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- Stress Resistance Pathways and Natural Variation in Human Longevity
- An Overview of the Clinical Data for DNA Methylation Based Aging Clocks
- Is CETP Contributing to More Than Just Atherosclerosis?
- Senescent Cells in the Liver Induce Senescence Elsewhere in the Body
- ATF3 Upregulation as a Basis for Restoration of Function in Aged Skin
- Exercise Reduces Risk of Atrial Fibrillation
- TYK2 Inhibition as a Basis for Treating Tauopathies Such as Alzheimer's Disease
- In Search of Ways to Selectively Inhibit Tumor Infiltrating Regulatory T Cells
- Exercise Produces Short Term Cognitive Benefits in Middle Age
- Considering the Sex-Frailty Paradox
- High Mobility Group Proteins in Cellular Senescence
- The Challenges of Assessing Mitophagy, or Indeed Any Form of Autophagy
- Atherosclerotic Plaque Reduction in Mice via Itaconate Delivered into Immune Cells
- Reviewing Evidence from Clinical Trials for the Role of the Gut Microbiome in Disease
- Correlating Time Spent Sedentary with Cardiovascular Disease Risk
Stress Resistance Pathways and Natural Variation in Human Longevity
https://www.fightaging.org/archives/2024/11/stress-resistance-pathways-and-natural-variation-in-human-longevity/
Cells have evolved a variety of ways to compensate for stress-inducing circumstance, such as heat, cold, low nutrient availability, mutational damage caused by toxins, and so forth. Perhaps the most studied of these mechanisms is autophagy, which recycles damaged cell components into raw materials. A cell structure is flagged, then engulfed by a membrane called an autophagosome, which is then transported to a lysosome, where it deposits its contents to be broken down by enzymes. It is clear from many lines of research that increased autophagy slows the progression of aging, most likely by removing more of the molecular damage that contributes to dysfunction.
Autophagy is far from the only stress resistance mechanism that operates in cells. Others focused on recycling of damaged proteins such as the ubiquitin-proteasome system and unfolded protein response are also influential on the pace of aging. So in humans, can one trace variants in gene sequence and gene expression to correlate performance of these stress resistance systems with longevity? That is the topic of today's open access paper, in which the researchers compare associations with stress resistance system performance and longevity in human data.
Biology of Healthy Aging: Biological Hallmarks of Stress Resistance Related and Unrelated to Longevity in Humans
Stress resistance is highly associated with longer and healthier lifespans in various model organisms, including nematodes, fruit flies, and mice. However, we lack a complete understanding of stress resistance in humans; therefore, we investigated how stress resistance and longevity are interlinked in humans. Using more than 180 databases, we identified 541 human genes associated with stress resistance. The curated gene set is highly enriched with genes involved in the cellular response to stress. The Reactome analysis identified 398 biological pathways, narrowed down to 172 pathways using a medium threshold. We further summarized these pathways into 14 pathway categories, e.g., cellular response to stimuli/stress, DNA repair, gene expression, and immune system.
There were overlapping categories between stress resistance and longevity, including gene expression, signal transduction, immune system, and cellular responses to stimuli/stress. The categories include the PIP3-AKT-FOXO and mTOR pathways, known to specify lifespans in the model systems. They also include the accelerated aging syndrome genes (WRN and HGPS/LMNA), while the genes were also involved in non-overlapped categories. Notably, nuclear pore proteins are enriched among the stress-resistance pathways and overlap with diverse metabolic pathways.
This study fills the knowledge gap in humans, suggesting that stress resistance is closely linked to longevity pathways but not entirely identical. While most longevity categories intersect with stress-resistance categories, some do not, particularly those related to cell proliferation and beta-cell development. We also note inconsistencies in pathway terminologies with aging hallmarks reported previously, and propose them to be more unified and integral.
An Overview of the Clinical Data for DNA Methylation Based Aging Clocks
https://www.fightaging.org/archives/2024/11/an-overview-of-the-clinical-data-for-dna-methylation-based-aging-clocks/
Cellular biochemistry changes in characteristic ways with age. Aging is a stochastic process of damage accumulation, followed by diverse consequences, but there are considerable similarities under the hood for all that the final dysfunctions are so varied and individual. An intricate iron structure left unprotected in the rain will collapse in any one of a hundred different ways, but underlying all of those possible breakages is the one common process of rust. Thus any sufficiently large body of data derived from individuals of various ages, whether omics or clinical chemistry or functional tests, can be used to produce algorithm combinations of values that reflect biological age. These algorithms are known as aging clocks.
The first, and still most widely used clocks are based on epigenetic data. Specifically they make use of the methylation status of CpG sites on the genome, decorations to nuclear DNA that change its structure to expose or hide specific regions, and thus change patterns of gene expression - which proteins are produced, and in what amount. A cell is in constant feedback with itself and its environment, DNA methylation constantly changing. But some of those changes are characteristic of damage and damaged environment of aged tissues.
The challenge with DNA methylation clocks, or any other aging clock, lies in understanding how the measurements made connect to underlying processes of aging and age-related diseases. Since the clocks are produced by machine learning approaches operating on data, that understanding doesn't exist yet. It is hard to take a clock measurement at face value without either knowing how its data relates to mechanisms of aging, or without a great deal of validation using real world data. It seems plausible that the real world validation approach will beat out the slow path to sufficient understanding, at least when it comes to justifying the use of some forms of aging clock for some forms of intervention in the matter of aging.
As today's open access paper notes, DNA methylation clocks have been used in a fair number of clinical trials for interventions that might be expected to modestly adjust the pace of aging or state of aging. There is enough data to start talking about when and how we should trust these DNA methylation clock measures. Nonetheless, this is still only the first step along a much longer road. In a world in which people continue to debate the conclusions of extensive clinical data for common therapies decades after their introduction - consider aspirin use for example - rapid consensus should not be the expected outcome for any tool or treatments.
DNAm aging biomarkers are responsive: Insights from 51 longevity interventional studies in humans
Aging biomarkers can potentially allow researchers to rapidly monitor the impact of an aging intervention, without the need for decade-spanning trials, by acting as surrogate endpoints. Prior to testing whether aging biomarkers may be useful as surrogate endpoints, it is first necessary to determine whether they are responsive to interventions that target aging. Epigenetic clocks are aging biomarkers based on DNA methylation (DNAm) with prognostic value for many aging outcomes. Many individual studies are beginning to explore whether epigenetic clocks are responsive to interventions. However, the diversity of both interventions and epigenetic clocks in different studies make them difficult to compare systematically.
Here, we curate TranslAGE-Response, a harmonized database of 51 public and private longitudinal interventional studies and calculate a consistent set of 16 prominent epigenetic clocks for each study, along with 95 other DNAm biomarkers that help explain changes in each clock. With this database, we discover patterns of responsiveness across a variety of interventions and DNAm biomarkers. For example, clocks trained to predict mortality or pace of aging have the strongest response across all interventions and show consistent agreement with each other, pharmacological and lifestyle interventions drive the strongest response from DNAm biomarkers, and study population and study duration are key factors in driving responsiveness of DNAm biomarkers in an intervention. Some classes of interventions such as TNF-alpha inhibitors have strong, consistent effects across multiple studies, while others such as senolytic drugs have inconsistent effects. Clocks with multiple sub-scores (i.e. "explainable clocks") provide specificity and greater mechanistic insight into responsiveness of interventions than single-score clocks.
Our work can help the geroscience field design future clinical trials, by guiding the choice of interventions, specific subsets of epigenetic clocks to minimize multiple testing, study duration, study population, and sample size, with the eventual aim of determining whether epigenetic clocks can be used as surrogate endpoints.
Is CETP Contributing to More Than Just Atherosclerosis?
https://www.fightaging.org/archives/2024/11/is-cetp-contributing-to-more-than-just-atherosclerosis/
If you are familiar with research into those parts of lipid metabolism presently considered relevant to the development of atherosclerosis, near entirely focused on the mechanisms by which cholesterol is transported around the body in the bloodstream, then you will know that the CETP protein is considered a target for therapies. This is due to (a) its role in transferring cholesterol between transport particles such as high density lipoprotein (HDL) and low-density lipoprotein (LDL), and (b) suggestive data for gene variants to affect risk of cardiovascular disease.
LDL particles carry cholesterol outwards from the liver into the arteries where atherosclerotic plaques form. HDL particles carry cholesterol back to the liver from the rest of the body. Present therapies aimed at reducing the amount of LDL-cholesterol, such as statins and PCSK9 inhibitors, have their origins in the discovery of human mutants with lower LDL-cholesterol and lower lifetime cardiovascular risk. In practice, the resulting drugs produce only modest benefits, failing to reverse atherosclerosis even when greatly reducing LDL-cholesterol, and only reducing risk of heart attack and stroke by at most 20%, if we are being generous in our interpretation of the data. Similarly, attempts to enhance HDL transport to drain cholesterol from arteries have met with failure.
Today's open access paper is an interesting look at one slice of all of this biochemistry, focused on CETP and whether or not it is a target worth pursuing. The development of many ways to achieve small gains derived from evidence for influence of one gene or another on cholesterol transport has perhaps made some people a little hesitant to jump on yet another similar gene and similar attempt. Yet one can line up a bunch of evidence to suggest that targeting CETP will achieve some benefits, not just for cardiovascular disease, and funding has been found for clinical trials of CETP-targeted therapies.
Cholesteryl ester transfer protein inhibition: a pathway to reducing risk of morbidity and promoting longevity
Cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein that is a member of the lipid transfer protein family. It facilitates the bidirectional exchange of cholesteryl esters and triglycerides among lipoprotein particles leading to a net mass transfer of cholesteryl esters from high-density lipoprotein (HDL) to low-density lipoprotein (LDL) and very low-density lipoprotein (VLDL) particles. In addition, triglycerides are transferred in the opposite direction from LDL and VLDL to HDL.
Interest in CETP inhibition as a therapeutic target began with the discovery in observational studies that some CETP gene polymorphisms were associated with reduced coronary heart disease (CHD) incidence and CHD mortality, although these results have not been entirely consistent. However, taking all evidence into consideration, observational studies, Mendelian randomization (MR) analyses, and randomized clinical trials of pharmaceutical agents indicate that CETP inhibition confers cardiovascular benefit and reduces risk of atherosclerotic cardiovascular disease (ASCVD). Additionally, emerging evidence suggests that CETP inhibition may promote longevity, presumably by lowering the risk of several conditions associated with aging such as new-onset type 2 diabetes mellitus (T2D), dementia, chronic kidney disease (CKD), and age-related macular degeneration (AMD), as well as promoting survival in septicemia. Some of these effects are likely mediated through improved functionality of the HDL particle, including its role on cholesterol efflux and antioxidative, anti-inflammatory, and antimicrobial activities.
At present, there is robust clinical evidence to support the benefits of reducing CETP activity for ASCVD risk reduction, and plausibility exists for the promotion of longevity by reducing risks of several other conditions. An ongoing large clinical trial program of the latest potent CETP inhibitor, obicetrapib, is expected to provide further insight into CETP inhibition as a therapeutic target for these various conditions.
Senescent Cells in the Liver Induce Senescence Elsewhere in the Body
https://www.fightaging.org/archives/2024/11/senescent-cells-in-the-liver-induce-senescence-elsewhere-in-the-body/
Cells become senescent constantly throughout life, in response to damage, stress, injury, or simply reaching the Hayflick limit on replication. In youth the immune system promptly removes this cells, but with age this clearance becomes inefficient, allowing senescent cells to accumulate. When senescent, a cell ceases to replicate and devotes its energies to the secretion of a mix of pro-growth, pro-inflammatory signals, the senescence-associated secretory phenotype (SASP). This is useful in the short term context of coordinating recovery from injury or drawing the immune system to destroy potentially cancerous cells, but becomes harmful when sustained. It is disruptive to tissue structure and function, a contribution to the chronic inflammation of aging.
Worse, and as noted in today's open access paper, the SASP provokes a greater incidence of senescence in distant cells. The more senescent cells in any one location, the more likely it is that cells elsewhere in the body will become senescent in response to stresses. Cellular senescence may be one of the more important mechanisms linking the age-related decline of function in any one organ with the age-related decline in function of other organs. The authors of this paper focus on the liver, but the point could just as well be made of the kidney, or visceral fat deposits, or other internal organs.
Hepatocellular senescence induces multi-organ senescence and dysfunction via TGFβ
The SASP is a central mediator of the non-autonomous effects of senescent cells. Here, we demonstrate that senescence can be transmitted to and affect the function of distant organs in a systemic manner. In the context of acute injury, senescence has often been described as part of a finely tuned mechanism with overall beneficial effects for wound healing. SASP factors have been shown to induce reprogramming in neighbouring cells, facilitating tissue regeneration. However, following severe injury, this mechanism may have the opposite effect, systemically, through excessive SASP production, including senescence itself. In turn, this excessive stimulus for senescence can be associated with compromised organ function.
Systemic transmission of senescence may be relevant to several diseases. Here, we use a series of models of hepatocyte-specific senescence to model an acute senescence phenotype, such as the one observed during acute liver failure. Acute liver failure is, itself, characterized by sequential multi-organ failure, typically beginning with the kidney progressing to also involve the brain, lungs, and other organs. This clinical progression may, at least in part, be underpinned by the systemic transmission of senescence. The data in patients with acute indeterminate hepatitis, showing that increased hepatocellular expression of p21 at initial presentation before multi-organ failure can predict ensuing multi-organ failure, requirement for liver transplant and/or death, provide evidence for a biomarker that both allows early risk stratification and selection of patients for specific therapies.
Similarly, the observation that TGFβ signalling is a central driver of systemic transmission of senescence may pave the way for therapeutic approaches in diseases where this phenomenon occurs. Whilst this effect may either be independent of solely p21-dependent senescence or a phenomenon related to TGFβ activity outside of senescence, it is in line with the beneficial effects of senolytics and senomorphics that have been elegantly demonstrated on numerous pathologies. Further research is required to dissect out the direct causal link between senescence in the primary tissue and the systemic effects and how they are affected by factors such as disease site or specific senescence phenotype, chronicity of senescence, and the interaction with concurrent or pre-existing senescence in other organs. Our results demonstrate that systemic transmission of senescence can induce systemic organ dysfunction, which may be central to multi-systemic sequelae in many diseases.
ATF3 Upregulation as a Basis for Restoration of Function in Aged Skin
https://www.fightaging.org/archives/2024/11/atf3-upregulation-as-a-basis-for-restoration-of-function-in-aged-skin/
To what degree should we be enthused by programs aiming to adjust expression of genes in cells to restore function in aged tissues? Evidence from recent years is suggestive that patterns of change in gene expression arise as a consequence of repeated repair of nuclear DNA damage, even if that damage itself is harmless to the cell. Adjusting those changes in gene expression therefore seems something close to rejuvenation. To the degree that harmful changes in gene expression instead arise from maladaptive reactions to damage, it may be that there is less to gain from trying to force a more youthful pattern of gene expression - the underlying damage remains, causing whatever other issues it causes.
Any given transcription factor regulates the expression of many other genes, and thus it has been suggested that one should focus on changes in transcription factor expression as a starting point in any attempt to understand the shifting landscape of gene expression in aging. It is plausible that more of gain could be achieved on a gene by gene basis by restoring youthful transcription factor expression than by focusing on other genes. In today's open access paper, researchers focus on skin aging and identify a transcription factor that can be upregulated to restore some of the function lost in aged skin. Of note, they conducted studies in human skin samples and skin models and skin cells; I'd be happier seeing a mouse study in addition to this work, assuming the biochemistry is similar.
Human skin rejuvenation via mRNA
Aging is characterized by a gradual decline in function, partly due to accumulated molecular damage. Human skin undergoes both chronological aging and environmental degradation, particularly UV-induced photoaging. Detrimental structural and physiological changes caused by aging include epidermal thinning due to stem cell depletion and dermal atrophy associated with decreased collagen production. Here, we present a comprehensive single-cell atlas of skin aging, analyzing samples from young, middle-aged, and elderly individuals, including both sun-exposed and sun-protected areas. This atlas reveals age-related cellular composition and function changes across various skin cell types, including epidermal stem cells, fibroblasts, hair follicles, and endothelial cells.
Using our atlas, we have identified basal stem cells as a highly variable population across aging, more so than other skin cell populations such as fibroblasts. In basal stem cells, we identified ATF3 as a novel regulator of skin aging. ATF3 is a transcriptional factor for genes involved in the aging process, with its expression reduced by 20% during aging. Based on this discovery, we have developed an innovative mRNA-based treatment to mitigate the effects of skin aging. Cell senescence decreased 25% in skin cells treated with ATF3 mRNA, and we observed an over 20% increase in proliferation in treated basal stem cells. Importantly, we also found crosstalk between keratinocytes and fibroblasts as a critical component of therapeutic interventions, with ATF3 rescue of basal cells significantly enhancing fibroblast collagen production by approximately 200%.
We conclude that ATF3-targeted mRNA treatment effectively reverses the effects of skin aging by modulating specific cellular mechanisms, offering a novel, targeted approach to human skin rejuvenation.
Exercise Reduces Risk of Atrial Fibrillation
https://www.fightaging.org/archives/2024/11/exercise-reduces-risk-of-atrial-fibrillation/
Hunter-gatherer populations in which fairly high levels of exercise are the norm have excellent heart health in later life in comparison to more sedentary first world populations. Hunter-gatherers exhibit very little atrial fibrillation, for example. So it isn't all that surprising to see that greater levels of exercise in those first world populations correlate with reduced incidence of atrial fibrillation, one more item in the long list of reasons to undertake more rather than less physical activity.
Researchers focused on atrial fibrillation, a condition in which the heart's upper two chambers beat rapidly and irregularly instead of at a consistent pace. If left untreated, this can lead to stroke, heart failure, and other issues. While past studies have linked exercise to reduced risk of this type of arrhythmia, nearly all of these analyses have relied on participants' often inaccurate estimates of their own activity levels. The current study used data recorded from the fitness tracker Fitbit to objectively measure physical activity in more than 6,000 men and women across the United States. The results showed that those with higher amounts of weekly physical activity were less likely to develop atrial fibrillation. Notably, even modest amounts of moderate to vigorous exercise, which can range from taking a brisk walk or cleaning the house to swimming laps or jogging, were associated with reduced risk.
Specifically, study participants who averaged between 2.5 and 5 hours per week, the minimum amount recommended by the American Heart Association, showed a 60 percent lower risk of developing atrial fibrillation. Those who averaged greater than 5 hours had a slightly greater (65 percent) reduction. In the sole earlier study that used activity monitors to investigate atrial fibrillation, researchers provided Fitbit-style monitors to the participants and tracked them for only a week, an approach that may not have accurately captured their normal workout habits. The new investigation assessed participants for a full year and included only those who already owned the devices.
TYK2 Inhibition as a Basis for Treating Tauopathies Such as Alzheimer's Disease
https://www.fightaging.org/archives/2024/11/tyk2-inhibition-as-a-basis-for-treating-tauopathies-such-as-alzheimers-disease/
Alzheimer's disease progresses through stages. The well known, slow accumulation of misfolded amyloid-β over years is only the early foundation of the condition, in and of itself producing little more than mild cognitive impairment. Amyloid-β, however, enables the onset of a state of chronic inflammation and tau protein aggregation that feeds upon itself and grows in severity, disrupting function and killing brain cells until it ultimately kills the patient. Researchers here find a potential target to slow or prevent the aggregation of altered tau protein in mouse models. Since these models are highly artificial, as aged mice do not normally suffer anything resembling a tauopathy, further work will be needed to demonstrate relevance to the natural human condition of Alzheimer's disease.
Over two dozen different diseases have been identified so far whose hallmark neuropathological feature is the presence of neuronal and/or glial accumulations of tau protein. Tau is a predominantly neuronal protein that binds to tubulin to promote assembly of the microtubule network that underpins intracellular transport. Its function is regulated by numerous post-translational modifications, such as phosphorylation, ubiquitination, and acetylation. In pathological states, tau protein undergoes aberrant modifications - predominantly hyperphosphorylation - then dissociates from microtubules, misfolds, propagates to neighboring cells and accumulates into intracellular neurofibrillary tangles (NFTs).
Alzheimer's disease is one of at least 26 diseases characterized by tau-positive accumulation in neurons, glia or both. However, it is still unclear what modifications cause soluble tau to transform into insoluble aggregates. We previously performed genetic screens that identified tyrosine kinase 2 (TYK2) as a candidate regulator of tau levels. Here we verified this finding and found that TYK2 phosphorylates tau at tyrosine 29 (Tyr29) leading to its stabilization and promoting its aggregation in human cells. We discovered that TYK2-mediated Tyr29 phosphorylation interferes with autophagic clearance of tau. We also show that TYK2-mediated phosphorylation of Tyr29 facilitates pathological tau accumulation in P301S tau-transgenic mice. Furthermore, knockdown of Tyk2 reduced total tau and pathogenic tau levels and rescued gliosis in a tauopathy mouse model. Collectively, these data suggest that partial inhibition of TYK2 could thus be a strategy to reduce tau levels and toxicity.
In Search of Ways to Selectively Inhibit Tumor Infiltrating Regulatory T Cells
https://www.fightaging.org/archives/2024/11/in-search-of-ways-to-selectively-inhibit-tumor-infiltrating-regulatory-t-cells/
Cancers evolve to co-opt aspects of the immune system in order to suppress the immune response to cancerous cells. All tumor tissues make use of a variety of such mechanisms. In principle, sabotaging the immune suppression produced by tumor tissue should be a basis for both novel effective cancer therapies and enhancement of existing immunotherapies for cancer. Here is an example of early stage research in this part of the field, in which researchers identify mechanisms operating in regulatory T cells in tumor tissue. The metabolism of tumor resident regulatory T cells may be sufficiently distinctive to build approaches to treatment that can inhibit regulatory T cell function to harm the tumor without also harming necessary immune function elsewhere in the body.
T cells are central to the body's defense against cancer, with one subset, regulatory T cells (Tregs), playing a unique and often contradictory role in immune response. Unlike conventional T cells that attack tumors, Tregs prevent excessive inflammation and maintain immune tolerance. While this is essential for immune balance, Tregs within tumors, known as tumor-infiltrating Tregs (TIL-Tregs), allow cancer to evade immune attacks by suppressing the activity of effector T cells - the immune cells that actively target and kill tumor cells. Although targeting Tregs to restore anti-tumor immunity is an emerging area in cancer therapy, systemically inhibiting Tregs can cause severe autoimmune reactions.
TIL-Tregs possess unique characteristics compared to Tregs in systemic circulation, maintaining heightened suppressive capabilities within the nutrient-poor conditions of the tumor microenvironment, where effector T cells often falter. While GLUT1 is the primary glucose transporter in conventional T cells, GLUT3 plays a central role in glucose metabolism in TIL-Tregs. Typically associated with neurons, GLUT3 enables TIL-Tregs to efficiently absorb glucose from the tumor microenvironemnt, supporting their suppressive activity.
GLUT3-driven glucose absorption activates a metabolic pathway leading to protein modification with uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a sugar molecule. This modification process, called O-GlcNAcylation, regulates various proteins, including the transcription factor c-Rel, which is essential for TIL-Tregs' tumor-specific properties. By facilitating O-GlcNAcylation, GLUT3 provides TIL-Tregs with a metabolic advantage that enhances immune suppression within tumors.
This research highlights that TIL-Tregs have unique metabolic adaptations. This paves the way for innovative strategies in cancer immunotherapy that focus on rebalancing immune responses while minimizing adverse effects. Targeting GLUT3 or the O-GlcNAcylation pathway could precisely manipulate Treg activity within tumors, leading to better outcomes in cancer patients.
Exercise Produces Short Term Cognitive Benefits in Middle Age
https://www.fightaging.org/archives/2024/11/exercise-produces-short-term-cognitive-benefits-in-middle-age/
The brain has evolved to operate at the edge of its capacity; the normal operation of neural tissue requires a lot of energy, derived from nutrients and oxygen provided in the blood stream. That the increased blood flow that occurs following exercise improves cognitive function in the short term is indicative that there is room for improvement in the physiological support provided by the body for the normal operation of the brain. This remains true in later life, as the data here shows.
The research team leveraged smartphone technology to interact with participants multiple times during their regular daily lives. Over the course of nine days, participants checked in six times a day, approximately every 3.5 hours. During each check-in, participants reported if they had been physically active since their last check-in. If they were active, they were asked to rate the intensity of their activity - light, moderate or vigorous. For example, walking and cleaning were considered light intensity while running, fast biking, and effortful hiking were considered vigorous intensity. Participants were then prompted to play two "brain games," one designed to assess cognitive processing speed and the other designed to assess working memory, which can be a proxy for executive function.
The team analyzed data from 204 participants who were recruited for the Multicultural Healthy Diet Study to Reduce Cognitive Decline & Alzheimer's Risk. Data was collected during the study's baseline period. Participants were between the ages of 40 and 65 and residents of the Bronx, NY who had no history of cognitive impairment. The team found that when participants reported being physically active sometime in the previous 3.5 hours, they showed improvements in processing speed equivalent to being four years younger. While there were no observed improvements in working memory, the response time during the working memory task mirrored the improvements observed for processing speed.
Additionally, people who reported being active more often experienced greater short-term benefits compared to those who reported less physical activity overall. This suggests that cognitive health benefits may increase with regular physical activity. However, more research is needed to understand how much physical activity and the frequency and timing of being active influences cognitive health.
Considering the Sex-Frailty Paradox
https://www.fightaging.org/archives/2024/11/considering-the-sex-frailty-paradox/
Generally speaking, one should expect greater disability and disease in later life to correlate with greater mortality. Yet in many mammalian species, including our own, males die younger and females exhibit greater frailty while living longer. Biology is complicated! Here, researchers single out for attention the age-related dysfunction of the immune system that leads to a growing state of unresolved, constant inflammatory signaling. This state of inflammaging is thought to differ in women versus men, and may be one of the more important contributions to the observed sex-specific differences in outcomes.
Aging is a dynamic process that requires a continuous response and adaptation to internal and external stimuli over the life course. This eventually results in people aging differently and women aging differently than men. The "gender paradox" describes how women experience greater longevity than men, although linked with higher rates of disability and poor health status. Recently, the concept of frailty has been incorporated into this paradox giving rise to the "sex-frailty paradox" which describes how women are frailer because they manifest worse health status but, at the same time, appear less susceptible to death than men of the same age. However, very little is known about the biological roots of this sex-related difference in frailty.
Inflamm-aging, the chronic low-grade inflammatory state associated with age, plays a key pathophysiological role in several age-related diseases/conditions, including Alzheimer's disease (AD), for which women have a higher lifetime risk than men. Interestingly, inflamm-aging develops at a different rate in women compared to men, with features that could play a critical role in the development of AD in women. According to this view, a continuum between aging and age-related diseases that probably lacks clear boundaries can be envisioned in which several shared biological mechanisms that progress at different pace may lead to different aging trajectories in women than in men.
High Mobility Group Proteins in Cellular Senescence
https://www.fightaging.org/archives/2024/11/high-mobility-group-proteins-in-cellular-senescence/
Senescent cells accumulate with age and cause harm via their inflammatory signaling, contributing to the chronic inflammation of aging that is disruptive to tissue structure and function throughout the body. One faction of the research and development community wants to selectively destroy senescent cells via the use of a wide variety of senolytic therapies presently under development. Another faction wants to instead find ways to suppress the inflammatory signaling of these cells. Here find an example of this second area of research, a search for targets that can be manipulated to reduce harmful signaling generated by senescent cells, but which will produce minimal side-effects in non-senescent cells.
In this review, we summarize the current research progress on non-histone high mobility group proteins (HMGs) in the field of aging, particularly their structural characteristics and functional roles in regulating the aging process. As chromatin architectural regulators, HMGs, in collaboration with histones, exert critical influence on chromatin dynamics and gene expression. By competitively binding to specific DNA sites, HMGs alter chromatin accessibility and regulate gene activity, thereby exerting profound effects at various stages of cellular senescence. This regulation involves a wide array of mechanisms and pathways, with a particularly notable impact on the senescence-associated secretory phenotype (SASP) and senescence-associated heterochromatin foci (SAHF).
HMG proteins, particularly members of the HMGA and HMGB families, play pivotal roles in the formation and regulation of SASP and SAHF. SASP comprises pro-inflammatory factors and proteins secreted during cellular senescence, which not only drive the aging process but are also closely associated with various age-related diseases, including chronic inflammation, cardiovascular diseases, and cancer. HMGA proteins promote or inhibit the spread of inflammatory signals by affecting chromatin structure and regulating the expression of SASP-related genes. Meanwhile, HMGB proteins, acting as damage-associated molecular patterns (DAMPs), activate inflammatory pathways and exacerbate the release of SASP. SAHF, as highly compacted heterochromatin regions, silence genes related to proliferation and the cell cycle, marking cells' entry into a state of permanent cell cycle arrest. The dynamic regulation of HMG proteins is crucial for the formation and maintenance of SAHF.
Recent studies have shown that targeting and blocking HMG proteins, particularly HMGB1 and HMGA2, not only reduces the release of SASP but also effectively inhibits inflammatory responses, thereby slowing the progression of age-related diseases. By inhibiting the extracellular release of HMGB1, researchers have found that sterile inflammation and tissue damage can be alleviated, protecting cardiovascular health and delaying the development of age-related cardiovascular diseases. Targeting these proteins has become a key direction in aging research. Compared to traditional therapies, targeting HMG proteins offers a more precise means of modulating age-related pathophysiological processes with fewer effects on normal cells.
The Challenges of Assessing Mitophagy, or Indeed Any Form of Autophagy
https://www.fightaging.org/archives/2024/11/the-challenges-of-assessing-mitophagy-or-indeed-any-form-of-autophagy/
Autophagy is a complex collection of processes that recycle structures in the cell. Structures are in some way identified as damaged or surplus, then engulfed in an autophagosome membrane. That autophagosome is transported to a lysosome, where it fuses with the lysosome. The cargo is then broken down into raw materials by the enzymes contained in the lysosome. Measuring autophagy is difficult. Any given approach can be interpreted in different ways. Is increased expression of one autophagy protein indicative of more efficient autophagy or indicative of a part of the process that is breaking, degrading overall efficiency? This gives rise to some debate over how autophagy changes with age, and whether the interventions thought to slow aging via improved autophagy are in fact doing so. Here, for example, researchers argue that autophagy of mitochondria, called mitophagy, doesn't in fact decline with age in brain cells.
Autophagy is a disease-relevant homeostatic quality control mechanism. While we understand how different forms of cellular stress induce specific autophagy pathways in cultured cells, our knowledge of how physiological autophagy pathways are regulated in healthy brain aging is extremely limited. Studies in short-lived model systems suggest that diminished mitophagy and autophagic capacity may sensitize certain brain cell types to degenerative processes as we age. However, the spatiotemporal modulation of mitophagy during healthy brain aging remains unclear.
Here, we establish the first dynamic landscape of mitochondrial turnover in the intact, aging mammalian brain at the single-cell level using high-resolution confocal imaging and cutting-edge reporter mice. Our findings reveal that decreased mitophagy is not a general hallmark of healthy aging in vivo but that different brain regions and neural subsets exhibit distinct mitophagy dynamics over time, usually remaining stable or even increasing throughout the mouse lifespan. By comparing different regions of the brain, including disease-associated neuronal and non-neuronal cell types, we revealed uncoupled and cell type-specific regulation of mitophagy and generalized autophagy throughout natural aging.
We found that mitophagy levels gradually increased throughout the aging process in several cell types, including cerebellar granule cells and microglia, seemingly independent of basal autophagy levels. In some cases, we observed more complex trajectories: we detected an age-dependent increase in mitophagy in the hippocampus CA1 and dentate gyrus subregions up until middle age, followed by a significant decline during old age, although not falling below those of young subjects. It will be crucial to determine whether these altered autophagy dynamics are causally linked to age-related cognitive changes observed in healthy aging. Clarifying the mechanisms driving age-dependent mitophagy dynamics in these hippocampal subregions may hold interventional relevance for memory-related pathologies such as dementia and Alzheimer's disease.
Atherosclerotic Plaque Reduction in Mice via Itaconate Delivered into Immune Cells
https://www.fightaging.org/archives/2024/11/atherosclerotic-plaque-reduction-in-mice-via-itaconate-delivered-into-immune-cells/
Researchers here find a way to reduce atherosclerotic plaque in mice by delivering an anti-inflammatory metabolite associated with low fat diets directly to immune cells in the bone marrow and plaque. It is an interesting result, though the degree to which it will be applicable to humans is a question. Mice are more resistant to plaque formation, requiring both high fat diets and mutations affecting cholesterol transport to produce sizable plaques. When switched to a low fat diet, there will be some degree of plaque regression in mice previously on a high fat diet - but that doesn't tend to happen in humans. Will dialing up the mechanisms involved in mouse plaque regression on a low fat diet perform to any great degree in humans? It may be worth a try, given that even very small degrees of plaque regression produce sizable reductions in risk of heart attack and stroke.
Laboratory animals that develop atherosclerotic plaque when fed a prolonged high-cholesterol, high-fat diet (HCHFD) demonstrate plaque resolution when they are subsequently switched to a normal low-fat diet ("dietary cessation"). Here, we studied dietary cessation in two well-known atherogenic mouse models: AроE-/- and Ldlr-/-. Using these models, we discovered that dietary cessation-driven plaque resolution is characterized by altered levels of the tricarboxylic acid (TCA) cycle metabolite itaconate (ITA), an immunomodulatory molecule, and of the ITA-synthesizing enzyme immunoresponsive gene 1 (IRG1). We also report elevated levels of IRG1 in vulnerable human carotid plaques and the absence of IRG1 in early or stable plaques.
We next tested whether exposing plaques to exogenously delivered ITA could directly achieve plaque resolution. While the ITA derivative 4-octyl itaconate (OI) has been previously shown to induce plaque resolution, current ITA derivatives are not ideal for studying or replicating the biological effects of endogenous, unconjugated ITA, which differs from its derivatives. Thus, to achieve targeted and efficient delivery of unconjugated ITA, we synthesized an ITA-based lipid nanoparticlen.wikipedia.org/wiki/Solid_lipid_nanoparticle">lipid nanoparticle, termed ITA-LNP. We demonstrate that ITA-LNPs deliver unconjugated ITA intracellularly, accumulate in myeloid cells in plaque and bone marrow, and recapitulate immunomodulatory effects that are unique to unmodified ITA. We also show that ITA-LNPs are non-toxic and elicit epigenetic changes that lead to anti-inflammatory activity in plaques and myeloid progenitor cells in bone marrow. Additionally, we report that ITA-LNPs safely stimulate plaque resolution in several murine models with and without dietary cessation, including a model of unstable, vulnerable plaque that represents highly advanced atherosclerotic cardiovascular disease.
Reviewing Evidence from Clinical Trials for the Role of the Gut Microbiome in Disease
https://www.fightaging.org/archives/2024/11/reviewing-evidence-from-clinical-trials-for-the-role-of-the-gut-microbiome-in-disease/
Many lines of evidence strongly suggest that alterations to the gut microbiome are an important contributing factor in the onset and progression of many different conditions, including age-related conditions. Comparatively few clinical trials touch on this relationship, however, despite the recent approval of a fecal microbiota transplant intervention for the treatment of Clostridioides difficile infection. That will change with time, but for now there is sufficiently little clinical trial data that a short paper can summarize it all.
Composed of an elaborate ecosystem of bacteria, fungi, viruses, and protozoa residing in the human digestive tract, the gut microbiome influences metabolism, immune modulation, bile acid homeostasis, and host defence. Through observational and preclinical data, the gut microbiome has been implicated in the pathogenesis of a spectrum of chronic diseases ranging from psychiatric to gastrointestinal in nature. Until recently, the lack of unequivocal evidence supporting a causal link between gut microbiome and human health outcomes incited controversy regarding its significance. However, recent randomised controlled trial (RCT) evidence in conditions, such as Clostridioides difficile infection, cancer immunotherapy, and ulcerative colitis, has supported a causal relationship and has underscored the potential of the microbiome as a therapeutic target.
This review delineates the RCT evidence substantiating the potential for a causal relationship between the gut microbiome and human health outcomes, the seminal observational evidence that preceded these RCTs and the remaining knowledge gaps. The association between the gut microbiome and human health has long been supported by multiple lines of observational evidence including in vitro, in vivo, and epidemiologic data. Recent RCTs of microbiome therapeutics have bridged the gap between association and causation and have definitively demonstrated that microbiome-altering therapeutics can improve human health outcomes in CDI. Further, smaller RCTs in UC and cancer immunotherapy, but not obesity, suggest the probable benefit of microbiome therapeutics across other indications as well.
Correlating Time Spent Sedentary with Cardiovascular Disease Risk
https://www.fightaging.org/archives/2024/11/correlating-time-spent-sedentary-with-cardiovascular-disease-risk/
Epidemiological data on human health doesn't lend itself to concrete interpretation. For example, the role of time spent sitting or otherwise sedentary in the development of cardiovascular disease remains debated. Some studies suggest that sedentary time contributes to risk independently of level of exercise, others suggest that recommended levels of exercise eliminate any relationship between sedentary time and risk of disease. There remain the questions of the degree to which sedentary behavior is a proxy for other contributions to long-term health such as diet and weight. This is before we even arrive at the question of biological mechanisms and their relative importance.
Insufficient exercise is a known risk factor for cardiovascular disease (CVD). Over 150 minutes of moderate-to-vigorous physical activity per week is recommended by current guidelines to promote heart health. However, study experts say exercise is only a small fraction of overall daily activity, and the current guidelines don't provide specific guidance on sedentary behavior which accounts for a much larger portion of daily activity, despite evidence that it's directly linked with CVD risk. This study examined the amount of sedentary time at which CVD risk is greatest and explored how sedentary behavior and physical activity together impact the chances of atrial fibrillation (AF), heart failure (HF), myocardial infarction (MI), and cardiovascular mortality.
Among the 89,530 study participants of the UK Biobank, the average age was 62 years and 56.4% were women. Participants submitted data from a wrist-worn triaxial accelerometer that captured movement over seven days. The average sedentary time per day was 9.4 hours. After an average follow-up of eight years, 3,638 individuals (4.9%) developed incident AF, 1,854 (2.1%) developed incident HF, 1,610 (1.84%) developed indecent MI, and 846 (0.94%) died of cardiovascular causes, respectively.
The effects of sedentary time varied by outcome. For AF and MI, the risk increased steadily over time without major shifts. For HF and CV mortality, increase in risk was minimal until sedentary time exceeded about 10.6 hours a day, at which point risk rose significantly, showing a "threshold" effect for the behavior. For study participants who met the recommended 150 minutes of moderate-to-vigorous physical activity or more, the effects of sedentary behavior on AF and MI risks were substantially reduced, but effects on higher risk of HF and cardiovascular mortality remained prominent.
View the full article at FightAging
