Corona Virus CURE might be in the Offing: Peptide Therapies Mature

If you heard a story of a physician contacting COVID, his oxygen saturation plunging into the 80 within hours, and then his recovery in 3-4 hours, you might be skeptical.  That would be prudent.  And then you might explore.

Ok, here it is.

First point.  Viruses are invading pathogens that have to take over the cellular factory to make copies of themselves.  All they want is more of their own DNA/RNA, and coating proteins so that they can make their own packages.  The factory they take over is the mitochondria.  Your mitochondria are your energy factories, making up 10% of you.  Muscle cells have several hundred mitochondria, but your heart has 5,000 as does your brain.  That is as much as 30% of the weight of your heart is mitochondria.  COVID-19 is particularly good at that hijacking.  When you hijack your mitochondria, you feel extreme fatigue.  Of course  you do, your energy is turned off.

Now, your defenses against COVID require you to activate your Sirtuin Proteins, the family of proteins that nurture, groom, and defend your DNA.  The virus wants in, to take over your cellular command, and you want to hold it off.  The Sirtuin family does that.  Sirt-1 is the champion protector.  It's ONLY food is NAD+.  You turn on protection by having NAD+ around.  The problem with aging is that we don't make it anymore.  That makes an avenue by which you can fight back. You can take NAD+ as a supplement.  Easy, peasy.  You just need to hold the virus at bay long enough for your immune system to kick in and do it on your own.  The problem is that the virus is voracious. There is a frantic rush to who gets there first.  Does the virus invade and replicate faster than your immune system can ramp up? That's the key nexus.  Can you accelerate the ramping up and holding off?

This is where the race is decided.  Can you give your cells a lifeline of energy so that they can survive long enough for your own immune system to ramp up?   If we give you antibodies from folks who had the COVID-19 virus, we slow it down.  So, convalescent serum helps.  If we give heparin, we slow down the spiral of lethal clotting that gets activated in some folks, long enough for your immune system to balance things back again.  Ok, but that's pretty dramatic and is treatment after the cow is out of the barn.  How about just feeding your cells that have been attacked so they can hang in long enough to keep themselves together and not just explode with a shower of new viruses?  That's the thread to follow.

What do mitochondria use to make energy?  Two choices.  Carbs (glucose) or fat.  That's it.  Just two choices.  What happens with carbs?  Well, that's what the COVID-19 hijacks.  They take over the mitochondria and the whole mechanism of glucose production to divert making ATP and instead make fat to make viral membranes.  Can COVID-19 use fat?  NO!   And if they can't use it, well, you can.  What happens with adult-onset diabetics?  They are addicted to running on glucose and have a high baseline of insulin.  They are insulin resistant.  And any trace of insulin makes ketones (little tiny fat pieces) disappear.   Most COVID injured folks have insulin resistance or hypertension, both of which have key defects in the mitochondria.  

Read that three times and you will understand the key strategy here.  Ketones are present only, only, only when there is no insulin around.  Any intensivist in a hospital will tell you that they can cure diabetic ketoacidosis with 2 U of insulin infused per hour.  But in adult onset diabetes, it isn't the lack of insulin that's the problem, it's insulin resistance with super high, insulin levels.  That means there is high glucose circulating.  COVID-19 loves that.  They take over the mitochondria and they make lots and lots of fat molecules to make coating proteins.  So folks with diabetes are very vulnerable to COVID.  

We can make you ketogenic if you burn off the glucose stores in your body, including in your liver.  It takes 2-3 days to get there.  Or, we can get you ketogenic by giving you ketones.  Just cheat a little.  Buy ketones.  What we call "ketones" are actually a very simple molecule called beta-hydroxybutyrate.  It's a 4 carbon piece of fat that your chop off a longer fat molecule as you digest it.  You can buy them.  

And when you take ketones, your mitochondria love it. They can lap them up and the COVID-19 can't.  You bypass the roadblock the virus lays down and give a lifeline of energy to your cell. " Just give me a day or two of energy until my own immune system can mount an effective response".  That's all your cells are asking for.

Do you see the strategy that's emerging?   You want to be ready for COVID? Get yourself on the real ketogenic diet based on vegetables and fat and cut the carbs. Get rid of bread, rice, potatoes and any form of free carbohydrates.

And if you get COVID-19?  Ramp up your immune system with Thymosin-A1 and take Ketone-Esters.  Ketone Esters are the fastest way to get ketones into you.  They give your cells the vital energy you need and that your mitochondria can convert into ATP that the COVID-19 doesn't have access to.  

And that's it.  There is a buzz going around in the Functional Medicine world of giving COVID-19 patients in the ICU ketone esters orally.  And then ramping up their immune response with Thymosin A-1.  And folks with COVID are up and walking around in a day or two.  

WWW.What will work for me?  If I were to get ill with COVID, I would take Thymosin A-1 three times a day and Ketone Esters 4 times a day.  It's my plan.  I have a steroid inhaler to use to keep the virus tamped down on my lung receptors.  I have Vasoactive Intestinal Peptide to turn off the cytokine storm.  I'm taking NAD+,  and selenium, zinc, and Vitamin D every day.  And Melatonin every night.  I think we have a strategy to keep this virus at bay until we get a vaccine.  But start by ordering yourself some Ketone-esters.  Yes, they cost a little.  You are worth it.  We can order each of these for you is you want to get yourself prepared.  Better yet, wear a mask and wash your hands and get the vaccine.  But just in case.......

Pop Quiz

1.  The COVID-19 virus appropriates what process in your cell that saps your energy?     Answer: The glucose metabolism pathway.  It turns it around to make viral membrane fats.

2.  Anything else?   Answer: Well yes, if you said NAD+ you would have been right too.  It robs your NAD+, stealing your ability to nourish your Sirtuin proteins that protect your DNA

3.  What do you feel when that happens?   Answer:  Extreme fatigue

4.  What nutrient supplement can you take to bypass that and feed your starving cells?    Answer:  Ketone esters, called beta-hydroxybutyrate.  The virus can't use that so you trick it

5.  And just what does Thymosin A do?   Answer: It is the peptide you make to turn on your virus response in your white cells.  You have lots of it as a child but stopped making it a couple of decades ago.  Sorry, true.  It's been proven by good research to help you cure chronic hepatitis B, and now being extended to COVID-19.

References:  Trends in Microbiology, Science Direct, Am Jr Physiology, Medium, OHSU, Cell Symposia, Med

Corona Virus is FAR WORSE that we thought - It's Horrible for your Heart

It's not "just the flu".  It's not "just a virus".  It's a secret organ killer, and we don't understand yet just where it chooses to strike and how awful it is when it does.  This week's finding is on heart disease.  COVID attacks the heart.

We first had a report in early July from the Cleveland Clinic that cardiomyopathy incidence increased dramatically amongst COVID patients.  Cardiomyopathy is basically the muscle failing.    Their study showed that stress cardiomyopathy increased from 1.8% to 7.8% during the pandemic as they reviewed all their cardiomyopathy patients.  Now, that is terribly alarming because it was simply looking at what showed up.  They had enough patients to look for ordinary cardiomyopathy, that we often toss off as "usually caused by some sort of virus", which was only seen in 1.8% of folks before.  Now, with this COVID pandemic, that incidence quadrupled, and the population did not all have COVID. If everyone had had COVID, what would we see?

That's what this week's German Study reports on.  From 100 patients who had recently recovered from proven COVID, 33% had been hospitalized and 67 were able to recover at home.  They had MRI scans done of their hearts.  What they found was quite remarkable.  Ongoing inflammation showed up in 60% of the patients, who were studied on average 71 days after diagnosis.  Their troponin levels were still elevated above 3 in 71 of the 100 and above 13 in five.  That's enough to diagnose a heart attack!  The MRI scanner can see fibrosis of the heart muscle with so-called T1 and T2 measurements.   60% of the patients showed ongoing inflammation, regardless of pre-existing conditions or severity of illness.  The study leaders actually biopsied the hearts of those with the worst inflammation and found their heart muscle all filled up with lymphocytes.   This is a very important finding as it gets right to the "heart" of it.  COVID-19 damages your heart and results in scar tissue and reduced capability.   All this research is being done on the fly as a pandemic is in progress, so we have no long-term data to look to.  That will come in time.  

We've known COVID attacks the lungs and blood vessels.  We now know is has widespread involvement and damage to hearts.  But that's not all.  Did you know that half of COVID patients show damage to their liver with elevated liver function tests?  Kidneys?  Same thing

This is one nasty virus.  It certainly precipitates severe disease.  Is there a common thread?  I would propose one.  The COVID-19 has a predilection for taking over your NAD fuel system in mitochondria.  Your organs have 2-3000 mitochondria in each cell.  They burn a lot of energy. Your heart has 5000 mitochondria per cell : 30% of the mass of every heart cell is mitochondria.  It has to beat constantly.  Damage the mitochondria and you rip out the energy production that makes the cell work.  As we age, our mitochondria weaken and our ability to maintain our NAD supply weakens.  NAD comes from Vitamin B3 but it is essentially lacking as we get older.  COVID loves NAD.  What little there is, it gobbles up and uses for its own duplication.

Whoa!  That suggests a clue to help yourself.  If you are low on NAD, would it help to take more as a supplement?   Who knows.  Hasn't been studied.  If you had no other options, would you give it a whirl?

WWW: What will work for me.  David Sinclair has shown us that NAD supplementation is a critical anti-aging strategy.  If you are over 50, you should be on NAD-Riboside and NMN, for the rest of your life.  But now, with COVID, should you be on more?  I think it goes right to the biology of how COVID causes its damage.  So, I'm taking it every day.  And hearing this story helps me double down and increase my vigilance against getting it.  I'm getting much more patient with myself and doing much better wearing my mask.

References:  USA Today, JAMA Network Open, JAMA Cardiology, UEG Journal, Preprints, Nadovim

Pop Quiz

1.  If you are a person who gets COVID, what is the likelihood that your heart will show heart damage by MRI scan?   Answer: 60% if you measure those who had symptoms and documented disease.  We don't know about those who didn't realize they got the disease.  I suspect 10 years from now we will have studies on those who never realized they were sick but got a blood test that showed that they had had it.   I bet the number won't be zero.

2.  What is the likelihood that someone who didn't show any symptoms has heart damage?    Answer:  We don't know but it may not be zero.

3.  Is heart the only organ that is damaged?   Answer:   No.  Virtually every specialty is detailing how its organ is being damaged. There is certainly live and kidney damage.

4.  What is the unifying hypothesis that weaves these all together?   Answer: Damaged mitochondria with the known hijacking of NAD that viruses do, and COVID does exceptionally well.

5.  What happens if I take NAD as a supplement?    Answer.   To give an honest answer is going to take a randomized trial, which we don't have right now.   It is a known nutrient that declines with aging and its use as an antiaging supplement is well established.  Its use with COVID is conjectural, but taking it has no known harm, and certainly has benefit for antiaging purposes.  

COVID Strategy: Interferon

Have you ever heard of interferon?  Perhaps with cancer?  That's what this column is for.  I want to explain it in layman's terms so that you understand it.  And perhaps, understand how to benefit and turn your own interferon on.

Interferons are the proteins you make to fight back early against viruses and cancers.  You make three kinds of them.  Insufficient or inappropriately timed interferon production may explain why some folks get sick with COVID, and some folks don't.   This is all research on the fly as this particular COVID virus hasn't been studied intensively yet in mild cases.  But the carona viruses that make the common cold has been studied and comparisons can be made and some conclusions can be conjectured.  It's good to know this.

Type I interferons go by names like  IFN-α, β, ε, κ, and ω.  There are two other types, all produced by immune cells at different times of infections.  It's all in the timing and the amount of response that determines your body's ability to fight back against viruses and clear out the infected cells.   They can be released either by an infected cell, or by a cell that detects interferons being released by its neighbor and so joins in. That makes for a "feed-forward" system that accelerates the response.  The infected cell may be doomed but other responding cells may get their defenses up in time to limit the spread of the invader.  In particular, immune cells also get turned on and come to join the fray.  They can gobble up the virus, or inactivate it with antibodies.  All of this activity happens in a mad dash to contain the invasion.

Type I and II interferons are doing most of that immune response.  Type III stops viral replication inside the infected cells and shores up the integrity of membranes where the virus is coming in.  So, Type IIIs make your lungs better suited to getting infected.    It's I and IIs that are turning on the inflammatory cytokine storm that may overwhelm the host if it is badly timed.  

Now, viruses can fight back.  They usually carry their own genetic code for duplication, but also coating proteins and then, most importantly some proteins that neutralize host defenses. Carona viruses have about 10 different genes that either block interferon receptors or block their activation or even basic transcription.   Clever little devils.  But that's exactly what you would expect.  Evolutionary pressure on viruses forces that. They won't succeed and duplicate until they evolve and develop the genes to get around that.   So, we have to fight back.  Guess whether humans make a strong or weak response of interferons to the common cold carona virus!    Strong!    Guess what humans make to super dangerous carona viruses like SARS and MERS!  You got it.  Weak. 

There have been very tiny studies of patients in ICUs with COVID looking at the activated genes of sick folks.  Sure enough, a weak interferon response but an inappropriately abundant inflammatory response.  If you call in too many immune cells, you make "neutrophil extracellular traps" where you end up with tiny pus pockets, if you will, and cause complete dysregulation and blood clotting.  If you bring the hammer down of corticosteroid use, dexamethasone and heparin, you can stop that runaway "trapping" and clotting.  It's blunt instrument, but it appears to be working.  COVID survival is better with dexamethasone and heparin. 

So, who gets sick with COVID.  Old people.  And they don't make a sensible interferon response.  Nor do folks with cancer or diabetes.   Diabetes is an inflammatory disease in most cases where inflammation is already ramped up.  (See last week's blog)

There are some studies giving interferon as a drug.  In China, 3000 health care workers were given interferon nasal spray and not one got COVID. 

Can you get interferon?  Well, yes.  It is on the market but not widely used and few doctors are familiar with it.  And it's confusing as which do you use, when.  Type I? II?  III?   Might cost some $ 4000 dollars just for the drug, which insurance will not cover.  But a peptide called Thymosin A-1 might be similar in effect.  Cheaper and fewer side effects with the same outcome in one study comparing Thysomin 1 to Interferon in Chronic Hepatitis B infection.  Another peptide, VIP, also works to turn on interferon responses.  No one on VIP has developed COVID yet either.   Hmm.  There are options out there.   So does Vitamin D.  Selenium.  Melatonin

www. What will work for me.   Well, I'm taking Thymosin 1 myself.  Every day.  Will it work. Haven't a clue.  And the research on VIP is so intruiging, I suspect it may be another breaththrough drug when the RCT being conducted on COVID and VIP is completed.   But don't neglect the melatonin, Vitamin D, selenium.  They all work through the augmentation of interferons through your own equipment.  Equipment that has gotten rusty and beat up with aging.   Repair it a little. Go eat some Brazil nuts.

References:   Cell, MedRXiv, Medium, Antiviral Research, MedRxiv, Science Direct,  Jr Cell Physiology, Immunity and Ageing

Pop Quiz

1. What are interferons?     Answer: The proteins you make in response to invasion of "pathogens".

2.   Interferon response uses a "feed forward" system.  What does that mean?    Answer:  Infected cells turn on other cells and they all cycle upwards to contain the spread of viruses.  

3.   Why do some folks get severe COVID and some not?    Answer:  A robust early interferon response is characteristic of the common cold.  A weak response is seen in folks in ICUs with COVID.

4.   Who else has a weakened interferon response?    Answer:   Diabetics, cancer patients, overweight folks.  Anyone with inflammation already turned on.

5.   Can you raise your own interferon?    Answer.  Yup, yup, yup.  all it takes is some supplements, some Thymosin A1 or VIP.   Might be useful to consider.

How A High Fat Diet Makes you Diabetic

 Lose weight, eat fat! Go Keto! All the admonitions to eat fat so that you can lose weight. Is it real? What is the underlying premise and how does that all work? And is there a dark under-belly of problems? Well yes. Let's explain so that you understand the nuance.

First of all, losing weight is incredibly important for general health. In fact, in the short term, if you can muscle your way through any diet that gives you discipline, losing weight trumps every concern in this newsletter if you can keep it off. It is one of the main pillars of longevity: getting your BMI below 25. Ok, that said....

First, why is fat important in a weight loss diet? Fat doesn't turn on insulin. Fat is insulin neutral. Hence, when you eat fat, you feel sated and full. When you eat high glycemic carbs like bread, flour, sugar, rice, corn, or TOO MUCH protein, you turn on insulin which makes you store calories aka, weight gain. Everyone knows that foods that generate free carbohydrates quickly make you gain weight. Fats don't do that. So the first takeaway is that high glycemic foods will make you gain weight. The second is that too much-concentrated protein also turns on insulin as any extra protein gets turned into glucose, and then turns on insulin.....and you gain weight. (Get it? Insulin is the enemy).

The second key principle is that the nature of the fat you eat matters. Saturated animal fat (bacon fat, steak fat, animal fat) is the fat animals make when they eat too many carbs. Just like you. Force feed animals corn and beans instead of grass and they put on weight, just like you. They weigh more so the farmer gets paid more. You like that fat because it makes your steak taste juicy. And animal protein drives up TMAO, the chemical most closely associated with developing coronary artery disease.

A third critical principle is the magic nature of green vegetables. Above-ground vegetables like broccoli, spinach, Swiss chard, cauliflower..... is that they are secret fats in disguise. They get turned into BHB by the bacteria in your colon. When you eat a salad with olive oil, you are eating the fatty molecules in olive oil and your gut is changing the cell wells of the lettuce or other green vegetables into BHB in your gut. Neither affects insulin. That little magic trick might be the best takeaway from this blog for you. No effect on insulin by non-root vegetables (note: this does not include peas and beans).

Unsaturated fats break down easily to beta-hydroxybutyrate (BHB), the short tiny fatty acid that is the same fatty acid you make when you lose weight. The sequence is as follows. When your insulin level gets low enough, your fat cells open up and share their saved fats which get chopped up into BHB. That's called weight loss. Your mitochondria love BHB. In fact, it is one of the most conserved metabolic pathways in nature. You want to teach your body to run on BHB. It's good for your brain, your heart, your muscles your longevity. Olive oil and nut oils are champion precursors to BHB. Coconut oil is a combination of shorter saturated fats that can only be made into BHB. To lose weight, you must generate BHB and that happens ONLY when you have very low insulin.

But what's the real problem with saturated fat? That's the title of this blog. Get to the point! Ah, here is the most important takeaway today. Saturated fat has its own hidden secret. It is inflammatory. Here is the deep dive. Protein Kinase C-epsilon (PKC-e), is an enzyme that inhibits insulin action when it is activated. It puts a tag on the insulin receptor and makes it inactive. You need higher insulin. You become diabetic. That, by the way, is the definition of insulin resistance. For the last several years, it was thought that PKC-e was located in your liver. Not! It's in your fat tissue all over your body, most particularly, your gut. When PKC-e is turned on, your fat cells get big, engorged, and spew out inflammatory cytokines. They make your whole body inflamed. But what we really now see is there is a straight path from eating saturated fat to inflammation, insulin resistance, and diabetes. That pathway goes right through your fat cells and PKC-e. Once you are insulin resistant, you continue to have high insulin all the time and that makes you stay fat. Voila. A perfect trap you can only wiggle out of with careful attention to detail.

And if you simplify that and "reverse engineer it", that is the perfect way out of diabetes. Follow this. Stop eating high saturated fat food (animals fed on grains, eggs from chickens fed grains, milk, and cheese from cows fed grains) and high glycemic foods (potatoes, rice, bread, wheat, oats, corn, beans). Cut down on too much protein. Consider 6 oz a day as sufficient protein. Eat lots and lots of above-ground vegetables, olive oil, macadamia oil, avocado oil and coconut oils (A wee bit controversial but I think I'm right. The Kitavan study shows folks who eat no grains, smoke like chimneys and get 50-70% of their calories from coconut oil, and have no heart disease). Doesn't that sound like the Mediterranean diet? Yup!

WWW: What will work for me. I'm so eager for the farmer's markets to start working in these COVID times. I know, we have to keep our distance and wear masks, but I really want some farm-raised, organic vegetables. Some of our farmers will take orders you can pick up at the Farmer's market and spend less time being in the crowd. And we are cutting down our meat consumption and spreading out our cooking it. Tonight, pizza on the deck with friends, made with veges on cauliflower crusts, untouched by anyone in personal pizzas, and all of us 8 feet apart.

Pop Quiz

1. What foods turn on insulin? Answer: any carbohydrate product that has been processed by grinding such as wheat flour, or rices with their hulls removed, oats that are crushed, and any portion of animal protein that exceeds your metabolic need for protein. We eat about 3 times too much as a general rule.

2. What foods fail to turn on insulin? Answer: Fat. Two kinds of fat. The first kind looks like a fat, smells like fat, tastes like fat, must be fat. The second kind is the secret kind. Green vegetables that are digested in your gut to make beta-hydroxybutyrate, a short-chain fatty acid that is counted as a fat. (See Gorilla Diet: all green leaves but ends up being 60% beta-hydroxybutyrate - magic trick in your colon turning cell walls into fatty acids.)

3.  What fats are safe for you?   Answer: the ones that don't turn on PCEe, unsaturated fats.

4.  And just what does PCEe do?    Answer: Ah! Here is the rub.  It makes fat cells sickly, too big, inflamed and they proceed to spew out inflammatory cytokines that mess every part of your body up.  It's the slippery slope of diabetes.  

5.  What on earth can I eat?   Answer: eat like a gorilla.  Lots and lots of green, leafy vegetables that includes all the broccoli, cauliflower, avocado, spinach, Swiss chard....if it grows above ground, it's probably ok if you aren't sensitive to lectins, and it's not a legume or a grain.  Those who can tolerate lectins or who cook their legumes enough can tolerate and eat them.  And all the olive oil you want, all the safe nuts you want.  (Put cashews and peanuts last and choose almonds, walnuts, pistachios, macadamias first.)

References:  Diabetes, Medical News Today, Harvard Health Letter, Harvard Health Letter-Good Fats, NIH-Research Matter, Am Jr Physiology, Frontier Nutrition,  Cell Metabolism, Jr Nutrition


Understanding Longevity V: Does Resveratrol Really Make Me Live Longer?

I have a bottle of resveratrol sitting here in my closest.  I stopped taking it. Should I take it.  Does it do any good?  I can only take so many supplements.  Is it worthy of being on the list of the total I can handle?

It does have a role.  Let me see if I can explain it to you so that you understand right where it fits and where it provides you benefit.  Resveratrol blossomed some 20 years ago.  It was Sinclair's lab that brought it out in popularity. He was studying yeast cells to see how long they lived.  Twenty-five generations is a pretty old yeast cell.  It takes a lot of dedication to watch them under a microscope for 25 doublings, so Sinclair even set up a lab at his home so he could pull all-nighters.  To his horror and delight, yeast cells with resveratrol lived up to 35 generations (meaning he got much less sleep).  If they didn't have a SIRT-2 gene, it had no effect.  So resveratrol was activating the SIRT-2 gene.  Remember, the SIRT genes, all 7 of them in humans, are the team responsible for keeping your epigenetic code healthy and youthful.  And also, remember, it is the degradation of your epigenetic code that defines when you die.  Your genetic code is immutable.  Your epigenetic code is essentially the various on and off switches on your histone proteins that instruct your cells what genes to copy and when.  That acts like genetic code.  It tells your cells when to differentiate into different organs when to fight different infections when to start different metabolic processes.  It's your operating system.  Your "Windows 97".  We are only on Windows 10 for computers - our genetic code is way ahead of us, so far.  In essence, the SIRT system of proteins is your "longevity circuit" that is activated when your cells sense metabolic stress.  That's a nice way of saying your cells hunker down and live longer to wait out a lack of calories.  Intense exercise, fasting, calorie reduction are all means of engaging that longevity circuit.  

Where does resveratrol come from?  It's found most richly in stressed grapes.  Dark red ones are best.  Pinor Noir, for example.  White wine doesn't have it because we don't use the skins to make white wine.  Why is stress important?  Sinclair believes there is some natural synchronicity here.  We are talking about stressing your cells by reducing calories to engage the longevity circuit.  Grapes raised on poor sandy soil, with a touch of dry weather and with a bit of early frost have the most resveratrol.  They are plants being stressed.  The compounds they make to help their own longevity circuit activates yeast's longevity circuit and our human longevity circuit.

Other researchers have found the same.  You can stuff mice with a high-calorie diet, but on resveratrol, they still live longer.  When Sinclair first published his resveratrol data, red wine sales all over the world went up 30%.  

The problem with resveratrol is that it doesn't dissolve very well to get absorbed in your stomach. And it isn't really very potent.  That combo means it's not very effective.  You have to drink some 750 glasses of Pinot Noir a day to get the effect of longevity that Sinclair demonstrated on lab mice.  (Some would call that very good news.)

But that's where resveratrol lands.  It was the compound that really opened the floodgates into research into STACs: Sirtuin Activating Compounds.  What chemicals and compounds can we engage to address this disease called aging?  That's what resveratrol started.  There are now 100's of these compounds that work to variable degrees.  As science is prone to do, their names are odd and sound like code:  SRT 1720 or SRT 2104.  But with the discovery that NAD was sirtuin food, and in humans activated all 7 sirtuins, attention to resveratrol shifted to NAD and longevity research was off to the races.  

WWW:  What will work for me.  Should you take resveratrol every day?  Well, if you insist and don't mind gobbling one more capsule, no harm done.  But probably minimal benefit.  You will get about 1-3 mg of resveratrol in each glass of Pinot Noir, and no, you really shouldn't have 750 glasses of Pinot Noir a day.  But if the choice comes down to what pills can you tolerate adding, NAD or NMN is the real winner.  You can find NAD-riboside combined with resveratrol from some suppliers.  And if there is any combination, throw in metformin while your are at it.  850 mg a day of Metformin might be about the right dose.  I've been taking it for over a year now and take it right through my rounds of fast-mimicking dieting where I only eat 800 calories for 5 days. The prevailing admonishment is that you don't do metformin when you are fasting.  

Pop Quiz:  

1.   Where do you find resveratrol in nature?    Answer: the skins of grapes, most abundantly when they are raised in hot dry climates, with a touch of frost, stressing the grapes a little. Red wines are the best with Pinot Noir coming out first.  Nothing in white wine. 

2.  What does resveratrol do in the cell?    Answer: it activates SIRT-2, one of the sirtuin family of epigenetic code protection proteins.  

3.   How much resveratrol should I take as a supplement?    Answer:  If you are going to take it, you need a lot.  Find doses of some 1500 mg a day instead of 750 glasses of Pinot Noir.

4.   If I had to choose between resveratrol and NAD-riboside or NMN, which should I take?     Answer: Hands down, the NAD-riboside or NMN

5.   Back to that bottle on my shelf, should I take it?     Answer:  No, have friends over on your deck and share a glass of Pinot Noir. Tell the resveratrol story and leave it at that.   Remember, in COVID times, keep 6 feet of distance. I found Pinor Noir in single-serving bottles so didn't have to pass a bottle around. Prize-winning flavor?  Well, no.  But ok.  

References:   David Sinclair's Life Span, Nature, Nature

Belly Fat Predicts Dementia in Women

"My tummy keeps getting fatter, and I'm not even gaining weight!" she said.  This is such a common complaint in my practice, I could recite it for you.  You are age 57, postmenopausal, and you feel like your tummy won't get smaller, no matter what you do.  And it gets worse!  Here comes data that predicts that tummy fat is going to result in your developing dementia.

This week's study is from England where Alzheimer's is now the number one cause of death.  The Brits live some 3 years longer than Americans, which accounts for some of the difference, but Americans are on track to have dementia be our number one cause in a couple more years. So, just what is this study showing us?

The British ELSA (English Longitudinal Study of Ageing) study looked at 6582 adults over age 50who were dementia-free at the beginning of the study. Everything got measured and then followed for 11 years.  Women's waists over 88 cm (34.7 inches) and men's over 102 cm (40 inches) were considered too big.  The correlated pretty well with a BMI of greater than 24.9. When controlling for all the usual variables that make risk for dementia, including APOE-4, women with larger waist sizes had a 39% increased risk of developing dementia.  Now, that was just in 11 years.  Those who developed dementia were, on average, 71 years of age when they entered the study.  Those who didn't were, on average 10 years older.  This supports the notion, well documented elsewhere, that the longer you live, the higher your risk.   Now you have to add the "bigger your waist".

What could be going on with bigger bellies?   Well, belly fat isn't just idle calorie storage.  It is actually quite inflammatory stuff.  When you measure blood coming out of the portal vein of folks with high "visceral fat", their IL-6 is much higher than folks with normal-sized tummies and lower visceral fat.  (VIsceral fat is the stuff around your intestines and organs, not the stuff the plastic surgeon sucks out.  Sorry.  That's right, a tummy tuck won't help reduce your risk.). High IL-6 results in high CRP, which you can easily measure.  

Is it high insulin?  It's clear that the larger your fat mass, the higher your insulin level.  As you get bigger, your fat cells go rogue and start being less insulin-responsive.  You need a higher insulin level to control your blood sugar.  High sustained insulin is hard on your brain.  Curiously, you act as though you can only make so much insulin in a lifetime.  If you are forcing your body to make a lot to control high blood sugar by being overweight, you then eventually run out of insulin and deplete your ability to resist high sugar.  And that's what you see in humans.  Low grade elevated blood glucose, associated with a big belly in the 40s turns into higher sugar and a blood glucose controlling medication in the 50s turns into full-blown, insulin-dependent diabetes in the 60s. 

We can fix this.  The fast mimicking diet taught by Longo does it.  You will lose weight when you eat only 800 calories for 5 days.  Better yet, you will rebound with a burst of stem cells and repopulate your pancreas gland with more insulin-producing stem cells.  (At least in mice you will.  It's really hard to find humans willing to let themselves be sacrificed and their pancreas glands examined for the sake of science.  The informed consent for mice is shorter.). And Belly Fat appears to go first, along with waist size and CRP.   Nice combo.

References:  Int Jr EpidemiologyDiabetes,  Curr Opin End Diabetes, CellValterLongo

www.What will work for me.  Hmm.  I have a mother who developed dementia.  I'm concerned for myself.  My waist size hovers around 38.  I have work to do.  Join me.  Every month I spend 5 days eating 800 calories for the last 5 weekdays of the month.  It was hard the first time I did it but after 4-5 months it got to be easy and routine.  On day 3 my brain turns into a laser and I correlate that with my ketones rising above 2 on my Keto Mojo beta-hydroxybutyrate meter.  

Pop Quiz

1.  You are a 61 year old woman with a waist size of 35 inches, or even 36.  Should you be worried about dementia".             Answer:   YES!

2.   Ok, how worried?    Answer:  39% worried, in just 11 years.

3.    Whew.  You are a man so you don't have to worry as much with a big waist size.  T or F.   Answer: Curiously, true.  At least in this study.  There has to be more to this but for now, being a slightly pudgy man, at least an Englishman, is ok. Fee, Fi, Fo, Fum.....

4.   So you just saw a belly fat sculptor who was going to freeze off your belly fat.  That will reduce your risk of dementia.  T or F.    Answer:   Sorry. False.  You may feel better about yourself but all you did was take off the superficial stuff.  It does look ugly but the harm appears to come from the fat around your intestines and organs and that isn't sculpted off.  

5.   Belly fat looks awful but it's not really dangerous.  T or F.      Answer:  This study says it's not so bad for men, but for women, it carries a 39% increased risk of dementia.  It's got to be addressed if we are to reduce risk of dementia.  

Understanding Longevity IV: NAD+ and Metformin

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.  

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

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.  

Understanding Longevity II: The Horvath Clock

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.  

Understanding Longevity I: How Your Genes Work

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.