Understanding Longevity III: What You Can Do to Protect and Defend Your Epigenome

June 20, 2020

References:  David Sinclair's LifeSpan, JAMA Int Med, Experimental Gerontology, JACC, Biochemie, JAMANetwork, Cell


David Sinclair has been researching the molecular basis of aging for his entire career. His book convincingly argues that it is the degradation of your epigenome that causes aging. That makes it a disease that can be addressed. Your genes are inviolable, digital information that doesn't change one generation to the next (except for in the extraordinarily slow, rare mutations that drive evolution.). But the signals on your genes, the methyl groups that make up those signals and the histone proteins come all prepped and ready to go at birth, and slowly degrade and get damaged by life's story. Without the "analog" information on your epigenome, you age faster. Ok. So tell me a list of what I can do to change that and slow down that epigenetic erosion.

 His first advice on strategies to make your epigenome is to EAT LESS OFTEN.  This advice starts in yeast but is found in fruit flies, worms, mice, and humans and everything in between.  Nature has designed a delicate balancing act.  When you are short of calories, you focus on the organism living longer so that it can be around to duplicate later.   That's the nugget of sirtuins job, to clean up DNA and survive when times are tough and food is short.  When food is plentiful, you can duplicate but you also age.   It's hard to find or craft human examples except to travel around the world and observe peoples who have adopted lower calorie intake.  Okinawa has some of the highest numbers of centenarians in the world.  They make a cultural point of eating to 80% full.  School children eat 30% fewer calories that other Japanese school children.  But multiple attempts to get humans to eat less have failed.  One research study that was planning to reduce calories 25% was actually found to be 12% when all was well and done.  But that reduction was massively successful at health markers.  Longo has now shown that you don't need to do continuous fasting, just 5 day FAST MIMICKING every month or couple of months.  800 calories of vegan food, 50% fat will do.  

That adds 20 years to your life.  But compressing calories into 10 hours instead of over 14-16 also has proven benefit.  So, eat less.  At least keep your BMI below 25 (One of the 5 strategies of the DASH diet that adds 12 years to your life.)

What else?  Animal protein.  We eat too much.  No doubt it tastes good.  No doubt it has the 9 essential amino acids we don't make on our own.  No doubt it makes us feel satiated. All those are true.  Unfortunately, you have to play the sirtuin game.  Animal protein is what you need to reproduce successfully.  Your sirtuins get distracted from maintaining your epigenome.  You age faster.  We have it down to molecules.  It's really methionine, the chief culprit amino acid. We eat 2.5 times too much of it.  At least. And then there is carnitine in meat that is broken down into TMAO by bacteria in your gut: which then becomes the primary agent to push cholesterol into your arteries.  But plain and simple, replace animal protein with vegetable protein and all-cause mortality drops.  If you want to do a real deep dive, look up inhibition of mTOR by protein restriction.  mTOR is the uber enzyme that forces cells to spend less energy dividing and more in the process of cleaning up and recycling - living longer.  (Arginine, leucine, isoleucine and valine all activate mTOR too: the "Branched Chain Amino Acids", another deep dive for another day.). So what does bodybuilding do for you when you snarf down high leucine supplements?  Yes, you build muscle.  What message that that give your sirtuins?  Yes, times are good. Reproduce.  Ignore the epigenome. Live shorter lives. 


Then there is exercise.  What is it doing?  The deep dive.   Exercise burns up available calories.  If you push yourself to "failure", the point of exhaustion, you are pushing your individual cells to calorie limits.  Just for twenty minutes.  Then stop and rest.  Your cells rebound. What happened?  Your turn on your epigenome repair team because you activate mTOR and your Sirtuins.  You simulated calorie restriction and "tough times" by burning the calories.  Jogging at under 6 mph reduces all-cause mortality in over 60s by 45%.  Wow!!  You didn't want to reproduce over age 60 anyways.  What happens if you go higher intensity?  Yup, yup, yup.  Really scare your cells into thinking you are really calorie short.  Blast mTOR off like crazy.  That why higher intensity works better.  (You can chase this thread deep into the cell.  The health of a cell is defined by the conversation it has between its nucleus and your mitochondria.  But then you get an honorary PhD in Molecular Biology.)

How about exposure to cold?  Seriously. I live in Wisconsin.  What does cold do for you?  It kills you.  What if you expose yourself for just a tiny bit?  You turn on uncoupling proteins that short circuit energy production into heat production.  You make brown fat, the fat the produces heat instead of waistline.  You are turning on survival genes as exposure to cold panicked your sirtuins.  Once they are turned on, they repair your epigenome and hunker down.  You make brown fat.  You survive the cold.  You live longer.  (Reproduce tomorrow when it's warmer.)  And for the NERD in you, it's SIRT3, the sirtuin that's activated by cold.  What does it take?  How about a 15-minute walk in a Tshirt on a cold day?  Just like those crazy teenage boys you see out without their jackets.  Join them.  Just for 15 minutes, once a week.  Shiver a little.

What about heat?  The Finns have proved that frequent saunas cut heart disease in half. How?  Hasn't been studied but the best guess is it is all about NAD.  You increase it's level.  What benefit is that?  Deep dive next week.  

That's the disaster team your body has to deal with.  The concept is simple.  You create stress on your cell by reducing calories and making mitochondria short of fuel.  You activate your longevity genes: AMPK, turn down mTOR, boost NAD, lengthen telomeres and activate all your sirtuin proteins.  They turn to repairing the epigenome and ignoring reproduction.  Your body is "hunkering down" to make it for the long haul.  And that's the point.  

WWW. What will work for me.  This is all rehashed stuff you have heard before in pieces.  But now you have a few threads here that weave it together to make it understandable and into a unified construct of aging.  Perhaps you don't want to body build quite so avidly.   Perhaps you want to push your exercise a little more.  I like the idea of under 6 mph jogging.  I like under 5 mph better.  A bit of shivering isn't so bad now that it's mid-June and today is the Soltice, and shivering is a few months off.  I want to live long enough to see my grandchildren past this epidemic.  So, I better go for a walk this morning.  And eat less animal protein.

Pop Quiz

1.  What do your sirtuin proteins do?   Answer: they are the key link in your survival circuit. They repair and maintain your epigenome, the markers of healthy robust DNA on the surface of your chromosomes whose degredation causes aging.  You prevent degradation by turning on your sirtuin proteins.

2.   Name three things you can do to turn them on.    Answer:  Eat less, fast once in a while, compact your calories, eat less animal protein, eat less protein overall, exercise, expose yourself to cold and heat.  Stress yourself to a bit of a limit.  

3.  What is that stress doing?   Answer: inside your cells you are reducing available energy and switching on the pathways that turn on conservation and longevity.

4.  Can you train yourself to be better accomodated to cold?   Answer: Sure can. But you can do it relatively easily by not putting on too much clothing on a simple walk for 10 minutes.

5.  How much do I need to exercise?   Answer: Every day.  Make it a lifestyle.