Biology subjects

Kavanagh, K.

Publications and source records attributed to Kavanagh, K..

8 recordsLinked to original sources

bioRxiv2026

Integrative Multi-Omics Analysis Reveals Molecular Signatures of Age-Related Decline in Vervet Leg Skeletal Muscle

Age-related decline in skeletal muscle function, often manifesting as slower gait speed, contributes significantly to frailty and loss of independence. To uncover the molecular basis of this decline, we investigated coordinated changes across the transcriptome, miRNome, and methylome in vastus lateralis muscle from female vervet monkeys (Chlorocebus aethiops sabaeus), contrasting middle-aged animals with normal gait speed versus older animals with declining gait speed. Through multi-omics integration, we identified a molecular signature that sharply distinguishes these two groups. This signature involves key regulatory molecules, including miR-181a-5p, miR-320b and miR-425 control of SYNCRIP, miR-193b-3p regulation of MCL1 and PLAU, as well as a multi-omic regulatory network governing ZNF274 and ANP32E gene expression, and altered levels of mRNAs such as VEZT. Functional annotation implicates miRNA signatures with inverse expression of their mRNA targets operating within systems of skeletal muscle biology, metabolism, and potential immune-inflammation mechanisms. Collectively, these findings reveal an interconnected network of epigenetic, post-transcriptional, and transcriptional alterations associated with impaired muscle function during aging. This molecular signature provides novel insights into potential mechanisms driving sarcopenia and highlights specific molecules as potential targets for interventions aimed at preserving muscle health.

bioinformatics↗

bioRxiv2024

Comparative lifespan and healthspan of nonhuman primate species common to biomedical research

There is a critical need to generate age- and sex-specific survival curves to characterize chronological aging consistently across nonhuman primates (NHP) used in biomedical research. Sex-specific Kaplan-Meier survival curves were computed in 12 translational aging models: baboon, bonnet macaque, chimpanzee, common marmoset, coppery titi monkey, cotton-top tamarin, cynomolgus macaque, Japanese macaque, pigtail macaque, rhesus macaque, squirrel monkey, and vervet/African green. After employing strict inclusion criteria, primary results are based on 12,269 NHP that survived to adulthood and died of natural/health-related causes. A secondary analysis was completed for 32,616 NHP that died of any cause. Results show a pattern of reduced male survival among catarrhines (African and Asian primates), especially macaques, but not platyrrhines (Central and South American primates). For many species, median lifespans were lower than previously reported. An important consideration is that these analyses may offer a better reflection of healthspan than lifespan since research NHP are typically euthanized for humane welfare reasons before their natural end of life. This resource represents the most comprehensive characterization of sex-specific lifespan and age-at-death distributions for 12 biomedically relevant species, to date. These results clarify relationships among NHP ages and provide a valuable resource for the aging research community, improving human-NHP age equivalencies, informing investigators of expected survival rates, providing a metric for comparisons in future studies, and contributing to understanding of factors driving lifespan differences within and among species.

physiology↗

bioRxiv2021

Integrated Omics Analysis Reveals Sirtuin Signaling is Central to Hepatic Response to a High Fructose Diet

BackgroundDietary high fructose (HFr) is a known metabolic disruptor contributing to development of obesity and diabetes in Western societies. Initial molecular changes from exposure to HFr on liver metabolism may be essential to understand the perturbations leading to insulin resistance and abnormalities in lipid and carbohydrate metabolism. We studied vervet monkeys (Clorocebus aethiops sabaeus) fed a HFr (n=5) or chow diet (n=5) for 6 weeks, and obtained clinical measures of liver function, blood insulin, cholesterol and triglycerides. In addition, we performed untargeted global transcriptomics, proteomics, and metabolomics analyses on liver biopsies to determine the molecular impact of a HFr diet on coordinated pathways and networks that differed by diet. ResultsWe show that integration of omics data sets improved statistical significance for some pathways and networks, and decreased significance for others, suggesting that multiple omics datasets enhance confidence in relevant pathway and network identification. Specifically, we found that sirtuin signaling and a peroxisome proliferator activated receptor alpha (PPARA) regulatory network were significantly altered in hepatic response to HFr. Integration of metabolomics and miRNAs data further strengthened our findings. ConclusionsOur integrated analysis of three types of omics data with pathway and regulatory network analysis demonstrates the usefulness of this approach for discovery of molecular networks central to a biological response. In addition, metabolites aspartic acid and docosahexaenoic acid (DHA), protein ATG3, and genes ATG7, HMGCS2 link sirtuin signaling and the PPARA network suggesting molecular mechanisms for altered hepatic gluconeogenesis from consumption of a HFr diet.

systems biology↗

bioRxiv2021

Hypertension drives microbial translocation and shifts in the fecal microbiome of non-human primates

Accumulating evidence indicates a link between gut barrier dysfunction and hypertension. However, it is unclear whether hypertension dictates gut barrier dysfunction or vice versa and whether the gut microbiome plays a role. To better understand this relationship, first, we cross-sectionally examined hypertension and other cardio-metabolic risk factors and gut barrier function in a population of 150 nonhuman primates. Interestingly, the animals with hypertension showed evidence of gut barrier dysfunction (i.e., translocation of microbes through the gut wall), as indicated by higher plasma levels of lipopolysaccharide-binding protein (LBP)-1, compared to normotensive animals. Further, plasma LBP-1 levels were strongly correlated with diastolic blood pressure, independent of age and other health markers, suggesting specificity of the effect of hypertension on microbial translocation. In a subsequent longitudinal study (analysis at baseline, 12 and 27 months), hypertensive animals had higher plasma levels of LBP-1 at all the time points and greater bacterial gene expression in mesenteric lymph nodes compared to normotensive animals, confirming microbe translocation. Concomitantly, we identified distinct dysbiosis in the gut microbial signature of hypertensive versus normotensive animals at 12 and 27 months. These results suggest that hypertension drives microbial translocation in the gut and eventually unhealthy shifts in the gut microbiome, possibly contributing to poor health outcomes, providing further impetus for the management of hypertension. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=127 SRC="FIGDIR/small/454379v1_ufig1.gif" ALT="Figure 1"> View larger version (32K): org.highwire.dtl.DTLVardef@2b2990org.highwire.dtl.DTLVardef@1b5e678org.highwire.dtl.DTLVardef@12de192org.highwire.dtl.DTLVardef@1344f6a_HPS_FORMAT_FIGEXP M_FIG C_FIG

pathology↗

bioRxiv2020

Epigenetic clock and methylation studies in vervet monkeys

DNA methylation-based biomarkers of aging have been developed for many mammals but not yet for the vervet monkey (Chlorocebus sabaeus), which is a valuable non-human primate model for biomedical studies. We generated novel DNA methylation data from vervet cerebral cortex, blood, and liver using highly conserved mammalian CpGs represented on a custom array (HorvathMammalMethylChip40). We present six DNA methylation-based estimators of age: vervet multi-tissue epigenetic clock and tissue-specific clocks for brain cortex, blood, and liver. In addition, two dual species clocks (human-vervet clocks) for measuring chronological age and relative age, respectively. Relative age was defined as ratio of chronological age to maximum lifespan to address the species differences in maximum lifespan. The high accuracy of the human-vervet clocks demonstrates that epigenetic aging processes are evolutionary conserved in primates. When applying these vervet clocks to tissue samples from another primate species, rhesus macaque, we observed high age correlations but strong offsets. We characterized CpGs that correlate significantly with age in the vervet. CpG probes hypermethylated with age across tissues were located near the targets of Polycomb proteins SUZ12 and EED, and genes possessing the trimethylated H3K27 mark in their promoters. The epigenetic clocks are expected to be useful for age estimation of wild-born animals and anti-aging studies in vervets.

developmental biology↗

bioRxiv2020

Age-Related Colonic Mucosal Microbiome Community Shifts in Monkeys

Recent evidence suggests that gut microbiome changes that occur with age impact the health of the host. While it is known that the gut microbiome and physiological systems interact, the relationship between the microbiome in an aged body system remains to be clearly defined, particularly in the context of inflammation. Therefore, we aimed to evaluate systemic inflammation and the mucosal microbiome in young and old female vervet monkeys. Ascending colon mucosal biopsies and blood samples from healthy young and old monkeys were collected for 16S rRNA gene sequencing and cytokine analyses, respectively. To demonstrate microbial co-occurrence patterns, we used Kendalls tau correlation measure of interactions between microbes. We found elevated levels of plasma MCP-1 and CRP in old monkeys, which are indicative of higher systemic inflammation. Microbiome analysis revealed increases in abundance of opportunistic pathobionts such as members of the Proteobacteria phylum in old monkeys. At the family level, abundances of Prevotellaceae and Helicobacteraceae were higher in old monkeys than in young. We also found significantly lower Firmicutes to Bacteroidetes ratio (P= 0.03) and lower abundance of butyrate-producing microbes in old monkeys, consistent with a less healthy profile. Microbial community co-occurrence analysis revealed 13 nodes and 41 associations in the young monkeys, but only 12 nodes and 21 associations in the old monkeys. Our findings provided novel insights into systemic inflammation and gut microbial interactions, highlights the importance of the mucosal niche changes with age, and may facilitate further understanding of the decline in the stability of the microbial community with aging.

genomics↗

bioRxiv2020

Impact of Advanced Maternal Age on Physiologic Adaptations to Pregnancy in Vervet Monkeys

ContextThe trend to delay pregnancy in the United States has resulted in the number of advanced maternal age (AMA) pregnancies to also increase. In humans, AMA is associated with a variety of pregnancy-related pathologies such as preeclampsia (PE). While AMA is known to be a factor which contributes to the development of pregnancy-induced diseases, the molecular and cellular mechanisms giving rise to this phenomenon are still very limited. This is due in part to lack of a pre-clinical model which has physiologic relevance to human pregnancy while also allowing control of environmental and genetic variability inherent in human studies. ObjectiveTo determine potential physiologic relevance of the vervet/African green monkey (Chlorocebus aethiops sabaeus) as a pre-clinical model to study the effects of AMA on adaptations to pregnancy. DesignThirteen age-diverse pregnant vervet monkeys (3-16 y.o.) were utilized to measure third trimester blood pressure (BP), complete blood count, iron measurements and hormone levels. ResultsSignificant associations were observed between third trimester diastolic BP and maternal age. Furthermore, the presence of leukocytosis with enhanced circulating neutrophils was observed in AMA mothers compared to younger mothers. Moreover, we observed a negative relationship between maternal age and estradiol, progesterone and cortisol levels. Finally, offspring born to AMA mothers displayed a postnatal growth retardation phenotype. ConclusionsThese studies demonstrate physiologic impairment in the adaptation to pregnancy in AMA vervet/African green monkeys. Our data indicate the vervet/African green monkey may serve as a useful pre-clinical model and tool for deciphering pathological mediators of maternal disease in AMA pregnancy.

physiology↗

bioRxiv2019

Type-2-diabetes alters CSF but not plasma metabolomic and AD risk profiles in vervet monkeys

Epidemiological studies suggest that individuals with type 2 diabetes (T2D) have a 2-4 fold increased risk for developing Alzheimers disease (AD), however the exact mechanisms linking the two disease is unknown. In both conditions, the majority of pathophysiological changes (including glucose and insulin dysregulation, insulin resistance, and AD-related changes in A{beta} and tau) occur decades before the onset of clinical symptoms and diagnosis. In this study, we investigated the relationship between metabolic biomarkers associated with T2D and AD-related pathology, including A{beta} levels, from cerebrospinal fluid (CSF) and fasting plasma of healthy, prediabetic (PreD), and T2D vervet monkeys (Chlorocebus aethiops sabeus). Consistent with the human disease, T2D monkeys have increased plasma and CSF glucose levels as they transition from normoglycemia to pre-diabetic and diabetic states. Although plasma levels of acylcarnitines and amino acids remained largely unchanged, peripheral hyperglycemia correlated with decreased CSF acylcarnitines and CSF amino acids, including branched chain amino acid (BCAA) concentrations, suggesting profound changes in cerebral metabolism coincident with systemic glucose dysregulation. Moreover, CSF A{beta}40 and CSF A{beta}42 levels decreased in T2D monkeys, a phenomenon observed in the human course of AD which coincides with increased amyloid deposition within the brain. In agreement with our previous studies in mice, CSF A{beta}40 and CSF A{beta}42 were highly correlated with CSF glucose levels, suggesting that glucose levels in the brain are associated with changes in A{beta} metabolism. Interestingly, CSF A{beta}40 and CSF A{beta}42 levels were also highly correlated with plasma but not CSF lactate levels, suggesting that plasma lactate might serve as a potential biomarker of disease progression in AD. Moreover, CSF glucose and plasma lactate levels were correlated with CSF amino acid and acylcarnitine levels, demonstrating alterations in cerebral metabolism occurring with the onset of T2D. Together, these data suggest that peripheral metabolic changes associated with the development of T2D produce alterations in brain metabolism that lead to early changes in the amyloid cascade, similar to those observed in pre-symptomatic AD.

neuroscience↗