Aging remains a challenging biological process to quantify. Designing effective aging therapeutics hinges on the ability to reliably measure it.
One promising strategy is assessing age-related changes to the 3D structure of DNA. Epigenetic clocks quantify these structural changes, using them as inputs to predict the biological age of the tissue.
In addition to the nucleotide sequence, the 3D structure of a DNA strand holds valuable information, too. The most common structural change to DNA is methylation – the addition of a methyl group to a cytosine base at a cytosine/guanine nucleotide pair (CpG site). Methylation changes the shape, and therefore the function, of certain areas of DNA; the methylation status of certain CpG sites change predictably with age.
These changes can be used to create epigenetic “clocks” to quantify the age of an animal or tissue. Just like DNA, methylation can be easily and cheaply sequenced. Different epigenetic clocks weight different combinations of CpG sites, often 1000s, to calculate the predicted age of an animal or tissue.
The use of epigenetics in aging drug development
Loyal is developing drugs intended to extend lifespan (years of life) and healthspan (quality of life). However, it inevitably takes years to determine whether a potential aging drug actually impacts the aging process. Epigenetic clocks may allow one to predict the efficacy (or lack thereof) of a novel aging drug potentially years before measurable changes in healthspan and lifespan.
Put simply, a reliable epigenetic clock may help us understand if an animal is aging quickly or slowly in relation to its peers, and whether a specific intervention has affected that rate of aging.
Loyal has licensed a novel clock and methodology from the Ideker Group at The University of California, San Diego.
This clock identified aging-relevant CpG sites that are conserved between mice, dogs and humans, laying the foundations for conserved aging quantification. In their Cell Systems publication, the Ideker Group showed that their epigenetic clock can determine, within one year, the chronological age of a dog. The paper also proposes a more accurate conversion of dog and human years, especially relevant given Loyal’s thesis that developing dog aging drugs will be a key step to developing human aging drugs.
In addition to determining the chronological age of a dog – especially important in the case of shelter dogs and others without birth records – this work out of the Ideker group may help:
- Provide early evidence for potential future customers that an aging treatment is indeed slowing or reversing the aging process in their dog.
- Speed up drug development iteration by use as a surrogate endpoint/aging biomarker in clinical trials.
- Point to new aging targets by studying the specific structural changes to DNA and their downstream consequences.
In addition, Loyal has partnered with the Morris Animal Foundation to investigate the potential use of DNA methylation changes to predict cancer onset in Golden Retrievers .
B-cell lymphoma and hemangiosarcoma are the leading causes of death in Goldens; earlier detection and therefore intervention could result in longer, happier lives for this breed. Additionally, understanding conserved risk-factors for age-related cancers may help identify potential drug development targets for both Goldens and humans.
Most of the methodology for building epigenetic clocks has involved using basic linear regressions and simple representations of methylation as single numbers. Loyal is leveraging the latest machine and deep learning models – in addition to representations of genomic data gleaned from natural language processing algorithms – to access the full richness of information available within the epigenome. We believe this will yield insights beyond age measurement and provide a more holistic view of the aging organism.
- Wang T et al. Quantitative Translation of Dog-to-Human Aging by Conserved Remodeling of the DNA Methylome. Cell Syst. 2020 Aug 26;11(2):176-185.e6. doi: 10.1016/j.cels.2020.06.006.
- Morris Animal Foundation Partners with Loyal to Study Dogs’ Genetic Changes that Occur as They Age. June 7, 2021. https://www.morrisanimalfoundation.org/article/loyal-dog-aging-study-golden-retriever.