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.
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.
"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.
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.
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.
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!
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.
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.
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.
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.
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.
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.
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.
Do you have occasional floods of odd symptoms when you eat? Chest pains? Gas? Bloating? ER Visits? No Answers? I've heard of all of those, and we don't always have simple answers. And we see more of these in CIRS (Chronic Inflammatory Response Syndrome) than in the regular population. CIRS, or what you know of as chronic fatigue or fibromyalgia, is becoming better understood as a dysfunctional transcription of inflammatory genes. The word "transcriptomic" illness. You turn on odd, inappropriate genes that result in symptoms you can't understand. For example, if you turn on IRS2, a gene attached to glucose metabolism and the ability to burn glucose in mitochondria, you may end up with shutting the pore into mitochondria that imports glucose, a reduction in ATP production, lactic acidosis, an increased anion gap.........doesn't that sound frightening, all over an itty-bitty little food allergy? If you want to dive down that rabbit hole, you can find a whole lot of fascinating detail that is the cutty edge of microbiology that is all about gene expression and foods.
You've heard of aspirin sensitivity and certainly know some folks who have been a little sensitive to stomach irritation with aspirin. Those effects are chemical and occur immediately because of the acidifying. They aren't the topic here. We are talking about a gene-inducing and activating process. That takes some sort of trigger to get it started and then training. That training or persistent activation is basically nudging the gene to keep being turned on, again, and again. With food, that means you have to keep being reexposed to it. What foods might have salicylates in them? A lot! Salicylates were discovered in willow bark where they are highly concentrated as a poison to protect willow trees from insect predation. But that means nature has figured out how to make them, and those genes ended up in other plants to that use them to protect themselves in a similar fashion. So, you find 218 mg of salicylate in grams of curry powder. Raspberries are high. Apples, avocados, cherries, figs are all in the high group. Many of those foods are good for you, and there is something to be said for eating foods that provoke you to raise your own defense mechanisms. It just goes wrong when you become overly sensitized. And that happens when you don't have the ability to turn off your immune response properly.
We have heard this same story with latex allergies. What starts as the regular use of nice, stretchy gloves turns into hands covered with rashes, itching, bleeding, then asthma and fatigue. I've seen it happen myself. A little bandaid sets of days of terrible discomfort. Is latex allergy similar? Does everyone get it? Is it part of CIRS? No, everyone doesn't get it? But the frontier of medical research is now to the point of looking at those genes and watching how they are activated. And that is were we see the unique intersection of CIRS and salicylate allergy, latex allergy. (Did you know that latex allergy overlaps with many foods too? Yeah! Really: apple, avocado, banana, carrot, celery, chestnut, kiwi, melons, papaya, raw potato and tomato are on that list)
In CIRS, I keep hearing of ER visits for crushing chest pain with no identifiable cause. Horrible bloating and terrible abdominal pain, with no known cause. Frantic itching, with no known cause. Until we do the GENIE test. The GENIE is the very first test on the market that actually looks at the genes you have activated and are found in your serum floating around in exosomes. If you haven't heard of exosomes, become familiar with them. They carry your activated DNA messages all around your body. When I read your exosomes, I read what your body is naturally doing. I can see your IRS2 gene, your large ribosome protein-making gene, your histamine gene, your PTSD gene.......over 100 genes that are known to be activated around the CIRS diagnosis. It's new. It's raw. It's unrefined, but it is the next step forward as it gives us the path to find resolution. We can connect cause to action.
WWW.What will work for me? I'm being humbled every week by how much our own bodies know how to do that is filled with wonder and complexity. But also how it goes wrong. I'm personally not very sensitive to anything. But I see it in my clients. And what used to sound like crocky, crazy symptoms are beginning to have real, valid, measurable, scientifically validated causes to them. My ears burn with anguish that I didn't learn this earlier.
1. If you go to an ER with horrible chest pain and find nothing, you are likely a little nuts and don't have anything wrong with you? T or F Answer: False. Your symptoms are just from something we can't measure yet in conventional medicine. If you ask the doctor for a GENIE test, they might look at you with a startle.
2. What is a GENIE test? Answer: Expansion of the messenger RNA found in tiny exosomes in your blood. You have a couple of million exosomes per cc in your blood reflecting the messages every cell in your body is sending to every other cell. The GENIE grabs those, expands them, measures them and tells you exactly what your cells are doing.
3. Where is the GENIE being used? Answer: To solve the dilemmas of CIRS patients who have not yet gotten better.
4. Folks who eat apples and bananas may have? Answer: Salicylate or latex allergies, associated with CIRS, and turning on the same abnormal transcriptomic responses.
5. So, just what is CIRS? Answer: The eccentric and awful dysfunctional activation of genes brought about by toxins from water damaged buildings: a transcriptomic illness, a new field of medicine.
Just a month or so ago Japan was mired in Olympic cancellation controversy and foot-dragging over their response to the COVID-19 threat. Dire warning about an upcoming disaster with headlines of doom were common. Now, they have only had 16,000 cases and 784 deaths out of 126 million people, most of them much older than us. That's on the order of 5% of what's happened here in America with similar demographics. Last week in Tokyo, with 14 million people, Japan had just 3 new cases one day. New York is celebrating being under 100 deaths. How did they do it?
Now many large public venues like theaters and sports venues shut down earlier than in most countries. Prime Minister Abe even took heat for closing school sooner than most countries. Japan did move to stop crowding and the confined spaces early, which is remarkable when you consider their subways and trains with hired pushers to force extra riders to fit in. But most of the credit is being given to the natural instincts of Japanese to their own personal habits of polite public behavior and personal discipline. When folks have a cold in Japan or even a slight hint of spring hay-fever, they don a mask in public. That's just expected!
But there is some conversation in Japan going around that suggests it's also Japanese food and their inclination to eat natto. This may not be as crazy as it sounds. Follow this thread. Natto is a unique Japanese food. It is made from fermenting soybeans in wheat-straw that is a rich source of Bacillus subtilis, a bacteria that naturally makes lots of Vitamin K2. I mean really lots. One teaspoon of natto has 150 mg of K2, some 150 to 200 times the content of any other food. There is a quaint legend about its discovery 1,000 years ago when soldiers, cooking soybeans were called into battle. They dumped the half-cooked beans into some straw and left. Five days later, starving and exhausted, they remembered those beans and returned to the scene. It had rained. The beans were fermented, all gooey and stringy. They tasted delicious and natto was born. It is a unique Japanese dish and not all outsiders find it delicious. (Google Youtube "Eating Natto for the first time.")
Now K2 is slightly complex in its biology. K1 is well-known from dark green leafy vegetables. It helps clot blood. Animals that eat dark green grass make K2 (actually MK4) from the K1 in their gut. Guess what happens when you move your animals off the pasture into a feedlot and feed them corn and beans! You get virtually no K2 in their meat. The food chain from green grass, to animal's gut bacteria to human consumption relies on being grass-fed. In America we get little K2 at all unless we make a real effort to buy grass raised animals, never fed beans and corn. Now K2 has very little blood clotting effect and plays a dramatically different role in calcium proteins, both in bone and coronary arteries. Weston Price even noticed, over 100 years ago, that heart attacks declined during the season when butter and milk from grass-raised cows was available. K2 and D were part of his Activator X which he felt helped control many illnesses and was a critical component of healthy populations.
But was does K2 have to do with COVID-19? We aren't sure but there is this curious link with K2 and D and immunity. And then there is Japan with its amazing, serendipitous salutary response to COVID-19. And finally we know there is a strong effect of Vitamin D with COVID-19, and K2 appears to augment or make synergy with Vitamin D. Hmm.
www.What Will Work for me. Now, in my world, I maintain that everyone should be taking K2 for bone health and heart disease prevention. I take it. But K2 explains to me why Japan has done so well with COVID. There remains unexplained physiology about immune response and K2. Vitamins don't work in isolation. They work in complex webs in association with other nutrients. It is complex to parse out the separate actions. I'm awestruck at Japan's disciplined public behavior. Compare that to our bar scenes and boardwalks on the news. That just doesn't happen in Japan. But K2 is one simple intervention you should be undertaking just on general principles. If you take D, you should be on K2 as well. Time will eventually tell. Oh that I had 30 more years to track that data. I want to live long enough to see Weston Price proven right.
1. Vitamin K2 comes from where? Answer: either from animals that eat green plants, like grass, or from fermented foods like natto and sauerkraut.
2. American K2 has done what in the last 70 years? Answer: dropped some 80-90% because all of our animals
3. What did Weston Price observe about K2 and D? Answer: they were synergistic with each other. He didn't even know it was "K2". He just found the effect of grass raised butter was pretty potent. Even cured cavities.
4. Have you ever tried natto? Answer: ____________. Should you? Well, how about some grass raised meat. Or heck, just take the K2, MK4 form and be done with it. Rest of your life. 100 mcg a day.
5. What might be Japan's other secret weapon? Answer: Strong public ethic of self-responsibility and consideration for others. That we should have a little of that!
This might be the most important action you can take to build your immune system up to fight COVID-19. Yes, most important is just to not get it by lowering your risk of exposure, social isolation, hand washing, avoiding face touching, etc. But focus here, Vitamin D appears to play a central role in your immune system. Here is how.
First of all, the biology of Vitamin D. You make it in your skin when UVB rays from the sun hit a cholesterol molecule and break one chemical bond open. At age 20, a Caucasian American will make 20,000 IU of Vitamin D in June (sun directly overhead) with 20 minutes of mid-day sun. At age 70, that same person will only make 5,000 iu in 20 minutes. Skin pigment protects the degradation of folate by sunlight but slows down Vitamin D production. Africans living in Tanzania, getting optimal sunlight, have D levels of 40-55 ng living on the equator.
But living in northern cities, mostly indoors, African Americans have Vitamin D levels of 5-15 ng (personal research of roughly 500 ER patients). That is severely deficient. (To convert nanograms to nanomoles, the unit used in European studies, multiple ng by 2.5: 12 ng equals 30 nmoles). It is becoming widely accepted that Vitamin D has been the driving force of human populations' skin pigment. Folks living further north in Vitamin D deficient environments succeed only if they develop lighter skin, allowing them to generate D. That's why folks from Ireland, Scotland, Norway, Finland, and Russia sunburn so easily too.
You won't get rickets (severe Vitamin D deficiency) if your D level is above 12 ng, so some consider that as sufficient. However, there is clear and compelling evidence that you need a level of 32 ng to turn on cathelicidin, your natural antibiotic. Optimal levels of D then become 40-80 ng to defend against virus assaults. You can't protect yourself against virus infections when your D level is below 30 ng. In Wisconsin, Caucasians drop their D levels down to 20 ng during winter and rise up to 45 ng during the summer. That's why influenza shows up in winter. And goes away in summer. A meta-analysis of 17 studies has shown that Vitamin D is strongly associated with viral infections. The higher the D, the less viral infections.
This week's focused study is from Indonesia. 780 lab-confirmed cases of COVID were reviewed for Vitamin D levels and mortality. The majority of folks with insufficient low levels of D, with preexisting conditions, died. Another study from the Philipines put it into risk ratios. Folks with healthy levels of D had a 19.6 fold risk reduction of death. Did you get that? Read it again. 19.6 fold. This observation explains part of why folks with skin pigment appear to be more vulnerable, why nursing home residents are more vulnerable, why northeast American States have done worse while southern, sunny states have done better. It suggests that the virus will calm down a little during the summer but roar back in November (just like influenza did in 1919). It suggests that Africa will not be as severely affected.....unless you are really crowded, poor, diabetic, overweight.
But here is the rub. Vitamin D isn't a drug. It is a hormone tasked with turning on genes. That takes a while. Drugs work in 20 minutes. DNA and genes take days to weeks to start working. Fundamentally, Vitamin D turns stem cells into mature cells. It is stored in fat tissue. Overweight folks are almost always more deficient. If you just start taking a dose of 5,000 IU a day (5 minutes of sunshine in a young Caucasian), it will take over a year before you come to a new plateau. Because of the phenomenon of soaking up into fat tissue, you need a loading dose to get started. Most folks who haven't been taking Vitamin D need at least a 100,000 IU loading dose. African Americans need two loading doses, back to back. Each dose will raise your blood level about 14 ng (on average). To optimally protect yourself, you want to be on Vitamin D for several months before you get exposed and to have an optimal level when you are exposed. If you are elderly, your skin just doesn't make it anymore, and your dermatologist yells at you for being out in the sun. You just have to take it as a supplement. And best of all, a blood level to guide your decisions. Remember, 19.6 fold increased risk of dying. Plain and simple.
www. What will work for me. I'm older, living up north, with some propensity to be diabetic in my genes. If I get ill with COVID-19 and have no D, I'm toast. Taking it once a month has been touted as adequate because it simplifies taking it. The problem with that is remembering. There is some evidence that taking D every day is actually better. I suspect it is mostly because you get in the habit and remember to do it.
1. To fight viruses optimally, you want Vitamin D to be what level? Answer: At least 32 ng or 80 nmoles. Much higher than many recommendations for preventing rickets.
2. Folks living in northern cities have normal levels of D? Answer: False
3. African Americans with skin type 6 (very dark) need the same amount of sunlight to make sufficient Vitamin D. T or F. Answer: Horribly false. Proably need up to 6 times as much sunlight, which you can't get when you live indoors, in a cold climate, far up north where for 6 months a year you make no vitamin D at all.
4. How well does Vitamin D sufficiency protect you from dying with COVID-19? Ratio of 19.6
5. What should you do with Vitamin D to get started? Answer: Get a blood level, take a loading dose of 100,000 a day for every 14 ng you are below 50 ng and then take 5,000 iu a day
During these COVID-19 times, you and I are not going to restaurants. We are ordering carry out. It comes in plastic containers. We take those home and plop them in the microwave. With that, you are getting about a credit card worth of plastic a week into you. Hmmm.
If you take the industry spin on exposure to plastics, you will hear an extolling of the many uses of plastics that make our lives easier and better. There is "very little" evidence of harm.
But if you drill down to sizes, you will find that plastics break down to micro and nano-particles and have been found in Antarctic snow, Hawaiian beaches, Mariana Trench sediment. They are everywhere. Out of them leaches the chemicals that make plastics so versatile and flexible: Bisphenols, styrene, and phthalates. Leonardo Trasanda, MD, director of the NYU Center for Investigation of Environmental Hazards (author of the book: Sicker, Fatter, Poorer) details the endocrine-disrupting effects in plastics. Parts per trillion are now measurable, and our amazingly delicate and finely tuned endocrine system responds to those levels. This results in measurable effects when you do the magic of population epidemiology: 10,000 extra deaths per year of cardiovascular disease in men from the damaging effects of phthalates.
That's not the whole problem. Those tiny little particles are even more surreptitiously nefarious. They bind and soak up other wicked chemicals like PCBs, long banned and no longer sold, but circulating in the dark underworld of our environment. Plastic Microparticles pick them up and carry them around. You get the back when you ingest those ppt (parts per trillion) of plastics.
We collectively raised enough fuss about BPA back in the 2008 era to force most plastic manufacturers to reduce their use of BPA. Want to know what happened? Yup, bisphenol-S and bisphenol-F showed up, (It's NOT bisphenol-A after all.) says Patricia Hunt, of Washington State's School of Molecular Biosciences. She published a report in The Lancet suggesting that our traditional form of measurement underestimates the total BPA exposure by about 44 fold. We have left out all the metabolic breakdown products. Same problem with phthalates. Fetuses and pregnancies pick it all up and you get measurable results showing quite high levels.
This isn't any fun. We have to find a way of taking this seriously.
Consumer Reports details 6 steps you can do to keep yourself less plasticized.
1. Drink tap water, not plastic bottled water. (Unless you have lead or copper in your tap water)
2. Don't reheat your food in plastic containers. Stop it. Just don't. Glass or ceramic instead.
3. Buy and store food in glass, silicone, or foil. Plastic codes 3,6 and 7 are the worst. If you do use plastic containers, opt for codes 1 and 2. But still don't reheat anything in them. Ever.
4. Eat as much fresh food as possible. Even canned foods are lined with plastics. You can take reusable cloth bags to the grocery store to hold your vegetables instead of the plastic bags in the vegetable section.
5. Clean up dust in your home. Vacuum and wipe dust up. It has a lot of microparticles in it.
6. Act. Join local groups that encourage zero-waste behaviors. Help Upstream, a nonprofit working to create reusable takeout packaging. Vote. Lobby. It matters to you and your grandchildren. Trust the science we see playing out. It's not a joke.
1. Name one problem with plastics. Answer: They break down to microparticles that can soak up PCBs and other environmental toxins.
2. Ok, now name another. Answer: We think we have gotten rid of BPA with our attention to its problems, but we find it has been replaced with other bisphenols like -F and -S. These are all endocrine disruptors.
3. What do those endocrine disruptors do? Answer: We haven't found all the problems but 10,000 excess cardiovascular deaths a year, infertility, loss of hearing........have all been associated.
4. What might be the worst thing you can do to give yourself more plastics? Answer: well, how about heating up your restaurant carryout in a plastic container with a 9 label on it? (Until you melt part of it away)
5. Can you name one behavior you might do differently regarding plastics? Answer: _________. Do it.