Dog aging researchers identify LINE-1 “jumping” DNA as a potential drug target, while the relative effects of IGF-1 on aging during development and adulthood remain uncertain

Dog aging researchers identify LINE-1 “jumping” DNA as a potential drug target, while the relative effects of IGF-1 on aging during development and adulthood remain uncertain

On November 2, the Longevity for Dogs podcast from the Dog Aging Institute released a conversation between institute president Matt Kaeberlein and Noah Snyder-Mackler of Arizona State University. Snyder-Mackler is the senior author of an October 8 paper in Science that used DNA marks in blood samples from 894 dogs in the Dog Aging Project to estimate their rate of aging.

Large dogs have shorter lives than small dogs. To test whether this difference is reflected in their cells, the authors used an epigenetic clock, an algorithm that estimates age from DNA methylation: chemical marks that switch genes on and off. On average, the clock estimated large dogs to be older than their chronological age. The gap predicted mortality: the larger the gap, the greater the risk of dying within the next two years.

The marks were measured in blood immune cells; other organs may age differently. Evan MacLean of the Dog Aging Project noted that memory and thinking decline at similar rates in dogs of all sizes: “large dogs may simply die before they develop any cognitive impairment”.

To identify a mechanism behind this difference, the authors compared age-related loss of methylation marks across the genome. Large dogs lose these marks faster overall, with the most pronounced loss occurring in LINE-1 transposons, “jumping” DNA sequences that copy themselves and insert those copies into new locations. Methylation keeps them inactive. With age, methylation is lost particularly rapidly from “young” LINE-1 copies that remain capable of copying themselves. Cells mistake RNA and DNA fragments produced during LINE-1 copying for viral material and respond with inflammation, while a new insertion can initiate a tumor or damage a gene the cell needs.

The speakers suggest that loss of control over LINE-1 may be one of many causes of age-related disease. The sequence of events linking methylation loss to inflammation could be interrupted at an intermediate step. In their view, blocking transposon activity would probably meaningfully extend the years spent in good health and might also extend lifespan.

Reverse transcriptase inhibitors, antiviral drugs such as those used to treat HIV, are being tested against LINE-1. They block the enzyme that LINE-1 uses to convert its RNA copy into DNA. Vera Gorbunova’s laboratory has used these drugs to suppress LINE-1 in mice and in cells, but Snyder-Mackler says the evidence at the whole-organism level is mixed. In a preprint (a manuscript that has yet to undergo peer review), half of 99 retired sled dogs received one such drug, lamivudine, for about 30 months. The epigenetic clock slowed only in females and only during treatment, while lifespan did not change significantly.

The hormone IGF-1 is a major determinant of a dog’s size. Snyder-Mackler suggests that growth may link IGF-1 to methylation: more IGF-1 leads to more cell divisions, which are associated with less accurate maintenance of methylation marks. The speakers propose that high IGF-1 during early life establishes a state in which methylation declines faster. If so, lowering IGF-1 in an adult dog would have less effect on the component of aging mediated by methylation.

Lowering IGF-1 is the basis for LOY-001 and LOY-003 from Loyal, a company developing drugs to extend dogs’ lives. The drugs are intended for dogs whose skeletal growth is complete. The company states its hypothesis conditionally: “if we are right, LOY-001 and LOY-003 will extend lifespan in part by lowering IGF-1 levels”. The speakers say it remains an open question whether IGF-1 acts primarily during development or in adulthood. The Dog Aging Project could compare IGF-1 levels with DNA methylation in blood samples from the same dogs.