What is DNA methylation and how does it help us understand longevity?

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Zane Koch
by Zane Koch

When you go to the doctor, or your dog goes to the vet, measurements like blood pressure, height, and weight are often taken to build an understanding of the general health status of you or your dog. These are ‘biomarkers’—measurable indicators of the internal biological state of an organism. Different biomarkers serve different purposes, some help diagnose specific diseases and others measure general well-being. In the last decade, researchers studying aging have created new biomarkers for health and longevity, one of which is based on DNA methylation—a lens through which Loyal is studying aging in the X-Thousand Dogs study.

What is DNA methylation and epigenetics, and why does it matter for my dog’s health?

Before describing what DNA methylation is and how measurements of it can be used to promote healthy aging in dogs and humans, let’s discuss DNA. Inherited from an organism’s parents, DNA is an assembly manual for a body. DNA is a double-helix shaped chain of four different small compounds we call nucleotides and represent with the letters A, T, G, and C. Like an assembly manual, encoded in the structure of DNA are instructions for how to build each organ, tissue, and cell throughout a whole organism. The same DNA is replicated identically in nearly every cell of an organism, so in a dog every one of its cells has an essentially identical copy of its DNA.

Clearly, the wet tip of a dog’s nose is very different from its wagging tail, despite them both being made of cells containing identical DNA. The reason that the skin cells of a dog’s nose look so different from muscle cells in its tail is that only certain parts of the DNA are active in each – these active parts of the DNA are used as instructions to tell the cell what to construct and do. The mechanisms that control this activity of the DNA are called ‘epigenetics.’ There are many different components of epigenetics that can together be thought of as a table of contents for the assembly manual that is DNA. Each type of cell, whether that be skin, muscle, or otherwise, has a different table of contents telling it which sections of the assembly manual it is supposed to build from. DNA methylation is one of the many types of epigenetic modifications added to DNA that control which parts of the DNA are active in a cell. (For more on this check out our Epigenetics primer).

Specifically, a location in the DNA is said to be methylated when a methyl group (one carbon with three hydrogen atoms joined together) is added to it (Figure 1). A methyl group can only be added to locations where the nucleotide Cytosine (C) is followed by the nucleotide Guanine (G). These locations are called ‘CpG’ sites and are found throughout an organism’s DNA. Of the millions of CpG sites, which are methylated can be measured with a specific type of DNA sequencing using a saliva swab or blood draw.

DNA-methylation-de-methylation: on the left are 39 chromosomes for a male dog. Zooming into a chromosome, is highlighted cytosine groups. On the right, is an unmethylated cytosine and methylated cytosine.
Figure 1: A dog has 39 chromosomes. Within these chromosomes are DNA nucleotides which include methylated and unmethylated cytosines

As dogs age methylation changes, which can be modeled using epigenetic clocks

Recently, researchers have discovered that as time passes the patterns of DNA methylation in cells throughout an organism’s body change. Some CpG sites gain methyl groups, others lose them, and many remain relatively unchanged (Figure 2).

A graph showing % methylated on the y-axis and age (years) on the x-axis of many dogs and a chosen sample dog named Fido
Figure 2: Some CpG sites increase in % methylation with age, while others decrease

These changes in DNA methylation are closely linked to aging. So much so that computational models, called ‘epigenetic clocks,’ can accurately predict the age of an organism based on just its DNA methylation. Beyond predicting age, epigenetic clocks can also serve as biomarkers for health and aging. It has been shown that epigenetic clock predictions are associated with general physical capacities including frailty and grip strength, heart disease, mortality, and cancer (Lu et al. 2019, Levine et al. 2018). Furthermore, by studying DNA methylation, using epigenetic clocks and other methods, aging researchers–like those here at Loyal–can investigate fundamental questions about the molecular causes of aging.

Potential impactful applications of epigenetic clocks include: 

  • Providing a biomarker that veterinarians can use as a more accurate tool to assess your dog’s health.
  • Faster longevity drug testing. With further development, epigenetic clocks may become precise enough that the impact a supposed longevity-promoting drug has on an epigenetic clock prediction could become an initial step in assessing a drug’s efficacy. This would be substantially faster than waiting many years–or decades in humans–to assess whether a drug has slowed aging.

While there are many unanswered questions about the epigenetic changes that occur during aging, research in this domain has the potential to accelerate longevity research. At Loyal, we are building advanced tools that leverage our unique dog epigenetic datasets to predict health, longevity, and improve drug development. Soon you and your dog may benefit from these insights, either directly through a test informing health and lifestyle or indirectly through faster therapeutic development.

How can understanding epigenetic changes in dogs help us understand human aging and disease?

It turns out that in many ways dogs are actually a better species to study than humans if we want to understand healthy aging. This is because dogs live an accelerated life. They age faster than their human companions (Wang et al. 2020). So when we try to intervene in disease progression or to extend a dog’s health/lifespan, we will know more quickly whether the intervention works. Also, dogs have co-evolved with humans for tens of thousands of years, living in the same environments and leading similar lifestyles to their owners. This similarity allows researchers at Loyal to investigate the relationship between environmental and lifestyle factors with epigenetic changes that occur in dogs, and possibly humans, better than they could via a different model organism.

As size increases in the animal kingdom, lifespan increases. This is true of animals as small as a Shrew, Hummingbird, Rooster, up to larger animals like Emus, Polar Bears, Whales, and Elephants. On the other hand, German Shepherds do not life as long as their smaller counterparts, like toy breed dogs.
Figure 3: Generally, as size increases, lifespan increases, but the opposite happens in dogs

Dogs are special in many ways, but in one way in particular they truly stand out amongst the animal kingdom: the relationship between dog lifespan and body size. In almost all other species larger animals live longer lives (Figure 3). There are several theories as to why this occurs (Speakman et al. 2005). Dogs, however, are an exception—smaller dogs tend to live longer, whereas larger dogs unfortunately have fewer years on average. Why is this the case? What is it about dog biology that makes them such an outlier relative to other animals? We are currently researching this here at Loyal, and we believe that this relationship is a clue that will help us to unlock longer healthier lives for dogs and humans.

Jumbo, miniature american shepherd whispers in human's ear
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