Um, and DNA methylation is really important because it determines cell identity, it determines cell phenotype, and and basically how every cell is responding to its environment. So I like to use the analogy, I know there's a lot of analogies for epigenetics, or DNA methylation, but I like to use the analogy of a recipe. So basically, your genes are all the ingredients that you need to make anything. And your epigenetics or DNA methylation is the recipe on how each cell is going to make whatever it's going to go about doing. And essentially, what we know is that with age, this recipe gets a little messed up. So maybe you add too much of something, or you completely don't add a different ingredient. And this really is going to change the overall phenotype of the cell. So when we're looking at this data, to actually describe what this looks like, is we measure DNA methylation at what are called CPG sites. So a CPG dinucleotides. And so these cytosines can become methylated. And we measure this essentially, as a number between zero or one. So in your population of cells, what proportion of this exact cytosine are methylated, verse unmethylated. And we see really interesting changes of very specific CPG sites with age. So for instance, perhaps in this side of the scene, if I looked at a sample from a 20 year old, perhaps you would have 90% of cytosines, at this location would be methylated. First, if I looked at an 80 year old, maybe that drops to 60%. There are other regions that you get increased methylation with age, so this is in a single direction. So some, some CPG sites increase with age some decrease. So for this example, at the bottom and a 20 year old, perhaps you would have 5% of cells methylated, at this location versus an eight year old, you get 45%. Um, these two represent what we would call drift. So they're moving towards 50% from the two extremes, but you also get some interesting ones, which actually are also moving away. So you start perhaps as a 20 year old with 20%. And then by the time you look at an eight year old, only 1%. So because these changes are actually so precise, and actually, interestingly, even precise, across different tissue and cell types, people have developed what are called these epigenetic clocks. So basically, what we can do is we can take a blood sample, a tissue sample, or even cells and culture. And we'll see Graham's DNA methylation and get information on between 20,000 to oftentimes millions of CPG sites across the genome. And then people have applied different supervised machine learning approaches to actually train predictors of various aging outcomes. Usually, we're training predictors of chronological age, although the newer clocks have been training predictors of what we might call age correlates or phenotypes of aging. And then what we get is your predicted age based on some subset of these CPG sites, and you can compare those to the observed age of the individual or the sample and ask if kind of the discrepancy between that is predictive of, for instance, mortality risk, morbidity, risk, or any other outcome of aging that you're interested in. Um, so dozens of these epigenetic clocks have been developed. So the first one was developed in 2011, by Buckland at all. But since then, there's been a ton of these and actually, I don't even have all of them on, on this timeline, because there's so many, and I can't even really keep track of them, a new one seems to be coming out every month. Um, but, uh, so kind of these ones in the early that were developed earlier, what we might consider these first generation clocks. So again, these were trained to predict chronological age, whether in blood or in multiple tissues. However, some newer ones, like the one we did in 2018, the grim age clock, the belski piece of aging clock, or what we might consider second generation, so these weren't trained does chronological age predictors, but rather predictors of things like mortality, or some phenotypic age or other measures related to that. And today also, at the very end, I'll talk about the medic clock, which is a new clock that's part of this paper.