#386 – Aging clocks—what they measure, how they work, and their clinical and real-world relevance

Why aging clocks are being used as proxies for long-term health outcomes and the uncertainty surrounding their clinical value [2:00]

• If you wanted to run the perfect anti-aging trial, the endpoints would be really obvious
  • You’d want to see fewer heart attacks, fewer cancers, fewer dementia diagnoses, and ultimately fewer deaths
  • We would call these hard outcomes, real outcomes that matter
  • These are the clinical outcomes that we all care about
• Now, of course, the reason we don’t see these trials is that they would take a very long time
  • These would literally be 20-year trials
  • And with that would come enormous complexity and cost
• Furthermore, it would be very difficult to ensure that whatever intervention you put in place was being put in place for the duration of this time

Peter points out, “That would not be that hard to do if it was a drug trial because it’s relatively easy to take a drug, but it would be more challenging for a lifestyle trial.” 

• Every few years, the fields of geroscience and medicine and cardiovascular disease, etc., they go looking for a proxy or a shortcut, so some intermediate marker that could move faster than these hard outcomes, but that would still predict the hard outcome reliably

And over the past few years, what we’ve really seen is that aging clocks are the most interesting and popular proposed shortcut 

• Again, Peter doesn’t use the word “shortcut” with a sort of negative connotation
  • It’s like, this is what we need 
  • We do need a shortcut. We need a proxy

The idea here is pretty compelling 

• Imagine you could have a single number that would predict your actual aging or your actual biological age that’s different from your chronological age
  • Or maybe a rate of aging that reflects a new trajectory you’re on
• 1 – This could be very valuable in designing clinical trials or looking at interventions
• 2 – And even at the individual level, understanding if you’ve made a change and is it making a difference? 
• So think about this as a foray into precision medicine 

Now, there’s a little bit of a problem in Peter’s mind because these aging clocks are being marketed as the latest and maybe best way to keep tabs on your health 

• Lots of people are ordering them
• They’re available to anybody
• They’re sold by longevity docs who promise to improve your biologic age with groundbreaking combinations of peptides or other elixirs

But it’s worth looking into these a little more closely to understand what the science can actually tell us 

• And Peter thinks the best way to do this is to look closely at 2 very interesting studies, that can help us get at the fundamental questions that we really want to be asking around this, which is: What is the clinical utility of an aging clock?

How aging clocks use DNA methylation to predict age and how they compare to traditional mortality prediction models [5:00]

• Before we do that, Peter wants to make sure everybody’s starting from the same footing in terms of understanding the biology 

What is an aging clock?

• Basically at its core, it’s a prediction model

But let’s take a step back, your chronological age is also a prediction model 

• You see, if I told you that in front of me, there is a 20-year-old and there is a 70-year-old and I asked you to predict which one of those people is going to die first, I think everybody would (knowing nothing else) make the correct prediction
• Now we could layer onto that certain other factors
• Now have two 70-year-olds and one of them has cancer and the other one does not
• Do you predict which one of those is going to live longer than the other?
• And again, without knowing anything beyond what I told you, I think everybody would make the same prediction

This idea of using information to predict mortality is not new ‒ it is the entire basis of the actuarial underwriting industry 

• And there are companies that are exceptionally good at doing this: life insurance companies
• And their data are incredibly proprietary
  • And it’s really less so their data and more so what they do with the data that is incredibly proprietary
• They gather a lot of information about you
• They do a blood draw on you
• They know your age
• They know various factors about you
• They take your blood pressure, your weight, and things like that, relatively rudimentary stuff
• But from that, they have these tables (again, highly proprietary) that seem to do a very good job of predicting when you’re going to die

And so the question is, would one of these aging clocks be even better? 

Let’s talk about how these things work 

• They typically work by starting with some biological data
• And the most common thing that we’re going to hear about is epigenetic data (this is DNA methylation)
• And then they train an algorithm to look at that and predict something age related

It’s worth spending a minute on DNA methylation 

• Peter doesn’t want to go far down the rabbit hole on this, but you’ve undoubtedly heard the term 
• DNA methylation is a way that the body modifies epigenetically what the DNA expression is
• So it doesn’t change the sequence of DNA, but it can influence how the genes are “turned on” or “turned off”
  • That’s what we call expression of genes
• So when you modify the epigenome
  • Which is basically when you put a methyl group (that’s a carbon with 3 hydrogens) on the backbone of the DNA 
  • [The methyl group is shown in the figure below as yellow or red balls and highlighted on the cytosine base in red]
  • That impacts whether or not that section of DNA gets turned into RNA (that’s what we mean by expression)

Figure 1. Methylation of cytosine bases silences gene expression. Image adapted from: Nanomaterials 2023 and Novus Biologicals

• You may have heard the term CpG (but not in reference to consumer packaged goods): a CpG refers to the location where these methylations most commonly take place
  • If you remember back to high school biology, we have these 4 nucleotides ‒ the C is the abbreviation for cytosine
  • And so where these things [methylation] typically occur is right on the phosphate bond that links the C (the cytosine) with the G (the guanine nucleotide) 
  • So when we talk about CpGs, that’s just kind of another way that people quickly talk about the methylations

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