Biology subjects

Miller, R. A.

Publications and source records attributed to Miller, R. A..

36 records · Page 2Linked to original sources

bioRxiv2024

An integrated single-nucleus and spatial transcriptomics atlas reveals the molecular landscape of the human hippocampus

The hippocampus contains many unique cell types, which serve the structures specialized functions, including learning, memory and cognition. These cells have distinct spatial organization, morphology, physiology, and connectivity, highlighting the importance of transcriptome-wide profiling strategies that retain cytoarchitectural organization. Here, we generated spatially-resolved transcriptomics (SRT) and single-nucleus RNA-sequencing (snRNA-seq) data from adjacent tissue sections of the anterior human hippocampus in ten adult neurotypical donors to define molecular profiles for hippocampal cell types and spatial domains. Using non-negative matrix factorization (NMF) and label transfer, we integrated these data by defining gene expression patterns within the snRNA-seq data and inferring their expression in the SRT data. We identified NMF patterns that captured transcriptional variation across neuronal cell types and indicated that the response of excitatory and inhibitory postsynaptic specializations were prioritized in different SRT spatial domains. We used the NMF and label transfer approach to leverage existing rodent datasets, identifying patterns of activity-dependent transcription and subpopulations of dentate gyrus granule cells in our SRT dataset that may be predisposed to participate in learning and memory ensembles. Finally, we characterized the spatial organization of NMF patterns corresponding to non-cornu ammonis pyramidal neurons and identified snRNA-seq clusters mapping to distinct regions of the retrohippocampus, to three subiculum layers, and to a population of presubiculum neurons. To make this comprehensive molecular atlas accessible to the scientific community, both raw and processed data are freely available, including through interactive web applications.

neuroscience↗

bioRxiv2024

Transcriptomic characterization of human lateral septum neurons reveals conserved and divergent marker genes across species

The lateral septum (LS) is a midline, subcortical structure, which regulates social behaviors that are frequently impaired in neurodevelopmental disorders including schizophrenia and autism spectrum disorder. Mouse studies have identified neuronal populations within the LS that express a variety of molecular markers, including vasopressin receptor, oxytocin receptor, and corticotropin releasing hormone receptor, which control specific facets of social behavior. Despite its critical role in regulating social behavior and notable gene expression patterns, comprehensive molecular profiling of the human LS has not been performed. Here, we conducted single nucleus RNA-sequencing (snRNA-seq) to generate the first transcriptomic profiles of the human LS using postmortem human brain tissue samples from 3 neurotypical donors. Our analysis identified 5 transcriptionally distinct neuronal cell types within the human LS that are enriched for TRPC4, the gene encoding Trp-related protein 4. Differential expression analysis revealed a distinct LS neuronal cell type that is enriched for OPRM1, the gene encoding the {micro}-opioid receptor. Leveraging recently generated mouse LS snRNA-seq datasets, we conducted a cross-species analysis. Our results demonstrate that TRPC4 enrichment in the LS is highly conserved between human and mouse, while FREM2, which encodes FRAS1 related extracellular matrix protein 2, is enriched only in the human LS. Together, these results highlight transcriptional heterogeneity of the human LS, and identify robust marker genes for the human LS.

neuroscience↗

bioRxiv2024

Hypothalamic Sex-Specific Metabolic Shift by Canagliflozin during Aging

The hypothalamus undergoes significant changes with aging and plays crucial roles in age-related metabolic alterations. Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are anti-diabetic agents that promote glucose excretion, and promote metabolic homeostasis. Recent studies have shown that SGLT2i, Canagliflozin (Cana), can extend the median survival of genetically heterogeneous UM-HET3 male mice and improve central metabolic control via increases in hypothalamic insulin responsiveness in aged males, as well as reduced age-associated hypothalamic inflammation. We studied the long- and short-term effects of Cana on hypothalamic metabolic control in UM-HET3 mice. We show that Cana treatment reduced body weight and fat mass in male mice that was associated with enhanced glucose tolerance and insulin sensitivity observed by 12 months. Indirect calorimetry showed that short-term Cana treatment (5 months) increased energy expenditure in male, but not female mice, at 12 months of age. Long-term Cana treatment (18 months) increased metabolic rates in both sexes, and markedly increasing formation of both orexigenic and anorexigenic projections to the paraventricular nucleus of the hypothalamus (PVH) mostly in females by 25 months. Hypothalamic RNA-sequencing analysis revealed sex-specific genes and signaling pathways related to insulin signaling, glycogen catabolic pathway, neuropeptide signaling, and mitochondrial function upregulated by Cana, with males showing a more pronounced and sustained effect on metabolic pathways at both age groups. Overall, our data provide critical evidence for sex-specific mechanisms that are impacted by Cana during aging suggesting key targets of hypothalamic Cana-induced neuroprotection for metabolic control.

neuroscience↗

bioRxiv2023

Spatially-resolved transcriptomics of human dentate gyrus across postnatal lifespan reveals heterogeneity in markers for proliferation, extracellular matrix, and neuroinflammation

The dentate gyrus of the hippocampus is important for many cognitive functions, including learning, memory, and mood. Here, we investigated age-associated changes in transcriptome-wide spatial gene expression in the human dentate gyrus across the lifespan. Genes associated with neurogenesis and the extracellular matrix were enriched in infants, while gene markers of inhibitory neurons and cell proliferation showed increases and decreases in post-infancy, respectively. While we did not find evidence for neural proliferation post-infancy, we did identify molecular signatures supporting protracted maturation of granule cells. We also identified a wide-spread hippocampal aging signature and an age-associated increase in genes related to neuroinflammation. Our findings suggest major changes to the putative neurogenic niche after infancy and identify molecular foci of brain aging in glial and neuropil enriched tissue.

neuroscience↗

bioRxiv2023

Soquelitinb, A selective inhibitor of interleukin-2-inducible kinase (ITK), is active in several murine models of T cell-mediated inflammatory disease

Interleukin-2-inducible T cell kinase (or ITK) is a tyrosine kinase predominantly expressed by T lymphocytes. It plays a major role in T cell activation, differentiation, and receptor signaling. Studies in mouse models have established that the absence or inhibition of ITK reduces the secretion of Th2 and Th17 cytokines, while favoring the production of Th1 cytokines and the differentiation of T cells to regulatory T cells (T regs). We recently characterized the activity of soquelitinib (SQL), a selective, covalent inhibitor of ITK in vitro using mouse or human T cells and in vivo in murine models of cancer. We hypothesized that selective pharmacologic blockade of ITK could attenuate a variety of T cell-mediated inflammatory diseases including murine models that resemble asthma, pulmonary fibrosis, systemic sclerosis, psoriasis, and acute graft versus host disease. In each model, SQL demonstrated substantial ability to ameliorate the disease process along with effects on cytokines and/or T cell subsets consistent with the reported function of ITK. Our studies demonstrate that selective inhibition of ITK by SQL is potentially a novel therapeutic approach for several forms of T cell-mediated, inflammatory diseases.

immunology↗

bioRxiv2023

Selective inhibition of interleukin-2 inducible T cell kinase (ITK) enhances anti-tumor immunity in association with Th1-skewing, cytotoxic T cell activation, and reduced T cell exhaustion

ITK is a tyrosine kinase expressed predominantly by T lymphocytes. In mice, selective knock-out of the ITK gene produces Th1 skewing of T helper cell differentiation. We synthesized a covalent ITK inhibitor, soquelitinib, that binds ITK with greater than 100-fold selectivity compared to binding to resting lymphocyte kinase (RLK). In vitro studies with normal or malignant T cells demonstrated that soquelitinib suppresses Th2 cytokine production preferentially with relative sparing of Th1 cytokines. Soquelitinib inhibits the in vivo growth of several syngeneic murine tumors including those that do not express ITK. Treatment with soquelitinib leads to increased tumor infiltration of normal CD8+ cells that possess enhanced T effector function. Soquelitinib inhibited expression of T cell exhaustion markers and was able to restore T effector function to exhausted cells. Pharmacologic selective ITK inhibition may represent a novel approach to cancer immunotherapy.

cancer biology↗

bioRxiv2023

Targeting mitochondrial dysfunction using methylene blue or mitoquinone to improve skeletal aging

Declines in mitochondrial content and impaired cytochrome c oxidase activity (complex IV) can result in reduced energy metabolism and increased levels of oxidants. Methylene blue (MB) is a well-established antioxidant that has been shown to improve mitochondrial function in both in vitro and in vivo settings. Mitoquinone (MitoQ) is a selective antioxidant that specifically targets mitochondria and effectively reduces the accumulation of reactive oxygen species (ROS) within cells. To investigate the effect of acute and long-term administration of MB on skeletal morphology, we administered MB to aged (18 months old) female C57BL/J6 mice, as well as to adult male and female mice with a genetically diverse background (UM-HET3). Additionally, we used MitoQ as an alternative approach to target mitochondrial oxidative stress during aging in adult female and male UM-HET3 mice. Although we observed some beneficial effects of MB and MitoQ in vitro, the administration of these compounds in vivo did not alter the progression of age-induced bone loss. Specifically, treating 18-month-old female mice with MB for 6 or 12 months did not have an effect on age-related bone loss. Similarly, long-term treatment with MB from 7 to 22 months or with MitoQ from 4 to 22 months of age did not affect the morphology of cortical bone at the mid-diaphysis of the femur, trabecular bone at the distal-metaphysis of the femur, or trabecular bone at the lumbar vertebra-5 (L5) in UM-HET3 mice. Based on our findings, it appears that long-term treatment with MB or MitoQ alone, as a means to reduce skeletal oxidative stress, is insufficient to inhibit age-associated bone loss. This supports the notion that interventions solely with antioxidants may not provide adequate protection against skeletal aging.

pharmacology and toxicology↗

bioRxiv2023

Evolution of High-Molecular-Mass Hyaluronic Acid is Associated with Subterranean Lifestyle

Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) which plays an important role in development, cellular response to injury and inflammation, cell migration, and cancer. The naked mole-rat (NMR, Heterocephalus glaber) contains abundant high-molecular-mass HA (HMM-HA) in its tissues, which contributes to this species cancer resistance and possibly longevity. Here we report that abundant HMM-HA is found in a wide range of subterranean mammalian species, but not in phylogenetically related aboveground species. These species accumulate abundant HMM-HA by regulating the expression of genes involved in HA degradation and synthesis and contain unique mutations in these genes. The abundant high molecular weight HA may benefit the adaptation to subterranean environment by increasing skin elasticity and protecting from oxidative stress due to hypoxic subterranean environment. HMM-HA may also be coopted to confer cancer resistance and longevity to subterranean mammals. Our work suggests that HMM-HA has evolved with subterranean lifestyle.

evolutionary biology↗

bioRxiv2022

Neuroprotective effects of Canagliflozin: lessons from aged genetically diverse UM-HET3 mice.

The aging brain is characterized by a progressive increase in neuroinflammation and central insulin resistance, which contribute to neurodegenerative diseases and cognitive impairment. Recently, the Interventions Testing Program (ITP) demonstrated that the anti-diabetes drug, Canagliflozin (Cana), a sodium-glucose transporter 2 inhibitor (SGLT2i), led to lower fasting glucose and improved glucose tolerance in both sexes, but extended median lifespan by 14% only in male mice. Here we show that Cana treatment significantly improved central insulin sensitivity in the hypothalamus and the hippocampus of 30-month-old male mice. Remarkably, Cana-treated mice showed significant reductions in age-associated hypothalamic gliosis with a decrease in inflammatory cytokine production by microglia in both sexes. In the hippocampus, Cana reduced microgliosis and astrogliosis in males, but not in female mice. The decrease in microgliosis was partially dependent on mTOR signaling, as evidenced by reduced phosphorylation of S6 kinase in microglia of Cana-treated aged male, but not female mice. Remarkably, Cana treatment improved exploratory and locomotor activity of 30-month-old male but not female mice. Taken together, our findings demonstrate sex-specific neuroprotective effects of Cana treatment, suggesting its application for the potential treatment of neurodegenerative diseases.

neuroscience↗

bioRxiv2021

Aging is associated with increased brain iron through brain-derived hepcidin expression

Iron is an essential molecule for biological processes, but its accumulation can lead to oxidative stress and cellular death. Due to its oxidative effects, iron accumulation is implicated in the process of aging and neurodegenerative diseases. However, the mechanism for this increase in iron with aging, and whether this increase is localized to specific cellular compartment(s), are not known. Here, we measured the levels of iron in different tissues of aged mice, and demonstrate that while cytosolic non-heme iron is increased in the liver and muscle tissue, only the aged brain exhibits an increase in both the cytosolic and mitochondrial non-heme iron. This increase in brain iron is associated with elevated levels of local hepcidin mRNA and protein in the brain. We also demonstrate that the increase in hepcidin is associated with increased ubiquitination and reduced levels of the only iron exporter, feroportin-1 (FPN1). Overall, our studies provide a potential mechanism for iron accumulation in the brain through increased local expression of hepcidin, and subsequent iron accumulation due to decreased iron export. Additionally, our data support that aging is associated with mitochondrial and cytosolic iron accumulation only in the brain and not in other tissues.

cell biology↗

bioRxiv2021

Characterizing interactions between the microtubule-binding protein CLIP-170 and F-actin

The cooperation between the actin and microtubule (MT) cytoskeletons is important for cellular processes such as cell migration and muscle cell development. Full understanding of how this cooperation occurs has yet to be sufficiently developed. The MT plus-end tracking protein (+TIP) CLIP-170 has been implicated in this actin-MT coordination by associating with the actin-binding signaling protein IQGAP1, and by promoting actin polymerization through binding with formins. Thus far, CLIP-170s interactions with actin were assumed to be indirect. Here, we demonstrate that CLIP-170 can bind to filamentous actin (F-actin) directly. The affinity is relatively weak, but is strong enough to be significant in the actin-rich cortex, where actin concentrations can be extremely high. Using CLIP-170 fragments and mutants, we show that the direct CLIP-170:actin interaction is independent of the FEED domain, the region that mediates formin-dependent actin polymerization, and that the CLIP-170 F-actin-binding region overlaps with the MT-binding region. Consistent with these observations, in vitro competition assays indicate that CLIP-170:F-actin and CLIP-170:MT interactions are mutually exclusive. Taken together, these observations lead us to speculate that direct CLIP-170:F-actin interactions may function to reduce the stability of MTs in actin-rich regions of the cell, as previously proposed for EB1.

biochemistry↗

bioRxiv2021

Canagliflozin increases adenoma burden in female APCMin/+ mice

The diabetes drug canagliflozin acts primarily by inhibiting glucose reuptake by the sodium glucose transporter 2 (SGLT2) in the kidney proximal tubule, thereby lowering serum glucose levels. Canagliflozin also acts on SGLT1, a related transporter responsible for glucose uptake in the small intestine and more distal kidney tubules. Several cancers overexpress SGLT1 and SGLT2, where these transporters fuel tumor metabolism. A recent study by NIAs Interventions Testing Program (ITP) showed that canagliflozin treatment extends lifespan in male mice. Since cancer is the major cause of death in most mouse strains, including the UM-HET3 strain used by the ITP, this observation suggests that canagliflozin might exert anti-cancer effects in this context. Here, we treated a commonly-used mouse neoplasia model -- the intestinal adenoma-prone APCMin/+ strain -- with canagliflozin, to test the effects of drug treatment on tumor burden. Surprisingly, canagliflozin increased the total area of intestine involved by adenomas, an effect that was most marked in the distal intestine and in female mice. Immunohistochemical analysis suggested that canagliflozin may not influence adenoma growth via direct SGLT1/2 inhibition in neoplastic cells themselves. Instead, our results are most consistent with a model whereby canagliflozin aggravates adenoma development by altering the anatomic distribution of intestinal glucose absorption, as evidenced by increases in postprandial GLP-1 levels consistent with delayed glucose absorption. Our results suggest that canagliflozin exacerbates adenomatosis in the APCMin/+ model via complex, cell-non-autonomous mechanisms, and hint that sex differences in incretin responses may underlie differential effects of this drug on lifespan.

cancer biology↗

bioRxiv2020

"Scentsor": A Whole-Cell Yeast Biosensor with an Olfactory Reporter for Low-Cost and Equipment-Free Detection of Pharmaceuticals

Portable and inexpensive analytical tools are required to monitor pharmaceutical quality in technology limited settings including low- and middle-income countries (LMICs). Whole cell yeast biosensors have the potential to help meet this need. However, most of the read-outs for yeast biosensors require expensive equipment or reagents. To overcome this challenge, we have designed a yeast biosensor that produces a unique scent as a readout. This inducible scent biosensor, or "scentsor," does not require the user to administer additional reagents for reporter development and utilizes only the users nose to be "read." In this manuscript, we describe a scentsor that is responsive to the hormone estradiol (E2). The best estimate threshold (BET) for E2 detection with a panel of human volunteers (n = 49) is 39 nM E2 (15 nM when "non-smellers" are excluded). This concentration of E2 is sensitive enough to detect levels of E2 that would be found in dosage forms. This manuscript provides evidence that scent has potential for use in portable yeast biosensors as a read out, particularly for use in technology-limited environments.

synthetic biology↗

bioRxiv2020

Muribaculaceae genomes assembled from metagenomes suggest genetic drivers of differential response to acarbose treatment in mice

The drug acarbose is used to treat diabetes, and, by inhibiting -amylase in the small intestine, increases the amount of starch entering the lower digestive tract. This results in changes to the composition of the microbiota and their fermentation products. Acarbose also increases longevity in mice, an effect that has been correlated with increased production of the short-chain fatty acids propionate and butyrate. In experiments replicated across three study sites, two distantly related species in the bacterial family Muribaculaceae were dramatically more abundant in acarbose-treated mice, distinguishing these responders from other members of the family. Bacteria in the family Muribaculaceae are predicted to produce propionate as a fermentation end product and are abundant and diverse in the guts of mice, although few isolates are available. We reconstructed genomes from metagenomes (MAGs) for nine populations of Muribaculaceae to examine factors that distinguish species that respond positively to acarbose. We found two closely related MAGs (B1A and B1B) from one responsive species that both contain a polysaccharide utilization locus with a predicted extracellular -amylase. These genomes also shared a periplasmic neopullulanase with another, distantly related MAG (B2) representative of the only other responsive species. This gene differentiated these three MAGs from MAGs representative of non-responding species. Differential gene content in B1A and B1B may be associated with the inconsistent response of this species to acarbose across study sites. This work demonstrates the utility of culture-free genomics for inferring the ecological roles of gut bacteria including their response to pharmaceutical perturbations. ImportanceThe drug acarbose is used to treat diabetes by preventing the breakdown of starch in the small intestine, resulting in dramatic changes in the abundance of some members of the gut microbiome and its fermentation products. In mice, several of the bacteria that respond most positively are classified in the family Muribaculaceae, members of which produce propionate as a primary fermentation product. Propionate has been associated with gut health and increased longevity in mice. We found that genomes of the most responsive Muribaculaceae showed signs of specialization for starch fermentation, presumably providing them a competitive advantage in the large intestine of animals consuming acarbose. Comparisons among genomes enhance existing models for the ecological niches occupied by members of this family. In addition, genes encoding one type of enzyme known to participate in starch breakdown were found in all three genomes from responding species, but none of the other genomes.

microbiology↗

bioRxiv2020

Sex hormones underlying 17a-Estradiol effects on neuroinflammation

17--estradiol (17aE2) treatment extends lifespan in male mice and can reduce neuroinflammatory responses in the hypothalamus of 12-month-old males. Although 17aE2 improves longevity in males, female mice are unaffected, suggesting a sexually dimorphic pattern of lifespan regulation. We tested whether the sex-specific effects of 17aE2 on neuroinflammatory responses are mediated by sex hormones and whether hypothalamic changes extend to other brain regions in old age. Manipulating sex hormone levels through gonadectomy, we show that sex-specific effects of 17aE2 on age-associated gliosis are brain region-specific and are partially dependent on gonadal hormone production. 17aE2 treatment started at 4 months of age protected 25-month-old males from hypothalamic inflammation. Castration prior to 17aE2 exposure reduced the effect of 17aE2 on hypothalamic astrogliosis. By contrast, sex-specific changes in microgliosis with 17aE2 were not significantly affected by castration in males. While 17aE2 treatment had no effect of hypothalamic astrocytes or microglia in intact females, ovariectomy significantly increased the occurrence of hypothalamic gliosis evaluated in 25-month-old females, which was partially reduced by 17aE2. In the hippocampus, both male and female gonadally-derived hormones influenced the severity of gliosis and the responsiveness to 17aE2 in a regiondependent manner. The male-specific effects of 17aE2 correlate with changes in hypothalamic ER expression, highlighting a receptor through which 17aE2 could act. The results of this study demonstrate that neuroinflammatory responses to 17aE2 are partially controlled by the presence of sex-specific gonads. Interactions between sex-steroids and neuroinflammation could, therefore, influence late-life health and disease onset, leading to sexual dimorphism in aging.

neuroscience↗

bioRxiv2020

Canagliflozin Extends Lifespan in Genetically Heterogeneous Male But Not Female Mice

Canagliflozin (Cana) is an inhibitor of the sodium glucose transporter 2 (SGLT2), and is thought to act by blocking renal reuptake and intestinal absorption of glucose. Cana is FDA-approved for treatment of diabetes, and affords protection from cardiovascular and kidney diseases. In the context of the mouse Interventions Testing Program, genetically heterogeneous mice were given chow containing 180 ppm Cana at 7 months of age until their death. Cana extended median survival of male mice by 14%, with p < 0.001 by log-rank test. Cana also increased by 9% the age for 90th percentile survival (p < 0.001 by Wang/Allison test), with parallel effects seen at each of three test sites. Cana did not alter the distribution of inferred cause of death, nor of incidental pathology findings at end-of-life necropsies. No benefits were seen in female mice. The lifespan benefit of Cana is likely to reflect blunting of peak glucose levels, because similar longevity effects are seen in mice given acarbose, a diabetes drug that blocks glucose surges through a distinct mechanism, i.e. slowing breakdown of carbohydrate in the intestine. Interventions that control daily peak glucose levels deserve attention as possible preventive medicines to protect from a wide range of late-life neoplastic and degenerative diseases.Competing Interest StatementThe authors have declared no competing interest.View Full Text

pathology↗

bioRxiv2019

Universal assay for measuring vertebrate telomeres by real-time quantitative PCR

Telomere length dynamics are an established biomarker of health and aging in animals. The study of telomeres in numerous species has been facilitated by methods to measure telomere length by real-time quantitative PCR (qPCR). In this method, telomere length is determined by quantifying the amount of telomeric DNA repeats in a sample and normalizing this to the total amount of genomic DNA. This normalization requires the development of genomic reference primers suitable for qPCR, which remains challenging in non-model organism with genomes that have not been sequenced. Here we report reference primers that can be used in qPCR to measure telomere lengths in any vertebrate species. We designed primer pairs to amplify genetic elements that are highly conserved between evolutionarily distant taxa and tested them in species that span the vertebrate tree of life. We report five primer pairs that meet the specificity and reproducibility standards of qPCR. In addition, we demonstrate how to choose the best primers for a given species by testing the primers on multiple individuals within a species and applying an established computational tool. These reference primers can facilitate the application of qPCR-based telomere length measurements in any vertebrate species of ecological or economic interest.

molecular biology↗

bioRxiv2018

Changes in the gut microbiota and fermentation products associated with enhanced longevity in acarbose-treated mice

BackgroundTreatment with the -glucosidase inhibitor acarbose increases median lifespan by approximately 20% in male mice and 5% in females. This longevity extension differs from dietary restriction based on a number of features, including the relatively small effects on weight and the sex-specificity of the lifespan effect. By inhibiting host digestion, acarbose increases the flux of starch to the lower digestive system, resulting in changes to the gut microbiota and their fermentation products. Given the documented health benefits of short-chain fatty acids (SCFAs), the dominant products of starch fermentation by gut bacteria, this secondary effect of acarbose could contribute to increased longevity in mice. To explore this hypothesis, we compared the fecal microbiome of mice treated with acarbose to control mice at three independent study sites.\n\nResultsMicrobial communities and the concentrations of SCFAs in the feces of mice treated with acarbose were notably different from those of control mice. At all three study sites, the bloom of a single bacterial taxon was the most obvious response to acarbose treatment. The blooming populations were classified to the largely uncultured Bacteroidales family Muribaculaceae and were the same taxonomic unit at two of the three sites. Total SCFA concentrations in feces were increased in treated mice, with increased butyrate and propionate in particular. Across all samples, Muribaculaceae abundance was strongly correlated with propionate and community composition was an important predictor of SCFA concentrations. Cox proportional hazards regression showed that the fecal concentrations of acetate, butyrate, and propionate were, together, predictive of mouse longevity even while controlling for sex, site, and acarbose.\n\nConclusionWe have demonstrated a correlation between fecal SCFAs and lifespan in mice, suggesting a role of the gut microbiota in the longevity-enhancing properties of acarbose. Treatment modulated the taxonomic composition and fermentation products of the gut microbiome, while the site-dependence of the microbiota illustrates the challenges facing reproducibility and interpretation in microbiome studies. These results motivate future studies exploring manipulation of the gut microbial community and its fermentation products for increased longevity, and to test a causal role of SCFAs in the observed effects of acarbose.

microbiology↗