyloid accumulation follows a reliable trajectory. "You may hit the tipping point when you're 50; it may happen when you're 80; it may never happen. But once you pass the tipping point, you're going to accumulate high levels of amyloid that are likely to cause dementia. If we know how much amyloid someone has right now, we can calculate how long ago they hit the tipping point and estimate how much longer it will be until they are likely to develop symptoms."

Working Towards Biomarkers of Aging Based on Analysis of Saliva
https://www.fightagi...ysis-of-saliva/

There is much less interest in analysis of saliva than of blood or urine when it comes to mining metabolite and protein data in search of biomarkers of aging. Saliva has less to work with in terms of useful molecules. Nonetheless, some groups are making inroads in the analysis of biomolecules in saliva, as noted here. It should be expected that any sufficiently diverse set of biological data will exhibit characteristic changes with the accumulation of age-related damage and dysfunction. Somewhere in all of these options lies a simple, low-cost test that accurately reflects the state of that damage and dysfunction, and can thus be used to rapidly assess the degree to which any potential rejuvenation therapy actually works.

Researchers have conducted a comprehensive analysis of the metabolites that make up human saliva using samples given voluntarily from a group of 27-to-33-year-old individuals and a group of 72-to-80-year-old individuals. The sample collection was easy and noninvasive. Twenty-seven volunteers supplied their saliva, which they collected themselves at home. These were transferred to the laboratory for analysis. In general, the concentration of metabolites in saliva is very low compared to that in blood and urine, making it more challenging to detect them. However, using a comprehensive method, the researchers identified 99 metabolites, some of which were previously unreported in saliva. They also found that saliva contains information that reflects biological aging. Twenty metabolites, including those related to antioxidative activity, energy synthesis, and muscle maintenance, were lower in the elderly individuals than the young people, whereas one metabolite actually increased.

"It's interesting that ATP, the metabolite related to energy production, increased 1.96-fold in the elderly. This is possibly due to reduced ATP consumption in the elderly individuals. Amongst the metabolites that declined in quantity were two that are related to taste, suggesting that the elderly lose some ability to taste, and others that are related to muscle activity such as swallowing. These age-linked salivary metabolites together illuminate a metabolic network that reflects a decline of oral function during human aging."

Although this is the first comprehensive analysis to be performed on the metabolites of saliva, the researchers are planning to continue this work. In the future, they hope that saliva will be a sample that can be given readily and easily but could provide an enormous amount of information about an individual's health. "In saliva, age-linked metabolites are related to relatively broad metabolic conditions so that age-related information obtained from salivary metabolites may be distinct from that of blood and urine."

Bifidobacterium Longum in the Aging Gut Microbiome
https://www.fightagi...gut-microbiome/

This research is a representative example of ongoing efforts to better understand changes in the gut microbiome with age, identifying how and why specific microbial species are either protective or harmful to health. The gut microbiome is responsible for generating a range of helpful metabolites, but can also interact with tissues and the immune system to provoke chronic inflammation. It has been noted that some known beneficial populations decline while some known harmful populations grow in number with advancing age - though there is a great deal of work remaining to produce a full map of the effects of microbial species on health and aging. Fortunately, some short-cut approaches have been shown to favorably adjust an aged gut microbiome, such as fecal microbiota transplantation and flagellin immunization. Widespread clinical use still lies in the future, even through such approaches are quite accessible to self-experimenters.

Bifidobacterium species are pioneer colonizers of the gut and have been associated with various health-promoting effects, although the precise modes of action remain largely unknown. The abundances of various Bifidobacterium species in the gut vary widely among individuals according to dietary habits, age, and physiological status. One exception is Bifidobacterium longum (B. longum subsp. longum), which belongs to the human core microbiome. This species accounts for a higher proportion of Bifidobacterium species in the gut regardless of host age, is distributed broadly across the human lifespan, and is among a small subset of gut commensals that can colonize the gut for years.

Using a conceptual framework based on evolution and the pathogen transmission theory, we showed that B. longum had formed at least three geographically related populations and established the active transmission of B. longum strains across different types of hosts and according to geography and proximity. Interestingly, we identified a strong and statistically significant association between host age and genetic variations in B. longum genomes.

Our data also provide a molecular basis for host-microbe coevolution, and this knowledge could feasibly be used to promote host health. The causal link between the gut microbiota and host aging has been investigated extensively, and microbiome-based therapies such as dietary interventions, probiotics, and fecal microbiota transplantation have been shown to efficiently alleviate host aging. Some bacteria have been associated with a long human lifespan by analyzing the gut microbiota of centenarians. No chronological threshold or age is associated with an abrupt change in the microbiota composition; rather, these changes proceed gradually over time.

We identified a strong negative association of the genus Bifidobacterium with host age, consistent with previous observations of reduced bifidobacterial counts in the elderly compared with the gut microbiota of two or three other age groups. We further investigated the bifidobacterial species-level composition and identified B. longum as the most dominant of the core bifidobacterial species in the studied cohort. We further determined that the relative abundance of B. longum was also significantly correlated with host age. Interestingly, efforts to associate the genotype of this aging-related species with host age revealed a robustly significant association with the bacterial arginine biosynthesis pathway.

Previous studies have demonstrated many molecular mechanisms by which microbiota may favorably affect host health and aging, based on principles designed to seek possible solutions to those changes experienced during the aging process, including (1) decreased immune system functioning (i.e., immunosenescence) and low-grade chronic inflammation (i.e., inflammaging); (2) inappropriate oxidative stress; (3) impaired gut barrier function; (4) decreased energy supply for colon epithelial cells; and (5) perturbed gut metabolism (e.g., lipid metabolism, glucose homeostasis, vitamin B and conjugated linoleic acid production). Here, we propose another potent mechanistic route that key players (B. longum) in the gut microbiota are capable of generating age-related genomic adaptations in the arginine metabolism pathway, enhancing the bacterial arginine-enriching ability, further modifying arginine flux and the overall metabolome in the gut microbiota, and ultimately achieving protection against host aging.

Exercise Lowers Markers of Inflammation in Older Individuals
https://www.fightagi...er-individuals/

Researchers here note that structured exercise programs can reduce the burden of chronic inflammation in older individuals, a desirable outcome. The study is a reminder that being sedentary has a cost. Too little exercise and a lack of physical fitness in later life produces harmful consequences such as a raised level of chronic inflammation, and thus a faster progression towards all of the common and ultimately fatal age-related diseases. The fine details of our metabolism and its interaction with aging evolved in an environment of much greater regular physical exertion, all the way into later life, than is presently the case. When we fail to keep up with that level exercise, we suffer in its absence.

Increased basal low-grade inflammation is observed with advancing age, which is augmented by physical inactivity. However, data regarding the influence of lifelong exercise training and particularly high-intensity interval training (HIIT) on inflammatory mediators in older men are scarce. Therefore, we examined effects of 6 weeks of aerobic preconditioning followed by 6 weeks of HIIT on inflammatory mediators - interleukin (IL)-6, homocysteine, and high-sensitivity C-reactive protein (hsCRP) - in previously sedentary older men (SED) and masters athletes (LEX). Further, we investigated whether SED exhibited greater basal inflammatory biomarkers compared to LEX.

Twenty-two men (aged 62 ± 2 years) participated in the SED group, while 17 age-matched LEX men (aged 60 ± 5 years) also participated as a positive comparison group. In SED, preconditioning and HIIT caused a reduction in IL-6 compared to enrollment. SED homocysteine did not change throughout, while the decrease in hsCRP after preconditioning and after HIIT compared to enrollment was small. HIIT did not influence IL-6 or hsCRP in LEX. Homocysteine increased from enrollment to post-HIIT in LEX, but all other perturbations were trivial. IL-6 and hsCRP were greater in SED than LEX throughout the investigation, but homocysteine was not different.

Results of this study suggest moderate-intensity aerobic exercise and HIIT lowers IL-6 (and possible hsCRP) in previously sedentary older men. Moreover, lifelong exercise is associated with reduced concentrations of some inflammatory biomarkers in older males, and therefore, physical inactivity, rather than age per se, is implicated in chronic low-grade inflammation. Moreover, physical inactivity-induced inflammation may be partly salvaged by short-term exercise training.


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