Understanding Longevity IV: NAD+ and Metformin

June 27, 2020

References:  David Sinclair's Lifespan, Cancer Metabolism, Diabetolgica, J Diabetes Complications, Cell Metabolism

Alright.  We've got you to understand that your DNA falling apart is not why you age.  Sinclair argues, succinctly and convincingly that it is the degradation of the episome information tagged onto your DNA and maintained by the sirtuin family of proteins that defines aging.  Those proteins get pulled away to other jobs, distracting them from their epigenome maintenance, and voila, you age.  Toxins, X-rays, cigarettes, trans fats, sugar all act as "distractions".  Repeat: It's the epigenome, your analog genetic code, that degrades and leads to aging. Therein is the core of aging.  

And last week we learned about the lifestyle strategies that nudge your sirtuin proteins to get back on the job and clean up your epigenome.  Fasting, exercise, stress management, sleep, saunas, cold exposure.....stressors, ever so gently, help.   Cutting excess calories present in the cell appears to be the signal that "now is not the time to reproduce, now is the time to hunker down and wait it out".   Remember, that's the exact same dilemma yeast cells have when they are starving.  They live longer waiting for food to come along. That's the core "longevity dilemma".  Either reproduce or live longer. In humans, that is more nuanced and sophisticated, but it is the same decision.

In the 1950s, two Frenchmen investigated a lovely purple French Lilac derivative to see if it would help all the folks in their neighborhood with diabetes.  It had been used in folk medicine in France for centuries.  It worked!  It was first called dimethyl-biguanide  but is now called metformin, one of the world's most used drugs for diabetes.  Metformin mimics calorie restriction by uncoupling some of its glucose metabolism.  It lowers the calories your cells see.  It gets concentrated in your mitochondria 1000 fold over your blood and disrupts the first step in the electron transport chain.  

With that, your cells respond by turning on a magic protein called AMPK, an enzyme that responds to low energy states and restores mitochondria.  AMPK basically says, "stop making stuff and start burning energy".   You have reproduced a low energy state.  Just like exercise, or fasting.  Did you get that little bit of magic?  Fasting without the fasting.  Do you like it?  

And it's effect isn't little.  One study on metformin, started when folks were already frail and old showed that metformin use reduced cardiovascular disease 19% (WAY more than statins, dementia 4%, frailty 24% and cancer, 4%. 

How long does it take metformin to act?  Now that we can actually measure methylation markers on your epigenome, effectively measuring your biological age, we can see.  Give 12 healthy young folks who have never had metformin and one dose of it and this one study showed statistically significant improvements in the epigenetic methylation profile of DNA......are you ready?  In 12 hours.    Don't you want some of this stuff?

Are there other drugs that do it?  Well, yes! How about one that activates all 7 of your sirtuins?  No kidding, all 7.  A simple, basic vitamin called niacin.  Every tissue in your body can turn niacin into NAD and NAD is the magic potion that turns on all 7 sirtuins.  The problem with niacin is that you flush and turn red and stop taking it.  You use NAD in over 500 enzymes, most importantly in the sirtuins.  And here is the rub.  As you age, your NAD level drops precipitously.  It's actually destroyed by a protein called CD38.  But the older you are, the lower your NAD and your sirtuins are starved to death. 

Can you boost NAD without the niacin flush?  Yup.  From my alma mater, the University of Iowa came the discovery of NAD-riboside (NR), a trace element in milk that will dramatically boost your NAD levels and turn on Sirtuin 2.  Or, from Sinclair's group, a faster step than NAD-riboside was NMN, nicotinamide mononucleotide.  It's found in avocados, broccoli and cabbage.   Take NMN as a pill and your NAD levels will rise 25% over the next couple of hours.  That's the same effect as a good round at the gym with sweaty exercise.   Did you get that?   Exercise in a pill.  Wow.   

Now, NAD-riboside has been proven to make mice live longer, but NMN may have the edge. There is a ton of research going on with both.  But the barn door is open and the race is on.  NAD levels decline drastically as you age - or as CD38 levels go up.  You need NAD.  It is used in every sirtuin protein.  It is sirtuin fuel and you have to have it.  It is core to keeping your epigenome buffed and polished.  You can do a deep dive into this if you just Google NADriboside versus NMN.  

WWW: What will work for me.  Hmmm.  I'm convinced. I tried taking Niacin years ago and gave up after three months of horrible flushing.  It was too hard to maintain.  The simplest way to get NAD-riboside or NMN is  to just buy them from a reputable vitamin retailer and take it every day. Every day.  Maybe twice a day.  Metformin, you need a prescription.  Want to measure your epigenome before you do it?  I did.  And then measure it again. That curiosity will cost you $ 300 a pop so you might just consider taking them.  You are going to hear more about this as the field is just exploding.  Stay tuned.  Isn't this fun!

Pop Quiz

1.  What do sirtuin proteins do?    Answer: they maintain your epigenome, the markers and foldings of your DNA than function as a second layer of genetic coding.

2.   What happens to your epigenome as you age?    Answer: it degrades and that process is the best measure we have of your biological age.  

3.  What is the survival circuit?      Answer: the choice your sirtuin proteins have to make between longer survival (epigenome repair) or reproduction.

4.  And now does metformin fit into all this?    Answer:  It makes energy use less efficient, acting like calorie restriction.  That turns on your sirtuins

5.  And NAD?  What does it do?    Answer:  It's needed for every single sirtuin protein and degrades as we age.   Replacing it slows down aging. The race is on to see which form works best, NR or NMN.  But you should be on one of them.  They both work.