Biology subjects

Slack, C.

Publications and source records attributed to Slack, C..

2 recordsLinked to original sources

bioRxiv2021

The impact of low input DNA on the reliability of DNA methylation as measured by the Illumina Infinium MethylationEPIC BeadChip

BackgroundDNA methylation (DNAm) is commonly assayed using the Illumina Infinium MethylationEPIC BeadChip, but there is currently little published evidence to define the lower limits of the amount of DNA that can be used whilst preserving data quality. Such evidence is valuable for analyses utilising precious or limited DNA sources. Materials and methodsWe use a single pooled sample of DNA in quadruplicate at three dilutions to define replicability and noise, and an independent population dataset of 328 individuals (from a community-based study including US-born non-Hispanic Black and white persons) to assess the impact of total DNA input on the quality of data generated using the Illumina Infinium MethylationEPIC BeadChip. ResultsData are less reliable and more noisy as DNA input decreases to 40ng, with clear reductions in data quality; however samples with a total input as low as 40ng pass standard quality control tests, and we observe little evidence that low input DNA obscures the associations between DNAm and two phenotypes, age and smoking status. ConclusionsDNA input as low as 40ng can be used with the Illumina Infinium MethylationEPIC BeadChip, provided quality checks and sensitivity analyses are undertaken.

bioinformatics↗

bioRxiv2020

Zoledronate extends healthspan and survival via the mevalonate pathway in a FOXO-dependent manner

Increased longevity has not been paralleled by extended healthspan, resulting in more years spent with multiple diseases in older age. As such, interventions to improve healthspan are urgently required. Zoledronate is a nitrogen containing bisphosphonate, which inhibits the farnesyl pyrophosphate synthase (FPPS) enzyme, central to the mevalonate pathway. It is already used clinically to prevent fractures in osteoporotic patients, who have been reported to derive unexpected and unexplained survival benefits. In this study we show that zoledronate has beneficial effects on both lifespan and healthspan using Drosophila as a model. We found that zoledronate extended lifespan, improved climbing activity and reduced intestinal epithelial dysplasia and permeability in aged flies. Mechanistic studies showed that zoledronate conferred resistance to oxidative stress and reduced accumulation of X-ray-induced DNA damage via inhibition of FPPS. Moreover, zoledronate inhibited pAKT in the mTOR pathway and functioned via dFOXO, a molecule associated with increased longevity, downstream of the mevalonate pathway. Taken together, our work indicates that zoledronate, a drug already widely used and dosed only once a year to prevent osteoporosis, modulates important mechanisms of ageing. Its repurposing holds great promise as a treatment to improve healthspan.

pharmacology and toxicology↗