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Contents
- Slow Progress Towards Autologous Cell Therapies for Parkinson's Disease
- Epidemiological Evidence for Herpesvirus Infection to Increase the Risk of Alzheimer's Disease
- The Binarized Transcriptomic Aging Clock
- Arguing the Direction of Causation in Atherosclerosis and Clonal Hematopoiesis
- Piperlongumine Reduces Aortic Calcification in Mice
- Tsimane and Moseten Hunter-Gatherers Exhibit Minimal Levels of Atrial Fibrillation
- Bioactive Lipids and the Cell Membrane in Aging
- Higher Cardiovascular Health Score Correlates with Lower Epigenetic Age Acceleration
- Too Much of a Focus on What is Easy, Too Little on What Could Greatly Increase Lifespan
- CAR-T Therapy Continues to Perform Well for Patients Unresponsive to Chemotherapy
- A Popular Science View of Mitochondrial Uncoupling
- Age-Associated B Cells Contribute to Autoimmunity and Chronic Inflammation
- FOXO1 Influences Proteosomal Function via Regulation of the Expression of a Proteasome Subunit
- Age-Related Vision Impairment Correlates with Mortality
- An Approach to Allow Much Faster Bioprinting of Tissue
Slow Progress Towards Autologous Cell Therapies for Parkinson's Disease
https://www.fightagi...insons-disease/
Cell therapies for Parkinson's disease have been under development for a very long time indeed, decades at this point. The condition is characterized by aggregation of α-synuclein and loss of the small but critical population of dopamine-generating neurons in the brain. The latter is the proximate of cause of the loss of motor control and depression observed in patients. These cells are particularly sensitive to the combination of toxic α-synuclein biochemistry, mitochondrial dysfunction, chronic inflammation, and other contributing factors that manifest in this condition - and in aging in general. The motivation for a cell therapy approach to Parkinson's disease is the replacement of these lost cells, and thus restoration of the supply of dopamine in the brain.
Cell therapy has proven challenging to implement sufficiently well for widespread use in the case of Parkinson's disease. Early attempts used fetal cells, while later attempts produced neurons from embryonic stem cells and then induced pluripotent stem cells. A recent small trial used cell reprogramming to generate neurons for transplantation from a patient's own cells. This is the end goal, a therapy with patient-matched cells that are generated to order and have minimal risk of rejection. Things move very slowly in this part of the field, however, as demonstrated by the animal study discussed in today's research materials. This project has been ongoing for a decade in order to produce results in non-human primates, wile it has been more than thirty years since the first fetal cell transplants were carried out in human trials for Parkinson's disease.
Individualized brain cell grafts reverse Parkinson's symptoms in monkeys
Parkinson's disease damages neurons in the brain that produce dopamine, a brain chemical that transmits signals between nerve cells. The disrupted signals make it progressively harder to coordinate muscles for even simple movements and cause rigidity, slowness, and tremors that are the disease's hallmark symptoms. Patients - especially those in earlier stages of Parkinson's - are typically treated with drugs like L-DOPA to increase dopamine production.
Scientists have tried with some success to treat later-stage Parkinson's in patients by implanting cells from fetal tissue, but research and outcomes were limited by the availability of useful cells and interference from patients' immune systems. Researchers have instead spent years learning how to dial donor cells from a patient back into a stem cell state, in which they have the power to grow into nearly any kind of cell in the body, and then redirect that development to create neurons. "The idea is very simple. When you have stem cells, you can generate the right type of target cells in a consistent manner. And when they come from the individual you want to graft them into, the body recognizes and welcomes them as their own."
The application was less simple. More than a decade in the works, the new study began in earnest with a dozen rhesus monkeys several years ago. A neurotoxin was administered - a common practice for inducing Parkinson's-like damage for research - and researchers evaluated the monkeys monthly to assess the progression of symptoms. During the course of the Parkinson's study, the researchers injected millions of dopamine-producing neurons and supporting cells into each monkey's brain in an area called the striatum, which is depleted of dopamine as a consequence of the ravaging effects of Parkinson's in neurons. Half the monkeys received a graft made from their own induced pluripotent stem cells (called an autologous transplant). Half received cells from other monkeys (an allogenic transplant). And that made all the difference.
Within six months, the monkeys that got grafts of their own cells were making significant improvements. Within a year, their dopamine levels had doubled and tripled. The monkeys who received allogenic cells showed no such lasting boost in dopamine or improvement in muscle strength or control, and the physical differences in the brains were stark. The axons - the extensions of nerve cells that reach out to carry electrical impulses to other cells - of the autologous grafts were long and intermingled with the surrounding tissue.
Autologous transplant therapy alleviates motor and depressive behaviors in parkinsonian monkeys
Degeneration of dopamine (DA) neurons in the midbrain underlies the pathogenesis of Parkinson's disease (PD). Supplement of DA via L-DOPA alleviates motor symptoms but does not prevent the progressive loss of DA neurons. A large body of experimental studies, including those in nonhuman primates, demonstrates that transplantation of fetal mesencephalic tissues improves motor symptoms in animals, which culminated in open-label and double-blinded clinical trials of fetal tissue transplantation for PD. Unfortunately, the outcomes are mixed, primarily due to the undefined and unstandardized donor tissues.
Generation of induced pluripotent stem cells enables standardized and autologous transplantation therapy for PD. However, its efficacy, especially in primates, remains unclear. Here we show that over a 2-year period without immunosuppression, PD monkeys receiving autologous, but not allogenic, transplantation exhibited recovery from motor and depressive signs. These behavioral improvements were accompanied by robust grafts with extensive DA neuron axon growth as well as strong DA activity in positron emission tomography (PET). Mathematical modeling reveals correlations between the number of surviving DA neurons with PET signal intensity and behavior recovery regardless autologous or allogeneic transplant, suggesting a predictive power of PET and motor behaviors for surviving DA neuron number.
Epidemiological Evidence for Herpesvirus Infection to Increase the Risk of Alzheimer's Disease
https://www.fightagi...eimers-disease/
There is much debate these days over the contribution of persistent infection (such as by herpesviruses) to the development of Alzheimer's disease. Not everyone with the evident risk factors, such as obesity, frailty, chronic inflammation, and so forth, progresses from mild cognitive impairment to full blown Alzheimer's disease. Why is this? The state of viral infection and the ability of any given aged immune system to contain that infection could be the variables needed to explain why Alzheimer's disease is only prevalent rather than universal. Despite the results presented in today's open access study, the epidemiological evidence to date is mixed and contradictory regarding a significant role for herpesviruses in Alzheimer's risk.
The infection-senescence hypothesis suggests that a burden of infection results in a raised pace of creation of senescent cells, particularly in the immune system, including the immune cell populations of the brain. Over time, this overwhelms the systems responsible for clearing senescent cells. When too many senescent cells accumulate, all actively secreting pro-inflammatory signals, they collectively produce a self-sustaining state of chronic inflammation. That unresolved inflammation disrupts normal tissue function in many ways - and Alzheimer's disease is known to have a strong inflammatory component.
An alternative view is that persistent infection ramps up the generation of amyloid-β, in its role as an antimicrobial peptide, a component of the innate immune system. The early, preclinical stages of Alzheimer's disease are characterized by a slow accumulation of misfolded amyloid-β in the brain, and the amyloid cascade hypothesis is the dominant explanation for why the disease occurs: in essence, amyloid-β aggregates cause enough dysfunction and inflammation to trigger the later pathologies of the condition. Why do some people accumulate more amyloid-β than others? Perhaps because they have a greater burden of persistent infection. But again, a conclusive weight of evidence for this viewpoint has yet to emerge.
Herpesvirus infections, antiviral treatment, and the risk of dementia - a registry-based cohort study in Sweden
There is growing evidence to support the link between herpes infections and Alzheimer's disease (AD). Targeting herpesviruses with specific antiviral agents could provide new AD treatment possibilities if a preventive effect is confirmed. Herpes simplex virus type 1 (HSV1) is the herpesvirus most strongly associated with AD. Several population-based cohort studies have demonstrated an increased risk of AD development for carriers of HSV1. Both in vivo and in vitro, inoculation with HSV1 among other pathogens causes AD-related changes with amyloid deposition.
Another neurotropic member of the Herpesviridae family implicated in dementia development is varicella zoster virus (VZV). Herpes zoster ophthalmicus is a subtype of the herpes zoster infection that affects the ophthalmic division of the trigeminal nerve. VZV infection of the central nervous system (CNS) has previously been linked to long-term cognitive decline. Recent data suggest that herpes zoster ophthalmicus and herpes zoster infection are associated with a 3.0- and 1.1-fold increased risk of dementia development. It has been hypothesized that in the event of herpes zoster ophthalmicus, the virus more frequently spreads to the brain, thereby explaining a stronger association with dementia development.
Previous findings have indicated a potential protective role of antiviral treatment against dementia development, and these results need to be corroborated in other large-scale cohorts. The aim of this study was to investigate whether specific antiviral treatment that targets herpesviruses and herpes infection with VZV and HSV, in absence of treatment, affects the risk of subsequent dementia in a large registry-based cohort in Sweden. The matched cohort study followed 265,172 subjects with herpes diagnoses and antiviral treatment, and the same number of controls.
Individuals with herpes diagnoses who did not receive antiviral treatment had higher incidence rates of dementia compared to their controls (12.9 and 10.2 per 1000 person-years, respectively). In contrast, herpes-diagnosed subjects who received antiviral treatment had lower incidence rates of dementia than their controls (8.5 and 9.4 per 1000 person-years, respectively). Last, the dementia incidence rates of antiviral users irrespective of diagnosis and their controls were 6.6 and 7.4 per 1000 person-years, respectively). Specific antiviral treatment targeting herpesviruses was associated with an 11% risk reduction of dementia. In contrast, having received a herpes diagnosis without antiviral treatment was associated with a 50% increased risk of dementia compared to controls. These results are in line with previous register-based studies indicating the potential protective role of antiviral treatment in dementia.
The control group in this study comprised both seropositive and seronegative individuals as the seropositivity status of the subjects is unknown, especially considering that approximately 70% of the population could be expected to carry HSV1 and more than 95% VZV. It is reasonable to assume that the controls probably have better immunological resilience to herpes infections with fewer episodes of symptomatic reactivations because they have not received a herpes diagnosis or been subjected to specialist medical care for this. Importantly, the herpes diagnoses primarily reflect symptomatic reactivation or primary infection with overt signs. Thus, the individuals with herpes diagnoses constitute a subgroup of those carrying the pathogen.
The Binarized Transcriptomic Aging Clock
https://www.fightagi...ic-aging-clock/
Patterns of epigenetic regulation of gene expression (and thus RNA and protein levels) change constantly in response to cell state and environment. Some of those changes are characteristic responses to the damage and dysfunction of aging. Since the demonstration of the first epigenetic clocks, those that predict age based on an algorithmic combination of the status of DNA methylation at CpG sites on the genome, researchers have produced any number of new clocks based on mining epigenomic, transcriptomic, proteomic, and other databases for correlations with age. Today's open access paper is yet another example of a new transcriptomic clock.
It remains the case that in none of these clocks is there is a good, well understood connection between specific mechanisms of aging and specific components of the clock algorithm. This makes it hard to make good use of aging clocks: it isn't at all clear that any given result is meaningful. If one applies a potentially rejuvenating or age-slowing intervention, and it produces a change in the clock measurements taken before and afterward treatment, what does that change mean? Is a drop in measured age a sign that the therapy is great, or a sign that the clock is overly weighted towards the subset of mechanisms of aging that are targeted by the intervention? If the clock shows little to no change, does that mean the therapy is useless, or the clock is unhelpful for this class of intervention? And so forth.
Thus clocks and therapies will have to be calibrated against one another in order to make the clocks useful. This process is only in the earliest stages, where it is occurring at all. As matters progress, this calibration will most likely mean running the slow, costly life span studies that we'd all like to avoid by using the clocks instead. There is no free lunch here.
BiT age: A transcriptome-based aging clock near the theoretical limit of accuracy
Aging biomarkers that predict the biological age of an organism are important for identifying genetic and environmental factors that influence the aging process and for accelerating studies examining potential rejuvenating treatments. Diverse studies tried to identify biomarkers and predict the age of individuals, ranging from proteomics, transcriptomics, the microbiome, frailty index assessments to neuroimaging, and DNA methylation. Currently, the most common predictors are based on DNA methylation. The DNA methylation marks themselves might influence the transcriptional response, but aging also affects the transcriptional network by altering the histone abundance, histone modifications, and the 3D organization of chromatin. The difference in RNA molecule abundance, thereby, integrates a variety of regulation and influences resulting in a notable gene expression change during the lifespan of an organism. These changes sparked interest in the identification of transcriptomic aging biomarkers, an RNA expression signature for age classification, and the development of transcriptomic aging clocks.
While a large variety of data, techniques, and analyses have been used to identify aging biomarkers and aging clocks in humans, issues remain with regard to pronounced variability and difficulties in replicability. Indeed, a recent analysis of gene expression, plasma protein, blood metabolite, blood cytokine, microbiome, and clinical marker data showed that individual age slopes diverged among the participants over the longitudinal measurement time and subsequently that individuals have different molecular aging pattern, called ageotypes. These interindividual differences show that it is still difficult to pinpoint biomarkers for aging in humans.
Model organisms, instead, can give a more controllable view on the aging process and biomarker discovery. Caenorhabditis elegans has revolutionized the aging field and has vast advantages as a model organism. To date, no aging clock for C. elegans has been built solely on RNA-seq data and been shown to predict the biological age of diverse strains, treatments, and conditions to a high accuracy. In this study, we build such a transcriptomic aging clock that predicts the biological age of C. elegans based on high-throughput gene expression data to an unprecedented accuracy. We combine a temporal rescaling approach, to make samples of diverse lifespans comparable, with a novel binarization approach, which overcomes current limitations in the prediction of the biological age. Moreover, we show that the model accurately predicts the effects of several lifespan-affecting factors such as insulin-like signaling, a dysregulated miRNA regulation, the effect of an epigenetic mark, translational efficiency, dietary restriction, heat stress, pathogen exposure, the diet-, and dosage-dependent effects of drugs.
This combination of rescaling and binarization of gene expression data therefore allows for the first time to build an accurate aging clock that predicts the biological age regardless of the genotype or treatment. Lastly, we show how our binarized transcriptomic aging (BiT age) clock model has the potential to improve the prediction of the transcriptomic age of humans and might therefore be universally applicable to assess biological age.
Arguing the Direction of Causation in Atherosclerosis and Clonal Hematopoiesis
https://www.fightagi...-hematopoiesis/
A major challenge in the study of aging and age-related disease is establishing the direction of causation. A great many mechanisms of aging are known, but it is difficult to firmly establish the relationships between them. The body is made up of many interacting systems, and changes in any one system tend affect the others, directly or indirectly. Equally, any two specific aspects of aging can be quite disconnected from one another but nonetheless proceed in parallel because they are both influenced by a third underlying mechanism. For example, the chronic inflammation of aging is a systemic problem, driving dysfunction in tissues throughout the body and accelerating the onset and progression of a wide range of age-related conditions.
Today's research materials are an example of this point. Here, researchers debate the direction of causation between atherosclerosis and clonal hematopoiesis. In atherosclerosis, macrophage cells in blood vessel walls become overwhelmed by oxidized and excessive amounts of cholesterol, resulting in fatty lesions that weaken and narrow the blood vessels. Because immune cells are involved, inflammation tends to make things worse by further impacting the ability of macrophages to repair tissues. In clonal hematopoiesis, mutational damage to the hematopoietic cells in the bone marrow leads to growing populations of (possibly mildly dysfunctional) immune cells. It is a specific instance of the more general age-related issue of somatic mosiacism, in which mutations in stem cells spread throughout tissues via their daughter somatic cells. It remains unclear as to just how big of a problem this is, in terms of the degree to which it contributes to aging.
Is the relationship between these two aspects of aging bidirectional, or are the observed correlations driven by an underlying process such as chronic inflammation? Questions of this nature are hard to answer definitively. The best approach is to find a way to reverse and repair one of the processes, and observe the result on the other. In general this is what the research and medical communities should be working towards in any case. It is far better to forge ahead to produce therapies of rejuvenation rather than first establishing how all of the mechanisms of aging interact, as success in rejuvenation will answer most of those questions about the inner workings of aging along the way.
Atherosclerosis can accelerate the development of clonal hematopoiesis, study finds
Billions of peripheral white blood cells are produced every day by the regular divisions of hematopoietic stem cells and their descendants in the bone marrow. Clonal hematopoiesis is a common age-related condition in which the descendants of one of these hematopoietic stem cells begin to dominate substantial portions of the blood. Genome-wide analyses have determined that clonal hematopoiesis is frequently driven by recurrent genetic alterations that confer a competitive advantage to specific hematopoietic stem cells, thus giving them the ability to expand disproportionately. Multiple independent studies have shown that clonal hematopoiesis often goes hand in hand with atherosclerosis and cardiovascular disease. Since its discovery, this surprising association has been the subject of intense interest from clinicians and researchers alike.
In a new study, researchers now suggest a different, additional possibility: Atherosclerosis causes clonal hematopoiesis. Patients with atherosclerosis suffer from hyperlipidemia and inflammation, two conditions that are known to chronically boost hematopoietic stem cell division rates. In the new study, the researchers now demonstrate that this increased division accelerates the development of clonal hematopoiesis. "Patients with atherosclerosis essentially experience 'accelerated time.' This is because the speed with which genetic alterations arise and spread through the hematopoietic system is determined by the underlying rate of stem cell division. From a genetic point of view, you could say that atherosclerosis accelerates aging of the blood. Since clonal hematopoiesis is an age-related condition, atherosclerosis patients are prone to developing it earlier than healthy individuals."
Increased stem cell proliferation in atherosclerosis accelerates clonal hematopoiesis
Clonal hematopoiesis, a condition in which individual hematopoietic stem cell clones generate a disproportionate fraction of blood leukocytes, correlates with higher risk for cardiovascular disease. The mechanisms behind this association are incompletely understood. Here, we show that hematopoietic stem cell division rates are increased in mice and humans with atherosclerosis. Mathematical analysis demonstrates that increased stem cell proliferation expedites somatic evolution and expansion of clones with driver mutations. The experimentally determined division rate elevation in atherosclerosis patients is sufficient to produce a 3.5-fold increased risk of clonal hematopoiesis by age 70. We confirm the accuracy of our theoretical framework in mouse models of atherosclerosis and sleep fragmentation by showing that expansion of competitively transplanted Tet2-/- cells is accelerated under conditions of chronically elevated hematopoietic activity. Hence, increased hematopoietic stem cell proliferation is an important factor contributing to the association between cardiovascular disease and clonal hematopoiesis.
Piperlongumine Reduces Aortic Calcification in Mice
https://www.fightagi...cation-in-mice/
Piperlongumine, an extract of long peppers, was shown to be senolytic a few years ago. The compound is capable of selectively destroying senescent cells by sensitizing them to oxidative damage, provoking apoptosis. The accumulation of senescent cells is one of the causes of aging, and means of clearance are thus potentially valuable. For those considering introducing more long peppers into their diet, note that a senolytic dose of piperlongumine would require ingesting an impossibly large weight of pepper. Just a few peppers will do absolutely nothing, as they contain far too little piperlongumine individually to make any difference.
Interestingly, this discovery doesn't appear to have made its way all that far into that part of the research community that works with piperlongumine on a regular basis. I keep seeing papers in which scientists report on the evaluation of piperlongumine as a treatment for an age-related condition that is known to be caused in part by cellular senescence, in which there is no mention of senescent cells. It is odd.
Today's open access paper is an example of the type, in which piperlongumine is deployed to treat aortic calcification, a cause of vascular stiffness, hypertension, and consequent cardiovascular disease. There is good evidence for senescent cells to contribute to this process via their secretions, inflammatory signaling that causes cells in blood vessel walls to begin to behave as though they are in bone tissue, depositing calcium into the extracellular matrix. Not that you would learn that from this paper, which focuses instead on the downstream changes that take place in these misbehaving blood vessel cells.
Piperlongumine Attenuates High Calcium/Phosphate-Induced Arterial Calcification by Preserving P53/PTEN Signaling
Vascular calcification is a complex disease that can occur in large and small blood vessels throughout the body. The main feature of vascular calcification is the deposition of calcium-containing complexes along the blood vessel wall. These deposits are mainly composed of calcium and phosphate minerals in the form of hydroxyapatite crystals, which are similar to those in bone tissue. Vascular calcification is now recognized as an active biological process that shares many features with physiological bone formation. There are many causes of vascular calcification, including diabetic angiopathy, chronic kidney disease, lipid metabolism disorders, and genetic factors. Currently, no theory completely explains the pathogenesis of vascular calcification, and no specific treatment methods for vascular calcification are preferred. Therefore, the search for effective treatment methods for vascular calcification is of great significance for the future protection of human cardiovascular health.
Vascular smooth muscle cells (VSMCs) are thought to constitute the main cell type in vascular calcification. In calcified blood vessels, VSMCs show osteogenic differentiation, that is, transformation from a contractile phenotype to a bone/cartilage mineralized phenotype, which is characterized by the development of calcified vesicles, downregulation of mineralization-inhibiting molecules, and increased calcified matrix. This transformation is accompanied by loss of the smooth muscle cell marker smooth muscle 22 alpha (SM22α) and increase in osteochondrocyte markers, including runt-related transcription factor 2 (Runx2), bone morphogenetic protein 2 (Bmp2), osteopontin (OPN), osteocalcin, and alkaline phosphatase (ALP). Overexpression of Bmp2 in vascular smooth muscle cells increases the level of calcification, and Bmp2 expression is increased in the calcified atherosclerotic plaques of blood vessels.
Piperlongumine is a cell-permeable, orally bioavailable natural product isolated from the Piper longum L. plant species. The reported pharmacological activities of PLG include anti-inflammatory, antibacterial, anti-atherosclerotic, antioxidant, antitumour, antiangiogenic and anti-diabetic activities. In this study, we determined the effect of PLG on high calcium- and phosphate-induced vascular calcification, and we further explored its potential molecular mechanisms.
In vitro, PLG inhibited calcium deposition of VSMCs treated with high calcium/phosphate medium. PLG also decreased the expression of osteogenic genes and proteins, including Runx2, Bmp2, and OPN. In a vitamin D-induced aortic calcification mouse model, a 5 mg/kg dose of PLG decreased calcium deposition in the aortic wall as well as Runx2 expression. With regard to the mechanism, we found that the levels of P53 mRNA and protein in both VSMCs and mouse aortic tissues were decreased in the calcification models, and we observed that PLG preserved the levels of P53 and its downstream gene PTEN. Concurrent treatment of VSMCs with P53 ShRNA and PLG blunted the anti-calcific effect of PLG. In conclusion, PLG attenuates high calcium/phosphate-induced vascular calcification by upregulating P53/PTEN signaling in VSMCs.
Tsimane and Moseten Hunter-Gatherers Exhibit Minimal Levels of Atrial Fibrillation
https://www.fightagi...l-fibrillation/
Epidemiological data for the Tsimane and Moseten populations in Bolivia shows that they suffer very little cardiovascular disease in later life, despite a presumably greater lifetime burden of infectious disease (and consequent inflammation) than is the case for people in wealthier regions. The differences in lifestyle are fairly straightforward: a much greater level of physical activity throughout life, and a diet that is high in fiber and low in all of the terrible things, like processed sugars, that people in the wealthier regions of the world tend to consume these days.
Atrial fibrillation is the most common arrhythmia in post-industrialized populations. Older age, hypertension, obesity, chronic inflammation, and diabetes are significant atrial fibrillation risk factors, suggesting that modern urban environments may promote atrial fibrillation. Here we assess atrial fibrillation prevalence and incidence among tropical horticulturalists of the Bolivian Amazon with high levels of physical activity, a lean diet, and minimal coronary atherosclerosis, but also high infectious disease burden and associated inflammation.
Between 2005-2019, 1314 Tsimane aged 40-94 years (52% female) and 534 Moseten Amerindians aged 40-89 years (50% female) underwent resting 12-lead electrocardiograms to assess atrial fibrillation prevalence. For atrial fibrillation incidence assessment, 1059 (81% of original sample) Tsimane and 310 Moseten (58%) underwent additional electrocardiograms. Only one (male) of 1314 Tsimane (0.076%) and one (male) of 534 Moseten (0.187%) demonstrated atrial fibrillation at baseline. There was one new (female) Tsimane case in 7395 risk years for the 1059 participants with greater than 1 electrocardiogram (incidence rate = 0.14 per 1,000 risk years). No new cases were detected among Moseten, based on 542 risk years.
Tsimane and Moseten show the lowest levels of atrial fibrillation ever reported, 1/20 to ~1/6 of rates in high-income countries. These findings provide additional evidence that a subsistence lifestyle with high levels of physical activity, and a diet low in processed carbohydrates and fat is cardioprotective, despite frequent infection-induced inflammation. Findings suggest that atrial fibrillation is a modifiable lifestyle disease rather than an inevitable feature of cardiovascular aging.
Bioactive Lipids and the Cell Membrane in Aging
https://www.fightagi...brane-in-aging/
Researchers here discuss, in some detail, what is known of age-related changes in the levels of various lipid molecules in cell membranes. There is evidence for these changes to be disruptive to cell function, and thus a meaningful contribution to age-related degeneration. Like many of the areas of interest in the study of aging, this has the look of a form of disarray that is downstream of the molecular damage that lies at the root of aging. Nonetheless, it is suggested that supplementing the levels of specific lipids, where they decline with age, may be beneficial enough to be worth the effort.
Lipids are an essential constituent of the cell membrane of which polyunsaturated fatty acids (PUFAs) are the most important component. Activation of phospholipase A2 (PLA2) induces the release of PUFAs from the cell membrane that form precursors to both pro- and ant-inflammatory bioactive lipids that participate in several cellular processes. PUFAs GLA (gamma-linolenic acid), DGLA (dihomo-GLA), AA (arachidonic acid), EPA (eicosapentaenoic acid), and DHA (docosahexaenoic acid) are derived from dietary linoleic acid (LA) and alpha-linolenic acid (ALA) by the action of desaturases whose activity declines with age. Consequently, aged cells are deficient in GLA, DGLA, AA, AA, EPA, and DHA, and their metabolites.
LA, ALA, AA, EPA and DHA can also be obtained direct from diet and their deficiency (fatty acids) may indicate malnutrition and deficiency of several minerals, trace elements, and vitamins some of which are also much needed co-factors for the normal activity of desaturases. In many instances (patients) the plasma and tissue levels of GLA, DGLA, AA, EPA, and DHA are low (as seen in patients with hypertension, type 2 diabetes mellitus) but they do not have deficiency of other nutrients. Hence, it is reasonable to consider that the deficiency of GLA, DGLA, AA, EPA, and DHA noted in these conditions are due to the decreased activity of desaturases and elongases.
PUFAs and their anti-inflammatory metabolites influence the activity of SIRT6 and other SIRTs and thus, bring about their actions on metabolism, inflammation, and genome maintenance. GLA, DGLA, AA, EPA and DHA, and prostaglandin E2 (PGE2), lipoxin A4 (LXA4) (pro- and anti-inflammatory metabolites of AA respectively) activate/suppress various SIRTs, PPAR-γ, PARP, p53, SREBP1, intracellular cAMP content, PKA activity, and PGC1-α. This implies that changes in the metabolism of bioactive lipids as a result of altered activities of desaturases, COX-2 and 5-LOX, 12-LOX, and 15-LOX (cyclo-oxygenase and lipoxygenases respectively) may have a critical role in determining cell age and development of several aging associated diseases and genomic stability and gene and oncogene activation. Thus, methods designed to maintain homeostasis of bioactive lipids (GLA, DGLA, AA, EPA, DHA, PGE2, LXA4) may arrest aging process and associated metabolic abnormalities.
Higher Cardiovascular Health Score Correlates with Lower Epigenetic Age Acceleration
https://www.fightagi...e-acceleration/
Epigenetic age acceleration is the degree to which epigenetic age is higher than chronological age. Epigenetic age is assessed via one of the epigenetic clocks, measuring the status of DNA methylation at numerous CpG sites on the genome. Some changes in DNA methylation patterns are characteristic of aging, a reaction to the accumulation of damage and dysfunction in aged tissues. People with lower epigenetic ages are, on balance, less burdened by the damage and dysfunction of aging than their peers. The caveat is that it is not yet understood what exactly causes any specific change in the patterns of DNA methylation, and thus while correlations with health and mortality risk show up quite reliably in study populations, one cannot yet draw much of a conclusion from the data for any given individual. A measurement of epigenetic age isn't yet actionable, and does little other than reinforce the general sentiment of "work to improve your health".
In 2010, the American Heart Association defined the construct of ideal cardiovascular health (CVH) as the simultaneous presence of 7 ideal health factors: healthy diet, absence of smoking, healthy body mass index (BMI), and optimal levels of physical activity, blood pressure, fasting glucose, and total cholesterol. Higher levels of CVH have been prospectively associated with greater longevity and healthy longevity, as well as markedly lower incidence of chronic diseases related to aging. Higher CVH is also associated with lower incidence of cardiovascular disease.
DNA methylation markers of aging have been aggregated into a composite epigenetic age score, which is associated with cardiovascular morbidity and mortality. However, it is unknown whether poor CVH is associated with acceleration of aging as measured by DNA methylation markers in epigenetic age. Thus we performed a cross-sectional analysis of racially/ethnically diverse post-menopausal women enrolled in the Women's Health Initiative cohort recruited between 1993 and 1998. Epigenetic age acceleration (EAA) was calculated using DNA methylation data on a subset of participants and the published Horvath and Hannum methods for intrinsic and extrinsic EAA. CVH was calculated using the AHA measures of CVH contributing to a 7-point score.
We examined the association between CVH score and EAA adjusting for self-reported race/ethnicity and education. Among the 2,170 participants analyzed, mean age was 64 (7 SD) years. Higher or more favorable CVH scores were associated with lower extrinsic EAA (6 months younger age per 1 point higher CVH score), and lower intrinsic EAA (3 months younger age per 1 point higher CVH score). This work provides initial evidence for epigenetic age acceleration to be considered as a potential early detection biomarker for CVH. Future studies are needed to evaluate if measures to promote optimal CVH through lifestyle and behavioral interventions could substantially alter an individual's epigenetic signature and the clinical utility of such a signature
Too Much of a Focus on What is Easy, Too Little on What Could Greatly Increase Lifespan
https://www.fightagi...rease-lifespan/
It is comparatively easy to build companies that sell customized mixes of various supplements shown to modestly slow aging in mice, and the same goes for companies that offer personalized advice on health matters relating to aging. Neither of these options are going to do much to meaningfully extend the healthy human life span. As participation in the longevity industry grows, it will inevitably be the case that a great many participants will gravitate towards safer businesses and returns on investment, while doing very little to change the healthy human life span. I feel that we shouldn't encourage this sort of behavior. We all have only so much time left, and we have been given the opportunity to produce actual, working rejuvenation therapies by implementing the SENS programs to repair the cell and tissue damage that causes aging. We can collectively reach for that goal, or we can collectively waste our time working on yet another round of overhyped supplements that cannot move the needle on human life span. It is a very real choice, with very real consequences.
Switzerland is now home to what claims to be the country's first longevity company builder. Maximon will start several companies each year, providing what it calls "a comprehensive set of resources that empowers founders to focus on and create superior services and products and execute at speed on a global scale." Maximon says it plans to allocate more than 50 million over the next four years and to raise a larger longevity focused fund thereafter. The company is already in the process of building its first two companies, one focused on the development of precision longevity supplements and the other on the development of a digital platform for the provision of personalised longevity advice.
"The real difference is that we really build the companies from scratch, not just incubation or early seed money. We start with ideas, form the teams, bring the people together, give them money, and everything. Founders don't have to think about fundraising, we do that here, they don't have think about finding offices, we provide workspace and equipment, the HR is done, the insurance is done, and so on. I think that we're the first ones to do this in longevity." The Maximon principals believe that this approach will benefit the start-ups to emerge from Maximon, both in terms of speed of execution, but also in terms of equity.
While the idea for getting into the longevity area had been in their minds for several years, the Maximon principals say that the coronavirus pandemic provided the time needed for the co-founders to start making things happen - starting with last October's Longevity Investors Conference. "After the success of the conference, we thought about what else we could do. We knew that we were good at building companies and identifying what you can do with certain technologies in the market, and so out of this conference, the idea was born to start a company builder." Things have moved quickly since then, and the founders have assembled an initial 6 million to get things started with the first two companies in the Maximon family. After raising the rest of the 50 million or more, Maximon will be in a position to support the creation of eight to 10 new companies over the next few years.
CAR-T Therapy Continues to Perform Well for Patients Unresponsive to Chemotherapy
https://www.fightagi...o-chemotherapy/
CAR-T immunotherapy involves equipping T cells extracted from a patient with a chimeric antigen receptor (CAR), expanding them in culture, and then reintroducing these genetically engineered T cells into the patient. The artificial receptor allows the T cells to aggressively respond to the patient's cancer, as it is targeted to a cell surface feature that is characteristic of cancer cells. Different cancers have different features, and thus different CARs are used. CAR-T therapies were first trialed for blood cancers, and continue to do well on this front, as noted here.
A CAR T-cell therapy has generated deep, sustained remissions in patients who had relapsed from several previous therapies, an international clinical trial has found. The trial leaders report that almost 75% of the participants responded to the therapy, known as idecabtagene vicleucel (ide-cel), and one-third of them had a complete response, or disappearance of all signs of their cancer. These rates, and the duration of the responses, are significantly better than those produced by currently available therapies for patients with multiple relapses.
Multiple myeloma is a cancer of plasma cells, which are white blood cells responsible for making antibodies against invasive germs. Standard treatment for myeloma includes three main classes of therapy: immunomodulatory drugs, proteasome inhibitors (which block the action of protein-degrading structures in cells), and anti-CD38 antibodies. Patients who exhaust these approaches are in urgent need of better treatments. Like all CAR T-cell therapies, ide-cel is made by collecting a patient's T cells and genetically modifying them to express a receptor for a protein on cancer cells. Infused back into the patient, the CAR T cells lock onto tumor cells and destroy them.
The target of ide-cel is a protein on myeloma cells called B-cell maturation antigen, or BCMA. BCMA has several advantages as a therapeutic target in myeloma: It is expressed exclusively on plasma cells and in particularly large quantities on plasma-turned-myeloma cells; BCMA conducts signals important for myeloma growth and survival; and it is expressed in virtually all patients with the disease.
In the trial, 128 patients with active myeloma after receiving at least three previous therapies were treated with a single dose of ide-cel (different doses were tested in different patients). At a median follow-up of 13.3 months, 73% of the patients had a response - a measurable reduction in their cancer - and 33% had a complete response or better. Within this latter group, 79% had no detectable myeloma. The median progression-free survival - the length of time after treatment that the disease didn't worsen - was 8-9 months. Some of the patients have not relapsed more than two years after treatment.
A Popular Science View of Mitochondrial Uncoupling
https://www.fightagi...ial-uncoupling/
Mitochondrial uncoupling diverts the output of the electron transport chain into heat rather than the production of ATP. Induction of higher than usual levels of uncoupling is a calorie restriction mimetic strategy: it produces some of the same gains in health and longevity as the practice of calorie restriction, with some overlap in the processes affected and metabolic changes produced. Historically, the only available pharmacological approach to increased uncoupling, 2,4-dinitrophenol (DNP), has been regarded, correctly, as dangerous. Take a little too much and you will die, because your mitochondria generate enough heat to raise your body temperature to a lethal level. In recent years some progress has been made in finding safe ways to achieve the goal of mild, self-limiting mitochondrial uncoupling, but it is a little early to say how well these will fare as therapies.
In the past few years, there's been something of a renaissance in the mitochondrial uncoupling space. In 2019, the FDA gave Mitochon Pharmaceuticals permission to test DNP as a treatment for Huntington's disease. Mitochondrial energy production generates various toxic byproducts which make neurological diseases worse, and making the mitochondria less efficient might produce fewer of them. They suggest they might have some way of giving it as a prodrug with fewer side effects, but pharma companies are always saying this sort of thing.
Last year, an Australian team published a paper about a new mitochondrial uncoupler, BAM-15. They claim it's non-toxic, doesn't explode, and doesn't increase body temperature (all uncouplers produce heat, but the body has a certain capacity to adjust for that, and if the heat produced is below the body's adjustment capacity there's no fever). Everyone involved works for Continuum Biosciences, an ambitious-looking biotech startup including anti-aging expert David Sinclair, so I'm sure they're not missing the implications. But I haven't seen any clear signs of where they're going with this.
Closer to home, a team from UCSF recently figured out the specifics of natural mitochondrial uncoupling. All mitochondria contain certain uncoupling proteins - think of them as doors, in contrast to 2,4-DNP punching holes in the wall - for generating heat. These are well-understood in brown fat, a special kind of fat used to maintain body temperature, but most of the rest of the body is a mystery. The new paper suggests that uncoupling in other cells is orchestrated by the mitochondrial ADP/ATP carrier, a protein which helps shuffle the "depleted cellular battery" ADP into the mitochondria and the "recharged cellular battery" ATP out of it. At the same time, it lets a few protons escape the positively-charged side, uncoupling the mitochondrion a little bit. Depending on the relative level of ADP on either side, it might let more or fewer protons through. This forms a feedback loop that raises or lowers the level of uncoupling depending on the level of ATP in the cell.
This is a natural biological process - it's part of how your body generates heat. It seems pretty safe - if there's too little ATP, the feedback loop kicks in and closes the doors. A drug that modified this process could potentially replicate the fat-burning properties of DNP without its side effects. And if they targeted it to be a little less intense than DNP, it wouldn't be able to reach the point where it caused deadly fevers either. This group also hasn't missed the implications - they've started Equator Therapeutics, a biotech company focused on developing drugs to hit this target.
Age-Associated B Cells Contribute to Autoimmunity and Chronic Inflammation
https://www.fightagi...c-inflammation/
The immune system becomes disordered and dysfunctional with age in numerous different ways. The B cell component accumulates inflammatory and problematic cells that are known as age-associated B cells. Here, researchers show that these errant B cells produce antibodies that provoke autoimmunity. B cell aging is a problem with a solution demonstrated in animal models: just destroy all B cells. Mammals can get by without B cells for at least a short period of time, and the B cell population regenerates quite rapidly following clearance even in later life. The newly replaced B cells do not exhibit the problems of their destroyed predecessors, improving immune function as a result. There is still too little movement when it comes to adapting this approach for human medicine, alas.
Aging is associated with increased intrinsic B cell inflammation, decreased protective antibody responses and increased autoimmune antibody responses. The effects of aging on the metabolic phenotype of B cells and on the metabolic programs that lead to the secretion of protective versus autoimmune antibodies are not known. In this paper we evaluated the metabolic profile of B cells isolated from the spleens of young and old mice, with the aim to identify metabolic pathways associated with intrinsic B cell inflammation and with the secretion of autoimmune antibodies.
We focused on the secretion of autoimmune antibodies because our recent human B cell results have shown that higher intrinsic inflammation in unstimulated B cells from elderly individuals induces a "pre-activation" status associated with the secretion of IgG antibodies with autoimmune specificities, similar to what has been observed in autoimmune diseases. In order to identify the B cell subsets driving the phenotype and function of B cells in the splenic B cell pool of old mice, we sorted the major splenic B cell subsets, Follicular (FO) B cells and Age-associated B cells (ABCs).
Results have shown that ABCs are the cells driving the phenotype and function of B cells in the spleen of old mice. Hyper-inflammatory ABCs from old mice are also hyper-metabolic and supported by a specific metabolic profile needed not only to support intrinsic inflammation but also autoimmune antibody secretion. Our results allow the identification of a relationship between intrinsic inflammation, metabolism and autoimmune B cells, advancing our understanding of critical mechanisms leading to the generation of pathogenic B cells.
Pathogenic B cells that are hyper-inflammatory and secrete autoimmune antibodies can also induce pro-inflammatory T cells in both mice and humans, and it has been shown that immunotherapy of autoimmune (rheumatoid arthritis) patients with anti-CD20 antibody not only specifically depletes B cells, but also blocks glucose uptake and usage in T cells and impairs the differentiation of pathogenic T cells, leading to an improved health condition.
FOXO1 Influences Proteosomal Function via Regulation of the Expression of a Proteasome Subunit
https://www.fightagi...easome-subunit/
The proteasome is a complex structure in the cell that is responsible for breaking down unwanted proteins. Like other recycling processes, proteasomal function is connected to life span in short-lived species. Better cell maintenance in response to stress and damage improves cell function, organ function, and longevity. The proteasome is made up of many different proteins, produced in the cell at difference rates. The least produced proteins are rate-limiting for proteasomal activity, and researchers have shown that boosting production of some of the proteasome subunit proteins can improve proteasomal function and increase life span in flies and nematodes. In the work here, researchers suggest that the transcription factor FOXO1, known to influence life span, works at least in part through this mechanism: it may either influence proteasomal function by determining the number of subunit protein molecules that are available for use in the cell.
Proteostasis collapses during aging resulting, among other things, in the accumulation of damaged and aggregated proteins. The proteasome is the main cellular proteolytic system and plays a fundamental role in the maintenance of protein homeostasis. Our previous work has demonstrated that senescence and aging are related to a decline in proteasome content and activities, while its activation extends lifespan in vitro and in vivo in various species. In addition, pharmacological or genetic induction of the proteasome alleviates the pathological phenotype of protein aggregation-related diseases, such as Alzheimer's disease. Here, we demonstrate that the Forkhead box-O1 (FoxO1) transcription factor directly regulates the expression of the 20S proteasome catalytic subunit β5 and, hence, proteasome activity.
The 20S core proteasome has barrel-like configuration and is comprised by seven different α subunits and seven distinct β subunits. Three β subunits, namely β1, β2, and β5, possess proteolytic activities with different substrate specificities. We have shown that human mesenchymal stem cells (hMSCs) exhibit a senescence-related decline of proteasome content and aberrations in physiological assembly of proteasome complexes during prolonged in vitro expansion, while proteasome activation via overexpression of the catalytic β5 subunit can enhance their stemness and lifespan.
We demonstrate that knockout of FoxO1, but not of FoxO3, in mice severely impairs proteasome activity in several tissues, while depletion of IRS1 enhances proteasome function. Importantly, we show that FoxO1 directly binds on the promoter region of the rate-limiting catalytic β5 proteasome subunit to regulate its expression. In summary, this study reveals the direct role of FoxO factors in the regulation of proteasome function and provides new insight into how FoxOs affect proteostasis and, in turn, longevity.
Age-Related Vision Impairment Correlates with Mortality
https://www.fightagi...with-mortality/
Researchers here note an association between vision impairment and mortality in later life. This has the look of a correlation that exists because aging is a global process at work throughout the body. It stems from the accumulation of a few classes of cell and tissue damage. That damage causes downstream consequences that spread out into a complex, diverse array of degeneration and diseases. If vision is failing more rapidly in any given individual, then the odds are very good that this is also the case for other, more critical systems in the body.
For this systematic review and meta-analysis, we searched for prospective and retrospective cohort studies that measured the association between vision impairment and all-cause mortality in people aged 40 years or older who were followed up for 1 year or more. In a protocol amendment, we also included randomised controlled trials that met the same criteria as for cohort studies, in which the association between visual impairment and mortality was independent of the study intervention. Our searches identified 3845 articles, of which 28 studies, representing 30 cohorts (446,088 participants) from 12 countries, were included in the systematic review.
There was variability in the methods used to assess and report vision impairment. Pooled hazard ratios for all-cause mortality were 1.29 for visual acuity <6/12 versus ≥6/12; 1.43 for visual acuity <6/18 versus ≥6/18; 1.89 for visual acuity <6/60 versus ≥6/18; and 1.02 for visual acuity <6/60 versus ≥6/60. Effect sizes were greater for studies that used best-corrected visual acuity compared with those that used presenting visual acuity as the vision assessment method, but the effect sizes did not vary in terms of risk of bias, study design, or participant-level factors (ie, age). We judged the evidence to be of moderate certainty.
The hazard for all-cause mortality was higher in people with vision impairment compared with those that had normal vision or mild vision impairment, and the magnitude of this effect increased with more severe vision impairment. These findings have implications for promoting healthy longevity.
An Approach to Allow Much Faster Bioprinting of Tissue
https://www.fightagi...ting-of-tissue/
Now that some groups, such as Volumetric, are working on ways to print tissue with blood vessel networks, ways to more efficiently bioprint larger volumes of tissue will be necessary. Costs must come down in order for the technologies to spread and evolve more rapidly. The road to bioprinting of entire replacement organs lies ahead, given (a) a robust solution for the production of tissues containing small-scale blood vessels, and (b) bioprinters that can turn out tissues reliably and rapidly.
It looks like science fiction: A machine dips into a shallow vat of translucent yellow goo and pulls out what becomes a life-sized hand. But the seven-second video, which is sped-up from 19 minutes, is real. The hand, which would take six hours to create using conventional 3D printing methods, demonstrates what engineers say is progress toward 3D-printed human tissue and organs - biotechnology that could eventually save countless lives lost due to the shortage of donor organs. "The technology we've developed is 10-50 times faster than the industry standard, and it works with large sample sizes that have been very difficult to achieve previously."
It centers on a 3D printing method called stereolithography and jelly-like materials known as hydrogels, which are used to create scaffolds in tissue engineering. The latter application is particularly useful in 3D printing, and it's something the research team spent a major part of its effort optimizing to achieve its incredibly fast and accurate 3D printing technique. "Our method allows for the rapid printing of centimeter-sized hydrogel models. It significantly reduces part deformation and cellular injuries caused by the prolonged exposure to the environmental stresses you commonly see in conventional 3D printing methods." Researchers say the method is particularly suitable for printing cells with embedded blood vessel networks, a nascent technology expected to be a central part of the production of 3D-printed human tissue and organs.
View the full article at FightAging
