Biology subjects

Little, T. J.

Publications and source records attributed to Little, T. J..

9 recordsLinked to original sources

bioRxiv2026

Increased stress in early life epigenetically rewires pathways related to aging and longevity

Environmental conditions experienced early in life have profound consequences for vertebrate health, yet the molecular pathways linking developmental stress to aging and reduced lifespan remain poorly understood. Through a novel highly accurate epigenetic clock, developed from RRBS-based blood DNA methylation profiles, we show that experimental lifespan-reducing early-life stress rapidly accelerates epigenetic age in zebra finch chicks (Taeniopygia guttata). Corticosterone-treated 29-day-old chicks share differentially methylated loci with non-treated aged birds and cluster with 6-month-old birds. The transcriptional repressor ZBTB16 emerges as an epigenetically top age-correlated gene and is strongest affected by corticosterone. Elevated developmental corticosterone causes rapid epigenetic remodelling of metabolic pathways well-established in aging and longevity. Our results demonstrate epigenetic rewiring of the aging trajectory through conserved stress-survival mechanisms immediately following elevated early-life stress exposure.

developmental biology↗

bioRxiv2026

Optimal virulence in ageing populations

Global populations are ageing at an unprecedented rate. For many diseases, age is a strong indicator of susceptibility, morbidity, or mortality. Principles of evolutionary biology can be leveraged to understand how pathogens may optimally exploit new populations, and the impact of this on the global burden of infectious-disease-induced mortality. We parameterised an age-specific R0 model with 2017 epidemiological data on Measles, Tuberculosis, Meningitis, and Ebola, and age-specific demographic estimates for 2017 and 2050, for the seven Global Burden of Disease super-regions. We explored the theoretical trade-offs between pathogen virulence & transmission, and virulence & host recovery, parameterising trade-off parameters using Latin Hypercube Sampling. Population ageing between 2017-2050 saw an increase in virulence induced mortality in four settings: 1) Ebola in sub-Saharan Africa, 2) Measles in central/eastern Europe & central Asia region, 3) Measles in North Africa & the Middle East and 4) Tuberculosis in the central/eastern Europe & central Asia region. The decrease in infection duration due to an increase of elderly people drives pathogen virulence down for diseases in the remaining settings. Understanding the mechanisms that shape pathogen dynamics and leveraging this to predict future challenges is key to endemic disease management in a rapidly changing world. Author SummaryKey aspects of disease transmission including susceptibility to infection, the severity of infection, and the probability of dying from that infection, are affected by host age. Global populations are rapidly ageing, so that the mean age of most populations is generally higher than it used to be and is set to continue on this trajectory. This suggests that the dynamics of infectious diseases are also likely to change, although infectious disease dynamics tend to be non-linear as these key parameters interact. We have developed a dynamic modelling framework to explore how changes in population age structure might impact the optimal level of pathogen virulence in a population. We have chosen four infectious diseases as case studies, that differentially impact certain age classes to illustrate these dynamics. We have parameterised this framework with open access data for each of the seven Global Burden of Disease super-regions and show that population ageing can increase virulence for several diseases in differing global regions, whilst increased background rates of mortality can drive virulence down in others.

evolutionary biology↗

bioRxiv2025

Reducing food stress and parasitism may have unexpected consequences on faecal corticosterone in a wild rodent

In wild animals, glucocorticoid hormones play a key role in responses to environmental stressors and the maintenance of homeostasis, allocating energy between energy-demanding processes. Although acute rises in glucocorticoids are beneficial for short-term survival, prolonged exposure can be detrimental to reproduction and survival. Thus, understanding the factors driving glucocorticoid concentrations is crucial for understanding key processes in ecology and evolution. Here, we examined how manipulation of two environmental stressors - food availability and parasite burden, influence levels of faecal corticosterone in a wild population of wood mice (Apodemus sylvaticus). To do so, we experimentally altered nutrition via food supplementation and reduced gastrointestinal nematode infection by anthelmintic treatment, using Heligmosomoides polygyrus as an indicator of treatment efficacy. Faecal corticosterone was not found to be impacted by food supplementation or anthelminthic treatment. However, our results may be mediated by variation in resource availability or masked by other factors that affect corticosterone. For example, corticosterone declined seasonally and was higher in adult, female mice. While we expected higher food availability and lower worm burden to decrease stress, putatively higher rates of reproduction in food supplemented areas could neutralise any decreases in corticosterone associated with alleviation of food and parasite stress. Thus, alleviating stress in the wild may have unintended consequences on fitness.

evolutionary biology↗

bioRxiv2025

A DNA methylation-based clock for age estimates in the wood mouse (Apodemus sylvaticus)

Environmental stressors are expected to accelerate senescence but demonstrating this requires both a measure of senescence and knowledge of chronological age - data rarely available for most wild animals. Here, we constructed a DNA methylation-based epigenetic clock for the wood mouse (Apodemus sylvaticus) using known-aged laboratory individuals and applied it to a wild population of unknown ages. This represents one of the first demonstrations that a laboratory-trained epigenetic clock can be used to infer age structure in free-living animals. Multiple lines of evidence validated use of the clock in wild individuals: age estimates fell within expected ranges, recapitulated population demographic structure, and recovered predicted signatures of senescence, including an increase in infection probability with age. Moreover, wild mice given experimental food supplementation and parasite-removal drugs exhibited slower epigenetic ageing rates. Together, our findings demonstrate that epigenetic clocks can infer both chronological age and ageing rates in the wild, providing a powerful framework to identify the ecological and individual determinants of ageing.

genomics↗

bioRxiv2023

Elevated epigenetic age in wild compared to lab-raised house mice

Age is a key parameter in population ecology, with a myriad of biological processes changing with age as organisms develop in early life then later senesce. As age is often hard to accurately measure with non-lethal methods, epigenetic methods of age estimation (epigenetic clocks) have become a popular tool in animal ecology, and are often developed or calibrated using captive animals of known age. However, studies typically rely on invasive blood or tissue samples, which limits their application in more sensitive or elusive species. Moreover, few studies have directly assessed how methylation patterns and epigenetic age estimates compare across environmental contexts (e.g., captive or lab-based vs. wild animals). Here, we built a targeted epigenetic clock from laboratory house mice (strain C57BL/6, Mus musculus) using DNA from non-invasive faecal samples, and then used it to estimate age in a population of wild mice (Mus musculus domesticus) of unknown age. This lab mouse-derived epigenetic clock accurately predicted adult wild mice to be older than juveniles, and showed that wild mice typically increased in epigenetic age over time, but with wide variation in epigenetic ageing rate among individuals. Our results also suggested that, for a given body mass, wild mice had higher methylation across targeted CpG sites than lab mice (and consistently higher epigenetic age estimates as a result), even among the smallest, juvenile mice. This suggests wild and lab mice may display different CpG methylation levels from very early in life, and indicates caution is needed when developing epigenetic clocks on lab animals and applying them in the wild.

molecular biology↗

bioRxiv2021

Daphnia magna egg piRNA cluster expression profiles change as mothers age.

PiRNAs prevent transposable elements wreaking havoc on the germline genome. Changes in piRNA expression over the lifetime of an individual may impact on ageing through continued suppression, or release, of transposable element expression. We identified piRNA producing clusters in the genome of Daphnia magna by a combination of bioinformatic methods, and then contrasted their expression between parthenogenetically produced eggs representing maternally-deposited germline piRNAs of young (having their 1st clutch) and old (having their 5th clutch) mothers. Results from eggs were compared to cluster expression in three generations of adults. As for other arthropods, D. magna encodes long uni-directionally transcribed non-coding RNAs which consist of transposable element fragments which account for most piRNAs expressed. Egg tissues showed extensive differences between clutches from young mothers and those from old mothers, with 578 and 686 piRNA clusters upregulated, respectively, although most log fold-change differences for significant clusters were modest. When considering only highly expressed clusters, there was a bias towards 1st clutch eggs at 41 upregulated versus eight clusters in the eggs from older mothers. F0 generation differences between young and old mothers were fewer than eggs, as 179 clusters were up-regulated in young versus 170 old mothers. This dropped to 31 versus 22 piRNA clusters when comparing adults in the F1 generation, and no differences were detected in the F3 generation. These patterns were similar to that observed for D. magna micro-RNA expression. Little overlap in differentially expressed clusters was found between adults containing mixed somatic and germline (ovary) tissues and germ-line representing eggs. A cluster encompassing a Tudor domain containing gene important in the piRNA pathway was upregulated in the eggs from old mothers. We hypothesise that regulation of this gene this could form part of a feedback loop that reduces piRNA pathway activity explaining the reduced number of highly-expressed clusters in eggs from old mothers. Author SummarySmall RNAs shorter than 200 nucleotides often function by targeting RNAs with complementary nucleotide sequences for destruction. A subset of small RNAs, the Piwi-interacting RNAs or piRNAs are best known for silencing sequences of DNA that can jump between locations in the genome which can compromise the integrity of genomes. This protects offspring from sterility and other undesirable effects, hence piRNAs have been termed guardians of the genome. PiRNAs have several characteristics, such as a characteristic length and origin in genomic graveyards of junk DNA, that can be used to distinguish them from other small RNAs. Here, we used a combination of computational approaches to identify piRNA-producing clusters in the genome of the water flea Daphnia magna. We then contrasted expression of these clusters between genetically identical adults of different ages, their eggs, adult offspring and great-granddaughters. Adults and their eggs were markedly different in cluster expression by age, which was mostly lost by adulthood in offspring and not seen at all in great-granddaughters. By taking an innovative approach that can be applied to similar datasets of diverse organisms we have shown that piRNA expression, and therefore, stability of the genome can change with age.

genomics↗

bioRxiv2020

Methylation-Based Age Estimation in a Wild Mouse

The age structure of populations, or the ageing rate of individuals, impacts aspects of ecology, epidemiology and conservation. Yet for many wild organisms, age is an inaccessible trait. In many cases measuring age or ageing rates in the wild requires molecular biomarkers of age. Epigenetic clocks based on DNA methylation have been shown to accurately estimate the age of humans and laboratory mice, but they also show variable ticking rates that are associated with mortality risk above and beyond that predicted by chronological age. Thus, epigenetic clocks are proving to be useful markers of both chronological and biological age, and they are beginning to be applied to wild mammals and birds. We have acquired strong evidence that an accurate clock is possible for the wood mouse Apodemus sylvaticus by adapting epigenetic information from the laboratory mouse (Mus musculus). Apodemus sylvaticus is a well-studied, common small mammal in the UK and Europe, which is amenable to large-scale experimental perturbations and longitudinal sampling of individuals across their lives. These features of the wood mouse system offer opportunities to disentangle causal relationships between ageing rates and environmental stress. Our wood mouse epigenetic clock is PCR-based, and so requires only tiny amounts of tissue accessible through non-destructive sampling. We quantified methylation using Oxford Nanopore sequencing technology and present a new bioinformatics pipeline for data analysis. We thus describe a new and generalizable system that should enable ecologists and other field biologists to go from small tissue samples to an epigenetic clock for their study animal, which will enable investigations of ageing in the wild which where previously inaccessible.

genetics↗

bioRxiv2020

Daphnia magna modifies its gene expression extensively in response to caloric restriction revealing a novel effect on haemoglobin isoform preference

Caloric restriction (CR) produces clear phenotypic effects within and between generations of the model crustacean Daphnia magna. We have previously established that micro RNAs and cytosine methylation change in response to CR in this organism, and we demonstrate here that CR has a dramatic effect on gene expression. Over 6000 genes were differentially expressed between CR and well-fed D. magna, with a bias towards up-regulation of genes under caloric restriction. We identified a highly expressed haemoglobin gene that responds to CR by changing isoform proportions. Specifically, a transcript containing three erythrocruorin domains was strongly down-regulated under CR in favour of transcripts containing fewer or no such domains. This change in the haemoglobin mix is similar to the response to hypoxia in Daphnia, which is mediated through the transcription factor hypoxia-inducible factor 1, and ultimately the mTOR signalling pathway. This is the first report of a role for haemoglobin in the response to CR. We also observed high absolute expression of super-oxide dismutase (SOD) in normally-fed individuals, which contrasts with observations of high SOD levels under in CR in other taxa. However, key differentially expressed genes, like SOD, were not targeted by differentially expressed micro-RNAs. Whether the link between Haemoglobin and CR is the case in other organisms, or is related to the aquatic lifestyle, remains to be tested. It suggests that one response to CR may be to simply transport less oxygen and lower respiration.

genomics↗

bioRxiv2018

Genome-wide Methylation Patterns Under Caloric Restriction in Daphnia magna.

The degradation of epigenetic control with age is associated with progressive diseases of ageing, including cancers, immunodeficiency and diabetes. Reduced caloric intake slows the effects of aging and age-related diseases, a process likely to be mediated by the impact of caloric restriction on epigenetic factors such as DNA methylation. We used whole genome bisulphite sequencing to study how DNA methylation patterns change with diet in a small invertebrate, the crustacean Daphnia magna. Daphnia show the classic response of longer life under CR, and they reproduce clonally, which permits the study of epigenetic changes in the absence of genetic variation. Global CpG methylation was 0.7-0.9%, and there was no difference in overall methylation levels between normal and calorie restricted replicates. However, 453 regions were differentially methylated (DMRs) between the normally fed and calorie restricted (CR) replicates. Of these 61% were hypomethylated in the CR group, and 39% were hypermethylated in the CR group. Gene Ontogeny (GO) term enrichment of hyper and hypo-methylated genes showed significant over- and under-representation in three molecular function terms and four biological process GO terms. Notable among these were kinase and phosphorylation activity, which have a well-known functional link to cancers.

genomics↗