Understanding Longevity II: The Horvath Clock

June 14, 2020

References:  David Sinclair's LifeSpan, ZYMO Research

Last week we learned that the information that defines our "genetic" code is expressed in two fashions. First, we have precise, digital code enshrined in DNA that has to be copied precisely with inviolable accuracy, and has to be repaired instantly if damage. The best estimate is two trillion repair jobs a day in humans. Secondly, we have our "epigenome" expressed and enshrined on the surface of our DNA by both markers on our wrapping proteins and how we actually wrap up and hide certain segments of DNA within certain cell types, at certain times. That is our analog genetic code. How fast it degrades is how fast we age. How do you prove that?

This has been David Sinclair's life work. He started by designing mice called "ICE mice" (Nice!). ICE stands for "Inducible Changes in the Epigenome". He created two key new processes in those mice. He inserted a gene called I-PpoI which is a DNA editing gene discovered in a slime mold. In the slime mold, it cuts DNA and reinserts itself. In mice, it doesn't last as long and just cuts the DNA a few times. Using the CRISPR gene-editing tool that allows molecular biologists to insert genes into mammalian DNA, he inserted I-PpoI into mice and was able to show that indeed, it cut DNA, and the mice sirtuin protein went to work and repaired it. No damage done. (This sounds complicated but actually is now so routinely done, you can even order different mice embryos with different genetically modified stem cells from catalogs or companies that will do it for you. If you are going to do biology in college, you may well do this in your junior year.)

The nice ICE mice are born looking normal. The I part of ICE is "inducible" and this is key. When you feed them a tiny bit of tamoxifen (that estrogen-blocking drug we use in breast cancer" you induce the I-Ppol to chop DNA. It's like when you are preparing supper and take out the cleaver to chop up stew meat. Chop chop for a few minutes.

What happens? You know this. The sirtuins have to go to work repairing the DNA. That's their job. But what are they being distracted from? Maintaining the EPIGENOME, the genetic code that defines your rate of aging or your youthfulness. So what happens if we turn on the I-PpoI gene again and again? It's just like Harry Potter and the Goblet of Fire. Fred and George Weasley drink the magic potion and age faster. During the tamoxifen, the mice don't die. They don't look older. But a couple of months later. They do. They have dramatically aged. You can turn on the aging system with a flick of the switch. In this case, it was adding tamoxifen to mice chow for a day or two. More tamoxifen, faster aging. More tamoxifen, more cut DNA, more sirtuins being distracted to repair, and less time to maintain the epigenome.

The Horvath Clock. That's it in a nugget. It is a reproducible means of accurately measuring the methylation markers on your DNA. It starts ticking the instant you are born. And all of that happens without any impact on stem cells, any change in mitochondria, or telomeres or mutation of DNA. Hmmm, all the other longstanding theories of aging just got booted out. It's the degradation of your epigenome that defines your aging.

You can actually measure that clock in many different organisms. For example, the bristlecone pines of California's White Mountains, over 4,000 years old, simply have very few markers of aging. They almost don't. But ditto with many jellyfish. You can even reconstitute a whole jellyfish from a single cell, time and time again. Arctic sharks don't become sexually mature until they are 150. Bowhead whales are similar. 

The list goes on. We can even now measure your own FOXO3 gene variant on position rs2764264 on your DNA. If you have two Cs instead of two Ts, you live longer.

As you go through life, you are exposed to various stressors that accelerate challenges to your epigenome. Some result in good effects and all you to thrive. Some damage you and alter your epigenome. With that alteration, your cells lose their secure position and start to act out of character. They become cancers, or just don't follow the leader and do their intended function.

Is there something we can do about it? Yup, yup, yup. Next week, we'll explore. This is enough density for one week.

WWW.what will work for me. Whew, this is heavy. I've looked for ways to measure my own Horvath Clock and I found several companies that offers your DNA age!  Ha.  So, I signed up.   I have no idea how clinically relevant it is but I want to learn their material.  Mostly, I want to see if what I do to myself changes things.  This might be fun.  I've spent so many years thinking telomeres, stem cells etc.... etc..... were all the engines of our aging.  It's our epigenome. So, I want to encourage any commercial method of measuring that and see if it bears fruit.  Might.  Might not. Want to give it a try yourself?   myDNAage.   ZymoResearch.  They cost $ 299.  

Pop Quiz

1.   What is your epigenome?    Answer:  The information saved ON your DNA with different molecular markers that guide your cell on when to express your DNA, and when not to.

2.   What are the proteins called that guide, nurse, protect and nurture your epigenome?   Answer: Sirtuins

3.   What happens to your epigenome markers when you damage your DNA?   Answer: they get ignored and degrade faster.

4.  What is the name of the mice that are designed to do that experimental aging?   Answer:  ICE Mice.   

5.  What is the name of your epigenome clock?    Answer: The Horvath Clock. That you can now get measured on you from commercial companies.  MyDNAge is one such company. ZymoResearch is another.   Reliability to be determined.