Fight Aging! Newsletter, December 9th 2024
Fight Aging! publishes news and commentary relevant to the goal of ending all age-related disease, to be achieved by bringing the mechanisms of aging under the control of modern medicine. This weekly newsletter is sent to thousands of interested subscribers. To subscribe or unsubscribe from the newsletter, please visit: https://www.fightaging.org/newsletter/
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- A Growing Population of Harmful Megakaryocyte Progenitors Contribute to Age-Related Thrombosis
- Sarcopenia in the Context of the Hallmarks of Aging
- How Does the Heat Shock Response Modestly Slow Aging?
- Clonal Hematopoiesis of Indeterminate Potential Increases the Risk of Stroke
- The Physiological Aging Index Only Slightly Improves on the PhenoAge Clock
- Mapping Transcriptional Changes Produced by Intermittent Fasting and the Fasting Mimicking Diet
- ANGPTL4 and Microglial Lipid Accumulation to Link Obesity and Alzheimer's Risk
- PLX5622 Clears Inflammatory Microglia in an Alzheimer's Mouse Model
- Is Brain Volume Loss Following Anti-Amyloid Therapy Actually a Bad Thing?
- Mapping the Contribution of PAI-1 to Cellular Senescence and Aging in General
- Declining Autonomic Nervous System Function Correlates with Declining Physical Function
- Oxidative Stress Impairs Protein Mobility in the Cell
- Considering the Relationship Between Menopause and the Aging of the Gut Microbiome
- Newer Epigenetic Clocks Do Demonstrate Correlations with Risk of Alzheimer's Disease
- Preventing Enlargement of the Nucleolus Slows Aging in Yeast Cells
A Growing Population of Harmful Megakaryocyte Progenitors Contribute to Age-Related Thrombosis
https://www.fightaging.org/archives/2024/12/a-growing-population-of-harmful-megakaryocyte-progenitors-contribute-to-age-related-thrombosis/
Blood clotting relies upon platelets and the reaction of those platelets to circumstances that indicate clotting is required: when suitably provoked platelets adhere to tissue, change shape, and bind to one another to form a clot. Platelets are essentially small slices of cell membrane and cytoplasm, shed by a specialized form of bone marrow cell called a megakaryocyte. Like all complex processes, clotting is impacted by age-related changes in cells and tissue. Platelets become more willing to clot, and can produce inappropriate clotting inside blood vessels, leading to thrombosis. We might ask how much of this problem is innate to platelets versus arising from damage to the vascular endothelium and an altered signaling environment.
In today's open access preprint, researcher suggest that the problem is innate to platelets. The authors provide evidence for a minority population of megakaryocytes to grow in number with age. This population produces overly reactive platelets, and as these problematic platelets grow as a proportion of all platelets, so the risk of inappropriate clotting rises. This is analogous to other similar issues in the production of blood cells and immune cells in the bone marrow, in which aging produces unfavorable shifts in relative numbers. Evidence to date suggests much of this is driven by chronic inflammation, but that is no doubt far from the only mechanism in play.
A rare HSC-derived megakaryocyte progenitor accumulates via enhanced survival and contributes to exacerbated thrombopoiesis upon aging
Distinct routes of cellular production from hematopoietic stem cells (HSCs) have defined our current view of hematopoiesis. Recently, we challenged classical views of platelet generation, demonstrating that megakaryocyte progenitors (MkPs), and ultimately platelets, can be specified via an alternate and additive route of HSC-direct specification specifically during aging. This "shortcut" pathway generates hyperactive platelets likely to contribute to age-related platelet-mediated morbidities.
Here, we used single-cell RNA/CITEseq to demonstrate that these age-unique, non-canonical (nc)MkPs can be prospectively defined and experimentally isolated from wild type mice. Surprisingly, this revealed that a rare population of ncMkPs also exist in young mice. Young and aged ncMkPs are functionally distinct from their canonical (c)MkP counterparts, with aged ncMkPs paradoxically and uniquely exhibiting enhanced survival and platelet generation capacity. We further demonstrate that aged HSCs generate significantly more ncMkPs than their younger counterparts, yet this is accomplished without strict clonal restriction.
Together, these findings reveal significant phenotypic, functional, and aging-dependent heterogeneity among the MkP pool and uncover unique features of megakaryopoiesis throughout life, potentially offering cellular and molecular targets for mitigation of age-related adverse thrombotic events.
Sarcopenia in the Context of the Hallmarks of Aging
https://www.fightaging.org/archives/2024/12/sarcopenia-in-the-context-of-the-hallmarks-of-aging/
The primary challenge in the matter of understanding aging is not the generation of data - there is far more data on any aspect of aging than any one research group is capable of assimilating. Production of data is a great deal easier than making something of that data, and so the databases continue to grow at a faster pace than the understanding of that data. The primary challenge is to build bridges of established, comprehensible cause and effect between the various bodies of data, to show that age-related biochemical change A causes unfortunate consequence B, and that A is more important in the progression of B than any of the countless other biochemical changes observed to correlate with B. This is hard.
One first step along this path is to take what is known of the causes of aging (such as those outlined in the SENS view of rejuvenation biotechnology) and try to fix them, observing the results. This is not as popular an approach as might be imagined! More effort goes instead to taking what is known of observed outcomes in aging, and attempting to gain insight into their relationships to to one specific age-related condition. Since the publication of the Hallmarks of Aging paper, a lot of this latter sort of exploration has been undertaken. Today's open access paper is one example of the type, in which researchers give direction for others to explore more deeply the links between specific hallmarks of aging and the age-related loss of muscle mass and strength that leads to sarcopenia.
Sarcopenia and the biological determinants of aging: A narrative review from a geroscience perspective
Research on how molecular and cellular processes - referred to as the hallmarks of aging - are linked to clinically diagnosed sarcopenia and its muscular components. Understanding the biological mechanisms underlying sarcopenia and identifying signature biomarkers are essential for developing preventive strategies that could delay its onset. Among aging hallmarks, mitochondrial dysfunction appears to be the most closely associated with sarcopenia. This dysfunction is characterized by decreased electron transport chain (ETC) expression and activities, changes in metabolites from the TCA cycle, compromised OXPHOS, heightened oxidative stress, and lower antioxidant defenses. These findings were consistently observed across various populations.
Additionally, sarcopenia was associated with deregulated nutrient sensing, indicated by lower IGF-1 and insulin levels in sarcopenic individuals, alongside diminished mTOR signaling and potential influences from specific amino acids. Inflammatory indicators included elevated cortisol levels and oxidative stress markers, while CRP and other cytokines were not consistently associated with sarcopenia. Direct muscle evaluation also revealed no significant increase in inflammatory pathways. Lastly, a decrease in butyrate-producing bacteria and an increase in pathogenic flora were indicatives of gut dysbiosis in individuals with sarcopenia.
Additional connections between sarcopenia and other aging hallmarks, though indicative of potential links, are based on limited or inconsistent evidence. This applies to most of the primary hallmarks. Indicators suggest that genomic instability occurs in sarcopenia, evidenced by increased levels of cell-free mitochondrial and nuclear DNA, as well as epigenetic alterations. However, a deeper understanding of the specific pathways influenced by methylation in various DNA regions and other epigenetic processes is essential. There is a rationale supporting the influence of proteostasis on muscle function, and evidence of transcriptional changes in sarcopenia is apparent. However, the available information is not sufficient to confirm their direct link to sarcopenia. Moreover, lower concentrations of circulating progenitor cells and reduced activation of myosatellite cells in sarcopenic individuals indicate that stem cell exhaustion may contribute to the disease. More research, including mechanistic preclinical investigations, as well as longitudinal human studies, is necessary to explore how these factors relate to the development of sarcopenia.
The field of sarcopenia has witnessed significant advancements, evolving from establishing disease criteria to deepening our understanding of its mechanisms and exploring potential interventions. Despite this progress, the primary management strategies for sarcopenia are solely strength exercise training and nutritional support, as current evidence does not support the efficacy of pharmacological treatments. A recent systematic review examining both current and investigational medications for sarcopenia found no conclusive evidence to support the effectiveness of testosterone replacement or vitamin D supplementation in improving sarcopenia outcomes, reinforcing the findings of our review, which also did not find a consistent relationship between these endocrine networks and sarcopenia. Current preclinical research is investigating the roles of exerkines - molecules secreted by skeletal muscle fibers - and senolytic drugs in muscle health. Based on our findings, enhancing oxidative phosphorylation pathways and restoring energetic balance are also promising future targets for developing treatment options for sarcopenia.
How Does the Heat Shock Response Modestly Slow Aging?
https://www.fightaging.org/archives/2024/12/how-does-the-heat-shock-response-modestly-slow-aging/
Many forms of mild stress produce a corresponding increase in cell maintenance activities that lasts for a while longer, improving cell function, improving tissue and organ function, and over time extending life by slowing the accumulation of some of the forms of damage that drive aging. Low nutrient availability, cold, heat, toxins, all of these can be beneficial at some level and duration of exposure. For example, the practice of calorie restriction produces an upregulation of the cell maintenance processes of autophagy, and this appears to be the crucial outcome that drives improved health and a slowed progression of aging.
It is unfortunate that these effects have a much smaller effect on aging in long-lived species versus short-lived species. It means that most of the interventions discovered to influence the pace of aging turn out to be a poor basis for human enhancement therapies to extend healthy life span. In the case of nutrient sensing and its ability to extend life past a season of famine, there are sound evolutionary reasons as to why short-lived species undergo a greater extension of life relative to their life span - a season is a long time for a mouse, not so long for a human. But it isn't all that clear as to why this should also apply to, say, the heat shock response, other than it potentially using many of the same underlying mechanisms as the calorie restriction response. In today's open access paper, researchers find that this assumption may not be correct, or at least that matters are more complex than this, leading by a winding and indirect path to the mitochondria.
HSF-1 promotes longevity through ubiquilin-1-dependent mitochondrial network remodelling
Cells possess an array of protein quality control mechanisms collectively referred to as the proteostasis network (PN), which act to preserve proteome integrity. The PN coordinates protein synthesis, folding, disaggregation and degradation and integrates components of the translational machinery, molecular chaperones and co-chaperones and the proteolytic systems - the ubiquitin-proteasome system (UPS), and autophagy-lysosomal system - to ensure cell viability.
The cytosolic/nuclear arm of the PN is subject to regulation by heat shock transcription factor 1 (HSF-1), which protects the proteome by driving the expression of heat shock proteins (HSPs) that function as molecular chaperones. In line with its function, the knockdown of HSF-1 leads to increased protein aggregation, tissue dysfunction and decreased survival, whereas overexpression of HSF-1 maintains proteome integrity, promotes tissue health, and extends lifespan. While it is apparent that increasing HSF-1 activity is beneficial for longevity, our understanding of the mechanisms that act downstream of HSF-1 to prolong healthy tissue function remains limited.
It is widely believed that HSF-1 regulates ageing by upregulating the expression of HSPs. However, in addition to HSPs, HSF-1 also controls the expression of genes encoding cytoskeletal components, metabolic enzymes, ribosomal subunits, chromatin factors and components of the UPS. Moreover, recent work has demonstrated roles for autophagy, maintenance of the cytoskeleton and lipid regulation in HSF-1-mediated lifespan extension. These observations indicate that HSF-1 regulates longevity through mechanisms beyond HSP-mediated chaperoning of the proteome.
Here, we employ an RNA interference screen to identify the HSF-1 target genes that promote increased lifespan in C. elegans overexpressing HSF-1. We find that the sole worm ubiquilin, ubiquilin-1 (ubql-1), is necessary to increase lifespan. Ubiquilins are multifaceted, conserved shuttle proteins that localise to the cytoplasm and nucleus, where they function as chaperones that aid in the degradation of substrates through the ubiquitin-proteasome system and autophagy. Despite its central role in protein degradation, we find that ubiquilin-1 does not promote longevity by altering general proteostasis capacity. Instead it leads to transcriptional downregulation of all components of the CDC-48-UFD-1-NPL-4 complex, which is central to both endoplasmic reticulum and mitochondria associated protein degradation, and that this is complemented by UBQL-1-dependent turnover of NPL-4.1. As a consequence, mitochondrial network dynamics are altered, leading to increased lifespan.
Together, our data establish that HSF-1 mediates lifespan extension through mitochondrial network adaptations that occur in response to down-tuning of components associated with organellar protein degradation pathways.
Clonal Hematopoiesis of Indeterminate Potential Increases the Risk of Stroke
https://www.fightaging.org/archives/2024/12/clonal-hematopoiesis-of-indeterminate-potential-increases-the-risk-of-stroke/
A cell is a bag of molecules, all constantly slamming into each other at high speed. Damage to intricate structures such as the packaged DNA of the cell nucleus occurs all time. Most of it is fixed immediately by the highly efficient DNA repair machinery, but a tiny fraction slips through to produce mutations in the sequences describing proteins. In general, even this mutational damage is mostly harmless, except when it hits exactly the right gene to produce a cancerous cell. The damage usually occurs in regions of DNA not used in that cell, or in genes that are used but are not all that important to cell function, or it occurs in a cell that has only a few replications left before reaching the Hayflick limit, and thus any consequences are quite limited.
However, some mutational damage occurs in stem cell and progenitor cell populations, and this ensures that a mutation spreads throughout a tissue over time, present in every daughter somatic cell produced by the mutated stem cell. A layered spread of mutations throughout a tissue, occurring slowly over time as damage accrues in stem cells, is called somatic mosaicism. Researchers consider that this likely contributes to aging by spreading dysfunction, but connecting specific harms to the specific presence of somatic mosaicism has proven challenging.
The one form of somatic mosaicism for which researchers are finding connections is clonal hematopoiesis of indeterminate potential (CHIP), mosaicism in the populations of immune cells generated in the bone marrow. The immune system is influential on health, declines with age, and it seems plausible that one might see widespread effects resulting from significant mutational change in a sizable fraction of circulating immune cells. Today's open access paper is one of a number of examples in which CHIP correlates with unfavorable outcomes, likely because it is giving rise to greater inflammatory behavior in the aged immune system.
Impact of Clonal Hematopoiesis of Indeterminate Potential on the Long-Term Risk of Recurrent Stroke in Patients with a High Atherosclerotic Burden
Clonal hematopoiesis of indeterminate potential (CHIP), which has recently been shown to be an age-related phenomenon, is associated with cardiovascular diseases, including atherosclerosis and stroke. This study focused on the association between CHIP and short- and long-term stroke recurrence in patients with acute ischemic stroke and intracranial atherosclerotic stenosis (ICAS).
This study included 4,699 patients with acute ischemic stroke based on data from the Third China National Stroke Registry (CNSR-III), a nationwide prospective hospital-based registry. The ICAS assessment followed the criteria established by the Warfarin-Aspirin Symptomatic Intracranial Disease Study and Brain Imaging. Atherosclerosis Scores (AS) were used to assess the atherosclerosis burden, as determined by the number and severity of steno-occlusions in the intracranial arteries. The primary outcome was stroke recurrence three months and one year after the event.
Among the 4,699 patients, 3,181 were female, and the median age was 63.0 years. We found that CHIP significantly increased the risk of stroke recurrence at the 1-year follow-up in patients with ICAS (adjusted hazard ratio [HR] 2.71). Our results revealed that CHIP might have a significant impact on the long-term risk of recurrent stroke, particularly in patients with a higher atherosclerotic burden.
The Physiological Aging Index Only Slightly Improves on the PhenoAge Clock
https://www.fightaging.org/archives/2024/12/the-physiological-aging-index-only-slightly-improves-on-the-phenoage-clock/
Any sufficiently complex set of biological measures can be used to produce an aging clock: researchers establish a database of the measures in people of different ages and apply machine learning techniques to produce an algorithm that maps an individual's measured data to a predicted age. That doesn't mean it is a good clock, however. One then has to validate the algorithm against data from other populations and see how well it does in predicting disease, mortality, and other outcomes of interest. Much of the development of clocks is focused on epigenetic data, but distinctly from that line of research, the scientific community is also exploring clocks built on clinical measures, such as blood chemistry, physical performance, and so forth.
Of the clinical measure clocks, PhenoAge is probably the most widely used, both inside and outside the scientific community. Its popularity may derive from ease of use, as it employs only 9 parameters that can be obtained from a complete blood count and a couple of other blood chemistry measures. If proposing a new, more complicated clinical measure clock, one would have to demonstrate that it improves on PhenoAge to a meaningful degree. In today's open access paper, researchers fail to achieve this goal. Their Physiological Aging Index uses 17 parameters and only marginally improves on PhenoAge. It is perhaps interesting to consider why it is that clocks with fewer parameters can still perform well, even in diverse populations.
Estimation of physiological aging based on routine clinical biomarkers: a prospective cohort study in elderly Chinese and the UK Biobank
It has been known that for individuals of the same chronological age (CA), those with obesity, long-term nicotine exposure, or lower socioeconomic status are more likely to experience adverse health outcomes and increased mortality risk. Thus it is important to measure one's biological age (BA) to identify individuals with accelerated aging and to develop precision prevention and intervention strategies for major chronic diseases in an aging population. To date, researchers have developed a variety of predictors of BA using biomarkers such as telomere length, DNA methylation, gene expression, metabolites, or clinical biomarkers. While BA indices based on genomic data, such as DNA methylation, are accurate in predicting CA, clinical biomarkers are generally more affordable, interpretable, and modifiable. However, existing clinical biomarker predictors were primarily based on supervised models with CA as the training label and thus may have limited value to predict disease risks independent of CA.
In this study, we propose a physiological aging index (PAI) based on 36 clinical biomarkers from the Dongfeng-Tongji (DFTJ) cohort of elderly Chinese. In the DFTJ training set (n = 12,769), we identified 25 biomarkers with significant nonlinear associations with mortality, of which 11 showed insignificant linear associations. By incorporating nonlinear effects, we selected CA and 17 clinical biomarkers to calculate PAI. PAI aims to measure an individual's BA based on routine clinical biomarkers in the blood. We use restricted cubic spline (RCS) Cox models to capture potential U-shaped relationships between clinical biomarkers and mortality, and determine the optimal value of each biomarker for subsequent piece-wise linear transformation. We define PAI as a linear combination of CA and the transformed biomarkers, as well as ΔPAI as the residual of PAI after regressing on CA. Thus, ΔPAI measures physiological aging acceleration independent of CA.
In the DFTJ testing set (n = 15,904), PAI predicts mortality with a concordance index (C-index) of 0.816, better than CA (C-index = 0.771) and PhenoAge (0.799). ΔPAI was predictive of incident cardiovascular disease and its subtypes, independent of traditional risk factors. In the external validation set of the UK Biobank (n = 296,931), PAI achieved a C-index of 0.749 to predict mortality, remaining better than CA (0.706) and PhenoAge (0.743). In both DFTJ and UK Biobank, PAI calibrated better than PhenoAge when comparing the predicted and observed survival probabilities. Furthermore, ΔPAI outperformed any single biomarker to predict incident risks of eight age-related chronic diseases.
Mapping Transcriptional Changes Produced by Intermittent Fasting and the Fasting Mimicking Diet
https://www.fightaging.org/archives/2024/12/mapping-transcriptional-changes-produced-by-intermittent-fasting-and-the-fasting-mimicking-diet/
Forms of fasting and calorie restriction all function to produce sweeping, favorable alterations to metabolism. In short-lived animals, these changes significantly extend healthy life span. In long-lived animals, the effects on life span are more muted. The challenge in understanding the interaction between reduced calorie intake and pace of aging is that near everything changes in response to diet. There is no firm understanding at the detail level to link the copious observations into a coherent explanation of how aging is slowed. While evidence points to upregulation of autophagy as the primary mechanism connecting reduced calorie intake to slowed aging, it seems clear that researchers will still be writing papers like this one for decades yet.
Dietary restriction (DR) has multiple beneficial effects on health and longevity and can also improve the efficacy of certain therapies. Diets used to instigate DR are diverse and the corresponding response is not uniformly measured. We compared the systemic and liver-specific transcriptional response to intermittent fasting (IF) and commercially available fasting-mimicking diet (FMD) after short- and long-term use in C57BL/6 J mice.
We show that neither DR regimen causes observable adverse effects in mice. The weight loss was limited to 20% and was quickly compensated during refeeding days. The slightly higher weight loss upon FMD versus IF correlated with stronger fasting response assessed by lower glucose levels and higher ketone body, free fatty acids, and especially FGF21 concentrations in blood. RNA sequencing demonstrated similar transcriptional programs in the liver after both regimens, with PPARα signalling as top enriched pathway, while on individual gene level FMD more potently increased gluconeogenesis-related, and PPARα and p53 target gene expression compared to IF. Repeated IF induced similar transcriptional responses as acute IF. However, repeated cycles of FMD resulted in blunted expression of genes involved in ketogenesis and fatty acid oxidation.
ANGPTL4 and Microglial Lipid Accumulation to Link Obesity and Alzheimer's Risk
https://www.fightaging.org/archives/2024/12/angptl4-and-microglial-lipid-accumulation-to-link-obesity-and-alzheimers-risk/
One of the many interesting questions about Alzheimer's disease is why the relationship with being overweight or obese is tenuous in comparison to, say, type 2 diabetes. Why are there so many dramatically overweight people who do not develop Alzheimer's disease? As researchers here note, one can clearly point to Alzheimer's-adjacent mechanisms that obesity makes worse. Inflammatory dysfunction of the innate immune cells of the brain known as microglia has attracted a lot of attention in recent years, thought to contribute to all forms of neurodegeneration. Here, researchers look at one mechanism by which excess visceral fat tissue can harm microglia, giving rise to behaviors observed in the brains of Alzheimer's patients and animal models.
Increasing evidence suggests that metabolic disorders such as obesity are implicated in the development of Alzheimer's disease (AD). The pathological buildup of lipids in microglia is regarded as a key indicator in brain aging and the progression of AD, yet the mechanisms behind this process remain uncertain. The adipokine ANGPTL4 is strongly associated with obesity and is thought to play a role in the advancement of neurodegenerative diseases. This study utilized RNA sequencing to identify differential expression in lipid-accumulating BV2 microglia and investigated the potential mechanism through ANGPTL4 overexpression in BV2. Subsequently, animal models and clinical data were employed to further explore alterations in circulating ANGPTL4 levels in AD.
RNA sequencing results indicated a correlation between ANGPTL4 and microglial lipid accumulation. The overexpression of ANGPTL4 in microglia resulted in increased secretion of inflammatory factors, elevated oxidative stress levels, and diminished antiviral capacity. Furthermore, when simulating the coexistence of AD and obesity through combined treatment with Amyloid-Beta 1-42 peptide (Aβ) and Free Fatty Acids (FFA) in vitro, we observed a notable upregulation of ANGPTL4 expression, highlighting its potential role in the interplay between AD and obesity.
In vivo experiments, we also observed a significant increase in ANGPTL4 expression in the hippocampus and plasma of APP/PS1 mice compared to wild-type controls. This was accompanied by heightened microglial activation and reduced expression of longevity-related genes in the hippocampus. Clinical data from the UK Biobank indicated that plasma ANGPTL4 levels are elevated in patients with AD when compared to healthy controls. Moreover, significantly higher ANGPTL4 levels were observed in obese AD patients relative to their non-obese counterparts. Our findings suggest that ANGPTL4-mediated microglial aging may serve as a crucial link between AD and obesity, proposing ANGPTL4 as a potential biomarker for AD.
PLX5622 Clears Inflammatory Microglia in an Alzheimer's Mouse Model
https://www.fightaging.org/archives/2024/12/plx5622-clears-inflammatory-microglia-in-an-alzheimers-mouse-model/
Evidence strongly suggests that the inflammatory dysfunction of the innate immune cells of the brain known as microglia contributes to neurodegenerative conditions. There is a way to clear microglia from the brain, which is the use of CSF1R inhibitors such as PLX5622. A few weeks of treatment dramatically reduce the population of microglia, which will rebuild itself within a further few weeks after treatment has stopped. Researchers have observed that the new population is much less inflammatory than the old one. Researchers here note that this therapy fails to improve measures of Alzheimer's pathology in a mouse model by the end of a short ten day study - more time is required for effects to emerge.
While moderately activated microglia in Alzheimer's disease (AD) are pivotal in clearing amyloid beta (Aβ), hyperactivated microglia perpetuate neuroinflammation. Prior investigations reported that the elimination of ~80% of microglia through inhibition of the colony-stimulating factor 1 receptor (CSF1R) during the advanced stage of neuroinflammation in 5xFamilial AD (5xFAD) mice mitigates synapse loss and neurodegeneration. Furthermore, prolonged CSF1R inhibition diminished the development of parenchymal plaques. Nonetheless, the effects of short-term CSF1R inhibition during the early stages of neuroinflammation on residual microglia are unknown. Therefore, we investigated the effects of 10-day CSF1R inhibition using PLX5622 in three-month-old female 5xFAD mice, a stage characterized by the onset of neuroinflammation and minimal Aβ plaques.
We observed ~65% microglia depletion in the hippocampus and cerebral cortex. The leftover microglia displayed a noninflammatory phenotype with reduced NLRP3 inflammasome complexes. Moreover, plaque-associated microglia were reduced with diminished Clec7a expression. Additionally, phosphorylated S6 ribosomal protein and the protein sequestosome 1 analysis suggested reduced mechanistic targets of rapamycin (mTOR) signaling and autophagy in microglia and neurons within the hippocampus and cerebral cortex. Biochemical assays validated the inhibition of NLRP3 inflammasome activation, decreased mTOR signaling in the hippocampus and cerebral cortex, and enhanced autophagy in the hippocampus. However, short-term CSF1R inhibition did not influence Aβ plaques, soluble Aβ-42 levels, astrocyte hypertrophy, or hippocampal neurogenesis.
Thus, short-term CSF1R inhibition during the early stages of neuroinflammation in 5xFAD mice promotes the retention of homeostatic microglia with diminished inflammasome activation and mTOR signaling, alongside increased autophagy.
Is Brain Volume Loss Following Anti-Amyloid Therapy Actually a Bad Thing?
https://www.fightaging.org/archives/2024/12/is-brain-volume-loss-following-anti-amyloid-therapy-actually-a-bad-thing/
That loss of brain volume is a bad thing, resulting from the loss of necessary cells, is a concept central to the research and clinical fields. It occurs in later stages of Alzheimer's disease as cells die and cognitive function is lost. So it is interesting to see this view challenged in the context of the recently approved amyloid-clearing immunotherapies. Is brain volume loss following treatment a function of mechanisms other than loss of cells? Is it actually a beneficial outcome? I can see it requiring a great deal more time, funding, and data to convince the broader field that this is the case.
Researchers analysed data from a dozen different trials of amyloid-targeting immunotherapy. While brain shrinkage is usually an undesirable outcome, the team found that the excess volume loss was consistent across studies and correlated with how effective the therapy was in removing amyloid and was not associated with harm. As a result, the researchers believe that the removal of amyloid plaques, which are abundant in Alzheimer's patients, could account for the observed brain volume changes. And, as such, the volume loss should not be a cause for concern.
To describe this phenomenon, the research team coined a new phrase: "amyloid-removal-related pseudo-atrophy" or ARPA. "Amyloid-targeting monoclonal antibodies represent a significant therapeutic breakthrough. One area of controversy has been the effect of these agents on brain volumes. Brain volume loss is a characteristic feature of Alzheimer's disease, caused by progressive loss of neurons. Amyloid immunotherapy has consistently shown an increase in brain volume loss - leading to concerns in the media and medical literature that these drugs could be causing unrecognised toxicity to the brains of treated patients. However, based on the available data, we believe that this excess volume change is an anticipated consequence of the removal of pathologic amyloid plaque. We are calling for better reporting of these changes in clinical trials."
Mapping the Contribution of PAI-1 to Cellular Senescence and Aging in General
https://www.fightaging.org/archives/2024/12/mapping-the-contribution-of-pai-1-to-cellular-senescence-and-aging-in-general/
The PAI-1 protein is generated by the SERPINE1 gene. You might recall the discovery of a small human population with a loss of function mutation in this gene and longer lives then peers without the mutation. Here researchers map the relationships between PAI-1 and cellular senescence; PAI-1 is important in enabling onset of the senescent state. The accumulation of senescent cells with age is thought to be a meaningful contribution to degenerative aging, and the longevity of the PAI-1 loss of function population provides another piece of evidence in support of that hypothesis - to go along with all of the biochemical data, evidence of rejuvenation in aged animals following clearance of senescent cells, and promising clinical trials of senolytic drugs.
In this study, we aim to illustrate a pathway map of PAI-1, highlighting its contributions to cellular senescence and aging. PAI-1 is a critical component in the iniation of cellular senescence, and our findings underscore the pivotal role of the SERPINE1 gene in this process. Targeting PAI-1 offers a promising strategy to mitigate cellular senescence and associated age-related conditions such as emphysema, arteriosclerosis, organ fibrogenesis, and thrombosis. The publicly available PAI-1 pathway map will aid researchers in understanding the various molecules involved in modulating this pathway in pathological and physiological contexts. This resource provides insights for identifying other related molecules participating in this signaling network and may lead to innovative pharmacological means for managing cellular senescence and addressing diseases linked to PAI-1.
Accumulating evidence, including our laboratory's research, positions PAI-1 as a molecular signature of cellular senescence and a potential inducer and mediator of maturation. Our research team is currently exploring the essential function of PAI-1 and the fibrinolytic system in age-related fibrotic lung conditions through pharmacological PAI-1 inhibitors. In our ongoing and future studies, we aim to further clarify the crucial function of PAI-1 in cellular senescence and its connections to the fibrinolytic system, particularly in age-associated mortality and morbidity.
Declining Autonomic Nervous System Function Correlates with Declining Physical Function
https://www.fightaging.org/archives/2024/12/declining-autonomic-nervous-system-function-correlates-with-declining-physical-function/
Many aspects of aging tend to progress in parallel, which is much as one might expect if considering aging to be a collection of outcomes that all arise from the same underlying forms of cell and tissue damage. So finding a correlation isn't always evidence that there is some link between outcomes in aging. Here, researchers note an association between physical capacity and autonomic nervous system function in late life. It is quite possible to theorize on cause and consequence, and the mechanisms involved, in this situation - but actually proving any of those connections is quite a different story.
The autonomic nervous system plays unique and pivotal roles in maintaining physiological homeostasis. These roles are mainly exerted through their effects on the function of multiple organ systems. Aside from its well-known effects on cardiovascular and metabolic systems, recent experimental research even showed the previously unexpected close connections of autonomic nervous system activity with inflammation, immune responses, and skeletal muscle physiology.
Here, we conducted a longitudinal study with repeated measurements of heart rate variability (HRV), a measure of autonomic nervous system function, and functional capacity. We aimed to examine the longitudinal association of heart rate variability and its change with changes in functional capacity over time in older adults.
A cohort of 542 adults (mean age of 70.1 years) received repeated measurements of heart rate variability, an autonomic nervous system function marker, and chair rise time, a functional capacity measure. Linear mixed models analysis showed that 1 standard deviation (SD) lower power in low-frequency range of heart rate variability at baseline was associated with a 0.11 second/year faster increase in chair rise time during the follow-up, whereas 1 SD increase in power in high-frequency range and 1 SD decrease in the ratio of power in low-frequency range to power in high-frequency range during the follow-up were associated with a 0.22 second and 0.17 second increase in chair rise time. In conclusion, autonomic nervous system function and its changes were longitudinally associated with changes in functional capacity in older adults.
Oxidative Stress Impairs Protein Mobility in the Cell
https://www.fightaging.org/archives/2024/12/oxidative-stress-impairs-protein-mobility-in-the-cell/
Researchers here suggest that one of the issues arising from oxidative stress in a cell is a reduced ability for critical proteins to move about the cell to where they are needed. It is an interesting concept, but quite unclear as to what one might do about it beyond alleviating the issues that caused the oxidative stress in the first place. This is the case for much of the cellular dysfunction of aging - it is more practical to focus on the causes of dysfunction than to try to patch over it.
Many chronic diseases have a common denominator that could be driving their dysfunction: reduced protein mobility. Normally, most proteins zip around the cell bumping into other molecules until they locate the molecule they work with or act on. The slower a protein moves, the fewer other molecules it will reach, and so the less likely it will be able to do its job. Researchers found that such protein slow-downs lead to measurable reductions in the functional output of the proteins. When many proteins fail to get their jobs done in time, cells begin to experience a variety of problems.
The researchers studied proteins involved in a broad range of cellular functions, including MED1, a protein involved in gene expression; HP1α, a protein involved in gene silencing; FIB1, a protein involved in production of ribosomes; and SRSF2, a protein involved in splicing of messenger RNA. They used single-molecule tracking and other methods to measure how each of those proteins moves in healthy cells and in cells in disease states. All but one of the proteins showed reduced mobility (about 20-35%) in the disease cells.
Researchers suspected that the defect had to do with an increase in cells of the level of reactive oxygen species (ROS), molecules that are highly prone to interfering with other molecules and their chemical reactions. Many types of chronic-disease-associated triggers, such as higher sugar or fat levels, certain toxins, and inflammatory signals, lead to an increase in ROS, also known as an increase in oxidative stress. The researchers measured the mobility of the proteins again, in cells that had high levels of ROS and were not otherwise in a disease state, and saw comparable mobility defects, suggesting that oxidative stress was to blame for the protein mobility defect.
The final part of the puzzle was why some, but not all, proteins slow down in the presence of ROS. SRSF2 was the only one of the proteins that was unaffected in the experiments, and it had one clear difference from the others: its surface did not contain any cysteines, an amino acid building block of many proteins. Cysteines are especially susceptible to interference from ROS because it will cause them to bond to other cysteines. When this bonding occurs between two protein molecules, it slows them down because the two proteins cannot move through the cell as quickly as either protein alone.
Considering the Relationship Between Menopause and the Aging of the Gut Microbiome
https://www.fightaging.org/archives/2024/12/considering-the-relationship-between-menopause-and-the-aging-of-the-gut-microbiome/
The composition of the gut microbiome changes with age in ways that contribute to loss of function and inflammation throughout the body. Evidence from animal studies suggests that the influence of the gut microbiome on long-term health may be similar to that of lifestyle choices such as exercise and diet. Here, researchers discuss what is known of the relationship between menopause and the gut microbiome. As is the case for immune aging, this is likely a bidirectional relationship, each side negatively impacting the other.
The oral and gut microbiota, constituting the largest ecosystem within the human body, are important for maintaining human health and notably contribute to the healthy aging of menopausal women. This paper presents the current understanding of the microbiome during menopause, with a particular focus on alterations in the oral and gut microbiota.
While sex hormones shape the gut microbiome, resulting in sexual differences in microbial composition, the gut microbiome also participates in regulating sex hormone levels, indicating a bidirectional relationship. Glucuronic acid conjugation marks estrogens for biliary excretion through urine and feces, and the removal of glucuronic acid releases estrogens to reabsorb into the circulation. Some gut bacteria, such as Clostridium, Bifidobacterium, and Lactobacillus, yield β-glucuronides and β-glucuronidases, which deconjugate or conjugate estrogens. These gene products from gut bacteria that metabolize estrogens are termed the estrobolome. The proportion of β-glucuronides and β-glucuronidases in the gut regulates the quantity of circulating estrogens. Some gut bacteria produce enzymes that can selectively deconjugate certain estrogens, thus changing the profile of circulating estrogens. In addition to estrogens, other sex hormones, including androgens and progesterone, are similarly metabolized by the gut microbiota.
Studies suggest a bidirectional interplay between the gut microbiome and sex hormones during menopause. Estrogens and progesterone act as substrates for several bacterial species and therefore may contribute to elevated gut microbial diversity; moreover, the increased diversity and deconjugation activity of certain bacteria help to recycle sex hormones. Without production from the ovary, the estrogen and progesterone levels remain low in postmenopausal women; hence, the recycling of sex hormones by the gut microbiome may become a significant source of circulating estrogens and progesterone.
Newer Epigenetic Clocks Do Demonstrate Correlations with Risk of Alzheimer's Disease
https://www.fightaging.org/archives/2024/12/newer-epigenetic-clocks-do-demonstrate-correlations-with-risk-of-alzheimers-disease/
Researchers here report that more recently developed second generation epigenetic clocks do in fact demonstrate correlations between accelerated epigenetic age and risk of Alzheimer's disease. Clocks are developed from databases of the status of DNA methylation sites on the genome in people of various ages. Some of these sites tend to become more or less methylated with advancing age, allowing machine learning approaches to derive algorithms that match a pattern of methylation to a chronological age. An accelerated epigenetic age implies that an individual's epigenetics look more like those of someone with an older chronological age. The implication is that such an individual suffers a greater burden of age-related damage and dysfunction, and will thus have a higher risk of disease and mortality going forward.
Transgenic mouse models of Alzheimer's disease (AD) demonstrate unique epigenetic alterations associated with AD pathology and studies of human brain tissue show marked DNA methylation differences in AD when compared to normal aging brain. By contrast, data from clinical studies has been mixed. For example, a recent systematic review largely using cross-sectional studies found no strong evidence that epigenetic age estimates were associated with risk for dementia or mild cognitive impairment (MCI), while other smaller studies have suggested a limited though promising relationship with risk for AD or related disease biomarkers.
There are multiple possible explanations for these surprisingly discrepant findings as insights from mouse models and postmortem human tissue are translated into clinical settings, and, taken together, these findings suggest the need for additional studies using more sensitive longitudinal and biomarker data paired with well-established and validated epigenetic clocks. Therefore, we investigated the relationship between two well-validated second-generation epigenetic clocks, DNAmPhenoAge and DNAmGrimAge, and risk for MCI or AD using longitudinal analyses and multimodal neuroimaging. Specifically, we analyzed the rate of progression from cognitively normal (CN) aging to either MCI or AD, cortical thinning and white matter hyperintensities (WMH) on magnetic resonance imaging (MRI), and longitudinal cognitive changes.
Using survival analyses, we found that DNAmPhenoAge and DNAmGrimAge predicted progression from cognitively normal aging to mild cognitive impairment or AD and worse longitudinal cognitive outcomes. Epigenetic age was also strongly associated with cortical thinning in AD-relevant regions and white matter disease burden. Thus, in contrast to earlier work suggesting limited applicability of blood-based epigenetic clocks in AD, our novel analytic framework suggests that second-generation epigenetic clocks have broad utility and may represent promising predictors of AD risk and pathophysiology.
Preventing Enlargement of the Nucleolus Slows Aging in Yeast Cells
https://www.fightaging.org/archives/2024/12/preventing-enlargement-of-the-nucleolus-slows-aging-in-yeast-cells/
The nucleolus resides in the cell nucleus, and is where ribosomes are assembled. It is known that the nucleolus grows larger with age, and in cells that have undergone a sufficient number of divisions to approach the Hayflick limit. Here, researchers provide evidence for harms caused by enlargement of the nucleolus in aging, using a novel approach that prevents the nucleous from enlarging without manipulating other aspects of cell function. It remains to be seen as to how one might progress from this engineering exercise to interventions that target the nucleolus, and whether other approaches to rejuvenation might prevent this from being needed in the first place. Enlargement of the nucleolus may be a downstream consequence of molecular damage that is easier to fix than the nucleolus itself.
The nucleus holds the cell's chromosomes and the nucleolus where the ribosomal DNA (rDNA) is housed. The nucleolus isolates the rDNA which encodes the RNA portions of the ribosomes, the protein-building machinery. The rDNA is one of the most fragile parts of the genome, due to its repetitive nature making it more difficult to maintain and fix if damaged. If damage in the rDNA is not accurately repaired, it can lead to chromosomal rearrangements and cell death. In organisms from yeast to worms to humans, nucleoli expand during aging. On the flip side, anti-aging strategies like calorie restriction result in smaller nucleoli.
Researchers suspected that keeping nucleoli small could delay aging. To test this idea, they engineered an artificial way to secure rDNA to the membrane surrounding the nucleus of yeast cells so they could control when it was anchored and when it was not. The researchers discovered that tethering the nucleolus was enough to keep it compact, and small nucleoli delayed aging to about the same extent as calorie restriction.
Interestingly, nucleoli did not expand at the same rate during the entire lifespan as cells aged. They remained small for most of the yeast's life, but at a nucleolar size threshold, the nucleoli suddenly began to grow quickly and expand to a much larger size. Cells only survived for an average of about five more cell divisions after hitting this threshold. Passing the threshold appears to serve as a mortality timer, ticking down the final moments of a cell's life. During aging, DNA accumulates damage, some of which can be devastating to the cell. In tests, researchers found that large nucleoli had less stable rDNA than smaller ones. Also, when the structure is large, proteins and other factors that are usually excluded from the nucleolus are no longer kept out. It's as if the nucleolus becomes leaky, letting in molecules that can wreak havoc on the fragile rDNA.