Transposable Element Methylation Instability Impairs Overall Genomic Regulation in Large Breeds

Why do large dogs tend to live shorter lives than their smaller counterparts? According to a new study of nearly 900 dogs, the answer may be written into their epigenome. The findings reveal that larger and male dogs undergo accelerated molecular aging, with pronounced DNA methylation (DNAm) on the X chromosome and at transposable elements (TEs).

Aging is a universal process, but its pace and biological mechanisms substantially differ between individuals and species. Domestic dogs offer a particularly useful model for understanding the biology of aging because their lifespans vary dramatically with body size. For example, smaller breeds can live nearly twice as long as larger breeds.

Moreover, companion dogs also live in human environments, consume commercial diets, and receive routine medical care, making them a relevant translational model for studying how genetic background and environmental exposures shape aging. However, how intrinsic factors such as size and biological sex influence variation in dog aging and lifespan remains unclear. Previous research has demonstrated that DNAm is a useful indicator of biological aging, with "epigenetic clocks" offering a way to understand the factors that accelerate or decelerate biological aging.

Blaise Mariner and colleagues generated 1,640 methylomes from a cohort of 894 dogs in the Dog Aging Project. They combined these molecular data with detailed genetic and demographic data. Mariner et al. found that molecular aging occurs most rapidly early in a dog's life.

What's more, larger and male dogs – both of which have shorter lifespans than their respective counterparts – age more quickly at the molecular level. The authors identified different epigenetic patterns underlying these effects. According to the findings, sex-related changes were concentrated on the X chromosome, while body-size-related changes were especially prominent in TEs, stretches of DNA that can influence genome stability and gene regulation.