Understanding Longevity I: How Your Genes Work

June 07, 2020

References:  David Sinclair's "Lifespan"


We live about 120 years at the maximum.  There are many theories of why we age.  The strongest of them consider a variety of forces that degrade our bodies.  For example, at age 60 we make only 10% of the stem cells we made when we were 20.  Every organ in your body needs stem cells.  Another theory is that our telomeres shorten with each duplication of our chromosomes.  Telomeres are the "nonsense" DNA at the end of our chromosomes that allow the duplicating enzyme working space from which to copy DNA.  Without that tail on the end of our DNA, duplication will result in a shortening of our genetic code, and subsequent damage.  At age 45, we stop being able to reproduce and our sex hormones plunge.  Nature isn't much interested in you once you can't reproduce.  Another theory, our mitochondria lose the ability to duplicate and become unable to make energy.  Without working mitochondria, our cells lose energy and accumulate oxidants.  Hence, the frantic attempt by some to take "antioxidants" to prolong your energy source.  Finally, you can just argue teleologically.  In order for evolution to work, generations have to allow the experiment of genetic drift to play out and then get out of the way once offspring have resulted.  If we lived forever, evolution would take forever.  One species has to be in sync with the species around it that match their predation, environmental change and resource use with lifespan.  Which of these do you ascribe to?


David Sinclair provides a brilliant alternative theory that is gaining traction in the world of aging and Longevity.  I want to explore it with you and take a gander at explaining it in simple language.  


The first and core concept of DNA is that it is your genetic code.  The very, very, very first living organism with DNA had to have two key enzymes/functions.  Just two.  How to duplicate the DNA.  That's obvious.  And secondly, how to repair DNA when it got broken.  Aha! Duplication is what we call sex today.  We have to duplicate.  And we have to repair our genetic code.  If you don't repair, you can't survive.  In the duplication of cells, Sinclair states there are probably around 2 trillion fractures of our chromosomes each day as cells duplicate.  They have to be fixed.


We have a system of proteins called sirtuins that repair DNA.  Sirtuins keep your cells healthy and happy.  In that state, they can duplicate.  If DNA breaks happen, sirtuins have to switch to repair.  When repairing, duplication can't happen.  That's the survival circuit.  Two states of being: duplication or repair.  Survival.  The most preserved processes in all creation, present from simple yeast all the way up to humans.  Yeast cells have just one sirtuin.  Humans are more complicated.  We have 7 and they have more complex behaviors.   The original job of sirtuins was to silence the reproduction process until DNA was repaired.  Surival rotates between duplication and repair.


Since that very early first task of switching reproduction on and off to ensure that your DNA was repaired and precisely maintained, mammals have added more sirtuins to them.  They have new jobs assigned to the new sirtuins that all rotate around controlling fertility. Now they are also responsible for managing histones, the proteins that wrap around DNA, inflammation, glucose metabolism, mitochondrial health, and on and on.   They are sort of like FEMA in a hurricane, your disaster response team that spreads out and do everything to keep the body on a healthy track.


The problem is we don't have enough sirtuin proteins to do both things at the same time.  We can't keep repairing DNA endlessly because that keeps our sirtuins away from their home base.  When they aren't at home, their normal tasks don't get done and the "epigenome" degrades.


That unpacks a new insight.  We have a whole different set of "genetic code" in the way we label and pack our DNA, our epigenome.  Our DNA is fixed.  It's like your core genetic code.  It's like digital information.  Precise, accurate, and inviolable.  It can't change.  But your epigenome is also part of your genetic heritage and also has to function.  


It is the degradation of your epigenome over time that decides how fast you age.  Your epigenome is defined by the molecular signals on your histone proteins around which DNA is wrapped.  Methyl groups and acetyl groups attached at different places are read by your cell.  You can make an experiment with mice in which you accelerate mice to age faster by increasing the number of DNA breaks they have, forcing their sirtuins to be distracted from histone management and into DNA repair.  The epignome is then neglected and starts to accumulate damage and false messages.  It's like during a disaster the electric company calls workers from other states to come repair the downed power lines.  But at home, no one is mowing their lawns.  The borrowed workers are off fixing power lines.  Their homes are falling apart.  Their lawns look awful.  (And when they are away from home, they certainly can't "duplicate". ). Those mice age faster.

  

The cutting edge of aging science is exactly on that point.  Next week we will explain just that nugget of information: the Horvath Clock.  This is enough to wrap your brain around for one week.  At least it is for me.  

To learn these details gets right to the heart of aging so if you understand this and get these ideas, we can then build a new, more comprehensive insight into how we age, and how we can turn aging off.  And that is pretty exciting.  We have Longevity before us.


WWW. What will work for me.  The key idea here to soak up is that you really have two systems of information in your DNA code.  One system is the inviolable DNA.  It changes but very slowly.  Very slowly.  Over multiple generations.  Like your digital computer code, it is fixed.  The other system is your analog code.  It is defined by the molecular labels on the proteins that wrap up your DNA.  That is being turned off and on and being altered every day, all day long.  It takes active management.  If you neglect it, ignore it, challenge it, you speed up your aging.  Smoking cigarettes will challenge it.  Eating too much sugar will challenge it.  Now, some of the mysteries of how our aging processes are being understood.  Read Sinclair's book and keep up with me. This is exciting.


Pop Quiz

1.  What is the most basic process every cell on earth has to possess?   Answer: The ability to duplicate it's DNA and make sure the DNA is repaired so that you don't lose that precious digital code.  You can only afford to change it a tiny bit, then let some generations pass to see if that tiny change makes a difference.  That's called evolution.

2.   And how do you make that "survival circuit" work?   Answer:  Sirtuin proteins keep grooming your DNA's markers that identify when to turn on duplication and when to turn it off.  When there is a break in the DNA, they have to put that work down and go fix the break, ignoring the grooming.  

3.   What happens if sirtuin proteins have too many emergencies?   Answer: accelerated aging.

4.   What happens if you genetically put more sirtuin proteins into cells?   Answer:  Not fair.  You didn't get this information from reading this newsletter.  You had to read Sinclair's book to learn that inserting extra sirtuins makes mice live much longer.  

5.  That means you really have two systems of gene management.  What are they?    Answer: your "digital system" which is the precise DNA code.   Your second is your "analog" system, how you express and manage that code.  Both have an impact on how the organism adjusts to its surroundings.  But aging is not driven by your digital code.  It is driven by your analog code.  Therein is the secret.  

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