Notes from the Lifespan Podcast: Dr. David Sinclair and co-host Matthew LaPlante
Introduction: “How to be healthier at any stage of life.” Eight Episodes.
Dr. David Sinclair is a professor of genetics at Harvard University, who’s life focus is to understand why we age and how to slow its effects.
Below are snippets from the eight episodes. This is not a substitute for listening to the episodes but an addendum. We also suggest reading the Lifespan book although it is three years old and information is changing fast. Sinclair and Laplante’s forthcoming book should be out later this year or early next year. We included the show links as well as definition links to key terms.
“How to be healthier at any stage of ife.”
Episode 1: The Science Behind Why We Age
“Why we get old and why we may not have to… We are going to be able to live decades longer with science that comes out every week… Provide ACTIONABLE information… They communicate whether a study is in a mouse, yeast cell etc. b/c a study in a mouse is very different from that in a human… Not just what to eat but when to eat, pack meals in shorter times… These are things we can implement right now… Sinclair will keep people up to speed on all the new scientific developments… Aging happens every day and before we’re born… We can improve health and long term survival at any age, as well as look good and function optimally now… Sinclair argues that in his lab he can control aging, and that this can and will be done in humans, which will fundamentally change the course of human history… The first person to make it to 150 years old has already been born… Mole rats live decades longer than typical mice and rats due to specific molecular traits… Longevity genes get turned on by adversity… We can learn more about aging from a yeast cell that we can from Alzheimer’s… The same genes that control aging in yeast are the same in other animals including humans: 1) mTOR (mammal, target of rapamycin): longevity gene that senses amino acids, want mTOR levels low for longest lifespan, fly, worm, mice, etc. that are given rapamycin live dramatically longer, low mTOR activity signifies adversity which yields longer life, in lab yeast cell, mice, etc… Matt Caberling doing great work, treating dogs with Rapamycin, protects the heart, testing dog lifespan etc… Aging not that complicated as long as you understand the genes that control it… 2) AMPK (AMP-activated protein kinase) & Metformin: Want to activate AMPK, eat less,more sensitive to insulin, suck sugar out of bloodstream, ramps up energy producing centers of the body, membrane filled bags which are ancient bacteria known as mitochondria… Will Metformin, drug that activates AMPK extend lifespan? → Kulkarni AS, Gubbi S, Barzilai N. Study… Metformin frontline therapy for Type 2 diabetes, which treats high blood sugar… Sinclair Lab shows Metformin mice live longer and healthier… Type 2 diabetics live longer than folks without Type 2 diabetes, and protect against cancer, heart disease, etc… AMPK senses low energy and it protects the body → Hormesis: what doesn’t kill you makes you stronger → Activates other longevity genes etc… Longevity genes talk to each other and are part of a network, tweaking one affects the others so need to understand aggregate network effects and whether tweaking multiple genes is better than one or two, etc… 7 Sirtuins, SIRT2 etc. → Give body fear and it does wonders… Why are sirtuins doing what they’re doing? Ex-differentiation: genes that shouldn’t be readable become readable and cells get confused and become a general cell type instead of specific one → brain cell starts acting like skin cell etc… Sinclair believes that ex-differentiation is the cause of most diseases, Alzheimer’s→ Neurons become less tightly packed, the code becomes more readable, and gene pattern expression lose their identity, brain cells start to possess part skin cell, kidney cell etc., the cell loses its mind… Having high levels of blood sugar exposes you to heart disease, diabetes, dementia, frailty etc… Try to keep blood sugar low, which metformin treats… Cells that line blood vessels that suck glucose out system lose their function → Glut4 is the gene that sucks out the glucose, over time with aging, cells lose the ability to make Glut4 transporter and glucose stays in bloodstream longer which is toxic, thus metformin… Defensive genes partially reset aging as it slows down the ex-differentiation process so that cells behave the way they are supposed to i.e. skin cells act as skin cells, brain cells act as brain cells etc… Can drive aging forward by disrupting cellular spools in forward causing heart disease, evidence that disrupting the epigenome, the readers of the DNA, causes ex-differentiation, causing all these diseases in mice… Steve Horvath, as well as Greg Hannum, found can measure DNA methylation patterns which change over time and thus gives biological age, we know how to reverse that spooling and get cells to work like they used to… Anyone soon will be able to do a cheek swab and measure biological age for less than $1 due to evolving DNA sequencing technology… People that dont exercise, eat well, will die soonor in aggregate than those that do not… Biological age is malleable and can decrease over time… Greg Fahy, DHEA, metformin and HGH treatment rebuilt the thymus and the biological epigenetic clock was reduced by 2.5 years, Greg is showing that you can repeat this… To be immortal go back one year every birthday… How often can you reset the clock? Aging is the fundamental process of the ticking of the clock, the unspooling of the genes in a yeast, mouse, tree, worm and ourselves that causes nearly all diseases... The regulators are above this process, AMPK, mTOR, sirtuins, slowing down all the bad processes, caused by ex-differentiation. To slow aging then trigger the regulators… Genetics determines 20%, 80% how you live your life, the epigenome (eating, exercise, sleep, etc.) controls the longevity genes.. 3) Sirtuins are the 3rd group of longevity genes → control the spooling process, ex-differentiation process due to malfunction in the sirtuins (silent information regulator). We can maintain sirtuin function during old age by exercise, diet and being hungry sometimes, which take care of the packaging of the genome. Aging is akin to having scratches on a CD so that the reader (laser) is skipping and playing the wrong songs at the wrong time, equivalent of aging process where cells start losing identity and acting like other cells, brain cells transform and act akin to skin cells etc… To get rid of scratches or epigenetic junk, to reverse aging and then diseases of aging will go away… In later podcasts will talk about what supplements work, what manufacturers can be trusted, etc… One thing we can all do immediately is recognize that aging is the disease and is treatable, now we do whack a mole medicine where Dr.’s treat that specific disease not the cause of the process of aging. We can halt, slow down and reverse aging in all tissues and organs, brain included. Learn practical things to be able to maximize health, performance, how old we look, and ultimately longevity. We are going to have the type of lives that people only dream about right now…
Episode 2: What To Eat & When to Eat For Longevity
So much health info. out there. For longevity the ONE thing that will have the most impact on longevity, EAT LESS OFTEN. Not talking about malnourishment, pack meals into a shorter time period. The period of not eating is so important for boosting the body's defense against aging. Will naturally consume less calories so it’s even more important to eat nutritious food. And restricting calories will increase lifespan, but proper nutrition is critical. The Mediterranean Diet is the primary focus. WHEN AND WHAT to eat is critical… Yeast→ By changing glucose levels in yeast, lifespan extended. 5 sirtuins in yeast and 7 in humans. Sirtuins get activated by the hormetic effect (what doesn’t kill makes you stronger), in this case low energy led to the activation of sirtuins which took care of DNA repair and the stabilization of the epigenome. Sirtuins protect DNA and make sure genes stay on. Low energy (caloric restriction→ low glucose level) activates PNC1 in yeast and a certain gene NAMPT in humans. When we’re hungry these genes turn and make more NAD. Two ways to activate sirtuins synthetically 1) Resveratrol 2) NAD booster (NMN). Can mimic low glucose in yeast cells by giving them NAD boosters or turn on PNC1. mTOR (longevity gene) protein complex causes cells to build things. If you downregulate MTOR, Autophagy happens (remove junk) recycles proteins. When you’re hungry, autophagy gets all old proteins, recycles them into fresh proteins. Flies and mice can live 30% longer by simply reducing mTOR… AMPK (longevity gene) is an enzyme that makes mitochondria which increases when hungry. Drugs that inhibit mTOR, mimic fasting, boosts immunity and gives biochemical changes that mimic fasting and predict longevity. . Metformin activates AMPK, slows down other diseases of aging. Fasting AND the drugs that mimic fasting, are important for long term health. 1) activate AMPK→ makes mitochondria (Metformin, 2) downregulate mTOR (mimic fasting), activates autophagy→ recycle proteins→ when hungry gets all old proteins, puts them in the recycling bin and then brings them out as fresh proteins (inhibit MTOR and stimulate autophagy in mice alone extends lifespan by ~30%), 3) activate Sirtuins (fasting) → mimic low glucose → activate natural defense state by giving NAD booster… Baylor College of Medicine study by Mindicoglu→ Fasting dawn to sunset for 4 weeks→ decreased blood pressure, BMI, waist circumference, and upregulated DNA repair proteins… Type 1 Diabetes, Cancer, Macular Degeneration and MS benefit from fasting → Metformin mimics fasting why cancer patients prescribed Metformin… Sinclair uses InsideTracker to get dashboard/measurements to see how different eating regimes translate… Fasting mimic diet → Valter Longo plant based → less amino acid → helps patients get over chemo quicker… Long extended fasting 3 day+ (impossible for most but after 3 days start to burn muscle)... Time restricted feeding > 16 hours… Skip breakfast instead of lunch… Gluconeogenesis happens after a couple weeks → Liver starts to produce glucose so lose hunger; it learns to produce glucose so you need to give time restricted feeding a couple weeks… Glucose crashes gives brain fog thus sharper in gluconeogenesis… But some mice live less with caloric restriction thus need to track data! Trick for Sinclair is to be hydrated and if need to eat something eat nuts… IFAN → Intermittent fasting BUT NEED adequate nutrition → Athletic Greens. Otherwise causing more harm than good… BLOOD DATA IS KEY can’t emphasize enough. If you fast you have to track your numbers… If no fasting just don’t eat SUGAR → KILLER… Glucose spikes induce brain fog → glucose attaches to proteeins gives T2 diabetes and cardiovascular disease… AMPK and Sirtuins get switched off thus defenses against diseases implode. Proteins do not get modified… Avoid super high protein → long term mTOR and Sirtuins affected negatively…
3 Longevity Defenses
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AMPK increases with fasting (enzyme responds to low energy) → makes mitochondria→ metabolizes things we eat and makes chemical energy → have more energy, fight aging… Metformin → Slows down diabetes and other diseases of aging including dementia (arguably 55% less in )
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Downregulate mTOR (Rapomycin) by fasting → creates Autophagy → Recycles old proteins into new ones → combats ex-differentiation (cells losing identity/purpose) → Longevity
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Sirtuins activated by fasting → longevity… NAD and Resveratrol (mimic low glucose)
mTOR can turn on the recycling program called autophagy. There is no doubt whether autophagy is good for you- it is! Try to focus on plant based food so that we have less leucine molecules in the body so that we have a chance for mTOR downregulation to recycle proteins. Alzheimer’s is a good example of proteins that get modified and accumulate in the brain. We have all these old proteins that linger throughout the body which are reversible by recycling those proteins during autophagy. Having low level branched-chain amino acids (plant based diet) for at least part of the week helps downregulate mTOR which creates autophagy… Adventist health group study 2013- chance of dying based on certain diets. Hazard ratio goes down with vegetarian. Non-veggie at 1 vs. semi-veggie at .92, Vegan .85, best one was pesco-vegetarian at .81→ 19% reduction in probability of death. Recent study (Giovanni Marsala’s lab) → Women on Mediterranean diet focused mostly on plants, moderate alcohol, and exercising → reversed age. Okinawans → ~pesko→ good social structure→ work till 90’s. When they moved to Hawaii they didn't live long anymore… Xenohormesis- eating plants that have experienced stress → 20 plant molecules (polyphenols) activate Sirt1. Some plant molecules activate and inhibit pathways and proteins in just the right way; not coincidental → plant stress creates more polyphenols. Organic helps → best red wines are dehydrated or have fungus on them. Pinot Noir is stress sensitive thus the most Resveratrol… 5 takeaways: 1) Eat less often, skip a meal, don’t snack, no sugar. Programming the epigenome for long term health requires some hunger. It is OK to feel hungry. Don’t leave snacks out. We’ve evolved from thousands of years where there were always periods of hunger. Have to put the body in a state of want to prepare for stress. 2) Reduce meat intake, the data is the data and esp. processed meat which prevents mTOR from doing its good stuff, TMA goes into the bloodstream which the liver turns into TMAO which accelerates cardiovascular disease. If you like a good steak, eat grass fed, etc. Mediterranean diet vs. Western MASSIVE difference → Switching to Mediterranean diet under 80 reduces daily death probability by 31% in 1980 study but likely didn’t include those over 80 so if over 80 can still benefit. 3) Put sugar/carb at the end of the meal. 4)…. Obesity epidemic makes people age faster…
Episode 3: Exercise, Heat, Cold & Other Stressors for Longevity
Iron→ Too much iron accelerates aging. Need it but levels should be lower than previously thought. Lower iron and hemoglobin not a bad thing. Multivitamin with high levels iron leads to accumulation of senescent cells that cause aging and cancer. Ferris iron leads to free radicals which damage cells and senescent cells. Free radicals, 3 main types: 1) superoxide→ damages proteins, 2) superoxide anion → creates most of the oxidative stress in the body 3) hydrogen peroxide. Too much iron prevents glutathione from turning superoxides into water and instead turns it into hydroxyl radical which damages dna, rna, lipids, proteins → drives aging and senescence… Plant based diet, eat less often…
How to mimic adversity→ adversity memetics → Mutant worm that lived 2x due to single gene mutation → DAF2: insulin signaling molecule, mimicking adverse conditions. Single gene alteration can have a HUGE impact on lifespan. How do genes know that conditions are adverse and need to turn on? Sensors that control adversity getting turned on mTOR (sensing levels of amino acids → lower levels downregulate MTOR), AMPK (senses energy/glucose), Sirtuins sense NAD (goes up with exercise and hunger). When don’t have insulin signaling the body senses hunger/adversity. Modern society is built on comfort, can sit, eat → the worst thing for long term health. Need to mimic stress/the body perceiving adversity → trick the body into memetic effect. Less muscle → lower testosterone. Need to get body into hypoxic state where sucking in oxygen. Exercise can prevent 23% of cancers… Walk after you eat → turns on AMPK and begins glucose uptake… Hormesis idea (that which doesn't kill you makes you stronger). Vigorous exercise so important b/c induces hypoxia or low levels of oxygen (at least 10 minutes 2x a week). Hypoxic → turn on HIF-1 alpha → turns on a bunch of helpful genes that control blood vessel growth and mitochondria AND free radicals are generated which stimulates mitohormesis → manufacture of more mitochondria… As we get older body becomes less sensitive to insulin → ex-differentiation reduces GLUT4 protein, a glucose transporter → more glucose in the bloodstream damages the lining of the blood vessels → Type 2 diabetes and cardiovascular disease. VEGF(made by muscles after exercise) is a little protein that signals the formation of new blood vessels. If don’t have adequate blood vessels, the brain and muscles get starved of oxygen. As you get older VEGF production decreases. The way to restore VEGF, triggering new blood vessel formation is by turning on NAD. Aerobically active people vs. non 5.5 years younger biologically… Weight lifting helps maintain hormone levels, harder to build muscle over time so need to start from a good level… Exercise large muscles, increases testosterone… Senescent cells are “zombie” cells, alive but not dividing (cancer cells), excreting chemicals into the body. The fewer we have in the body the better (keep iron levels low.) But we can KILL THEM OFF by exercising; 10-15 minutes of hypoxic state 3-5 times per week makes enormous difference… Hyperbaric oxygen treatment → hyperbaric chamber, pressure increased, oxygen increased → reverses decay on the ends of chromosomes→ telomeres. Humans with Parkinson’s or dementia have improved symptoms, overall cognitive improvement. Theory is working similar to exercise, production of free radicals that stimulates mitohormesis. Sinclair theory is that the high to low oxygen differential creates similar molecular influences. Multiple high to low environments are more beneficial than singular as well. Thus HIIT workout routine, or sprint routine/workout routine of higher, more frequent hypoxic state and volatility destroys more senescent cells when compared to a more uniform, lower volatility oxygen state… Cold therapy → production of brown fat → mostly on back → when get cold increases brown fat → increases metabolism → burns white fat. Little proteins that get secreted out of brown fat that make the body healthy as well. PRDM16 → gene that turns fat from white to beige to brown. Mice that lack this gene develop Type 2 diabetes and cardiovascular disease. Dwarf mice lived 3x longer in lab, from being cold. Brown fat have a lot of mitochondria, within those mitochondria, there are high levels of UCP proteins which allow mitochondria to leak through the cell and create heat. Also get fewer free radicals when uncouple mitochondria with UCP proteins. High levels of UCP genes in worm, fly or mouse, live longer. Cold therapy apparently mimics this mechanistic behavior, increasing UCP genes and brown fat. Also, it’s harder to make brown fat as get older. Humans have been cold for 50k years or more, thus the body responds well to cold/shivering. Treatments → cold shower, cryotherapy, or simple sleep with little covers on bed, which lowers body temperature that activates uncoupling proteins and builds brown fat... Heat (taking body out of comfort zone) → Sauna → men (studies seem to be on men- oddly) who partake in sauna a few times per week → dramatic reduction in the rate of cardiovascular disease, up to 20%. Not building brown fat but appear to be activating HSP’s (heat shock proteins) which help fold proteins correctly and stimulate mitochondria and blood vessel growth. Sinclair cycles sauna and cold bath. Some evidence that infrared sauna can improve aspects of skin aging and oddly, hair growth… At cellular level heat and cold turn on the three pathways, AMPK, MTOR and sirtuins. At physiological and neurological level → stimulating endorphins… Hyperbaric treatment in the future, not realistic right now.
Episode 4: NMN, NR, Resveratrol, Metformin & Other Longevity Molecules
3 survival pathways AMPK, NAD and mTOR, all talk to each other, comprehension is evolving. If low on amino acid which turns on mTOR protection pathway, will turn on the others as well… If NAD (2nd most abundant molecule in the body) disappears we die within 30 seconds, without it we can’t make ATP. NAD helps us make energy and ACTIVATES the sirtuins → defensive enzymes that “send out the troops’. As we get older we make less NAD and destroy it more which reduces the ability to fight off aging and the diseases that causes. NAD is a sensor for adversity → exercise and fasting raise NAD levels. Will still have lower NAD levels no matter what as we age which is why supplements are thought to help b/c boosts NAD levels to near when we’re young. NR (vitamin B3+sugar), little to no side effects on 250mg or up to 1g it will boost NAD levels but not to the effect of NMN. Yeast live 30% longer when given NR → mimics caloric restriction which activates sirtuins and gives genome and epigenome stability. NAD synthesis gene PNC1 (nmpt)... NR turns into NMN when NR binds with a phosphate which turns into NAD. Mice with NR lived longer, more mitochondria, more athletic, less disease etc., also enhanced metabolism, which burned fat and staved off Type2 diabetes. Why not take vitamin B3 which is precursor to NR, and need the phosphate? The closer u get to NAD arguably the better which at the moment leads us to NMN as the best supplement... NR + a phosphate turns into NMN which turns into NAD → pathway not fully understood… Early results from NMN human study (10 week 250mg’s), improved insulin sensitivity (good thing keeps glucose out of the blood), hallmark of longevity. Other labs have shown that NMN protects organs when damaged (in mice). Sinclair studies in Harvard lab look promising but no results yet (next year). Other NAD boosting molecules, NCE (new chemical entities) are possibly better than NMN. Human studies forthcoming… NAD drips exist in Florida, CA, but no placebo controlled trial, dunno if work yet… In yeast the NAD molecule is too big, NMN smaller and NR smaller than that. NMN arguably raises NAD levels 2-3x. One study out of Washington, knocking NAD levels down, slowed tumor growth. In 2019 (Nacorelli) NAMPT increased senescent cells, mice that were predisposed to pancreatic cancer, developed more precancerous cells. Other mice that had no predisposal, lived longer, thus CONSULT WITH Dr. before taking NAD supplement… Resveratrol → SIRT activator → need to mix with olive oil or yogurt as it is hydrophobic (doesn’t dissolve in water). Anti-cancer activity, metabolism boost, mitochondrial boost, glucose levels, etc. In mice, fat mice on resveratrol lived as long as skinny mice, i.e. mimicked caloric restriction which reduces fasting glucose and increases insulin sensitivity. Improves cholesterol level dynamic and kidney function. No long term studies but the trajectory seems good. Fisetin is a plant molecule, not a lot of data, reduces inflammation, need more data before we know (extend mice lifespan up to 30% and healthier by killing senescent cells). Quercetin (+dasatinib): Jim Kirkland at the Mayo Clinic found that it kills senescent cells → dasatinib used to treat leukemia. Other studies Quercetin alone reduces fatty liver inflammation. Kirkland currently running clinical trials. Rapamycin extend the lifespan of every organism, downside is toxicity (attacks immune system) → works by mimicking low protein, so body starts recycling proteins aka autophagy. Spermidine → stimulates autophagy and stabilizes epigenome → Schwartz 2018 study 1.2g’s per day → significant enhancement of memory… Metformin works by activating AMPK → most scientists agree that Metformin lowers cellular energy/ATP → inhibit mTOR → mitohormesis (what doesn’t kill cell makes it stronger) → thus body makes more mitochondria and improve insulin signaling, sucks glucose out of the bloodstream and utilized → also raises NAD levels which activates the sirtuins. Metformin is a remarkable molecule, comes from the plant world. The French Lilac plant produces guanidines which are modified by putting methyls on it. NIH/Sinclair study extend mice lifespan, worms. Essentially, in animals and humans, Metformin lowers glucose, lowers inflammation, more mitochondria and muscle switching. Muscle switching: as we age muscles get more glycolytic (start to use more anaerobic mechanisms) → with metformin muscles get more athletic. Tens of millions of people are on Metformin → metformin lowers the risk of essentially all diseases. Type2 diabetics on Metformin live longer than non-type 2 diabetics… No studies have been completed yet and funded b/c Metformin is cheap and off patent, yet finally the Tame trial is looking at multiple outcomes, although still trying to get more $ (NIH and Albert Einstein’s Dr. Barzilai). Metformin not risk free has allegedly caused lactic acidosis 6-10 per 100,000 deaths but no causality defined. Generally, side effects are upset stomach and hunger mitigation. Muscle size of 5% reduction, but just as strong with less inflammation. Some folks only take Metformin on days they don’t exercise. Berberine is a plant molecule that can mimic Metformin, 1g-2g’s per day; works in mice and fruit flies, similar side effects.
What does Sinclair do? 1) 1g of Resveratrol per day since 2004 in the morning. 2) NMN 1g (over 10 days raises NAD 2x). Take in the morning b/c body raises NAD in the morning. NMN helps reduce jet lag and reset the body clock. 3) 800mg of Metformin at night after dinner. He pulses Metformin, doesn't do it days before lifting weights. 4) Recently added 1g Spermidine (stimulates autophagy and stabilizes epigenome) but no inside tracker data yet. Also advises a company that produces b/c he wants to see trial data. 5) Fisetin and Quercetin (aimed at senescent cells) ½ gram per day of each in the yogurt or olive oil. Mayo Clinic clinical trial currently examining 1x per week of 2g’s.
Episode 5: Medical Interventions (TRT, HGH, Stem Cells, etc.) For Longevity
Testosterone decreases age after 30-40 lose 1% per year, both men and women. TRT is now a multi-billion business. We want our bodies to be in a state of fear (adversity memetic) not complacency (abundance memetic). Testosterone is an abundance memetic thus probably not great for longevity and long-term health. Short term, improves aerobic and anaerobic capacity as well as libido increase. Side effects however, include breast enlargement, sleep apnea, testosterone can be turned into estrogen, bigger prostate (more bathroom visits), shrinking testicles, increased red blood cell protection which can lead to blood clots… HGH → low levels typically benefit longevity. Benefit going back to normal but too high is no good... Insulin resistance, etc. Tells body times are good not good for longer term health. Don’t eat close to bedtime → increases HGH levels and improves sleep… Peptide supplementation used by cells to communicate with each other. 1000 made by body yet only know what 20 or so do. Theory that over time these will help as part of aging is cellular communication breakdown. MOTS-c when injected into mice, lowers blood sugar levels and increases mitochondria; reduces fat in the body and reduces fatty liver. FDA shut down as not all perfectly safe. It seems like can induce arthritis as there may be negative immune responses where the immune system attacks the body to get rid of the foreign substance. Humanin helps diabetes in mice and neuro, but not clear in humans. Pinealon thought to treat memory and ADHD but no clue if true. Other peptides used and effective in mice but not clear helpful in humans. The main concern with Peptides are negative immune responses. Sinclair thinks those that mimic adversity like MOTS-c have promise but concerns… Exosomes may be able to tell us what is going on in our bodies and diagnose disease. Injections into mice have helped treat injury. Possible that exosomes can reverse senescence which essentially sends ex-differentiated cells back to differentiated cells. Exosomes can be delivered by IV but we still don’t have any safety data. Possible long-term treatment → early stages… Stem cells → cells that can divide asymmetrically that can go on to make tissues → retain youth → 2 classes 1) multi-potent can make different tissues, typically from embryo 2) pluri-potent can make any type of cell in any type of tissue. Shinya Yamanaka- godfather of stem cells. Now have the ability to grow brain cells, then drive aging forward and reverse. Sinclair uses domesticated gene viruses, package Yamanaka genes in cells, and then can turn on genes. The problem with pluri-potent stem-cells is that they can induce cancer. Cord blood is a legit way to possibly use stem cells in the future even though we don’t know how to use them yet. Sinclair would absolutely bank cells if possible for his kids.Science wasn’t clear when he had kids so didn’t.
Episode 6: The Science of Looking Younger, Longer
Hormonal issues not addressed in episode 5. Why does the female reproductive system age faster than others? Women have evolved to not be able to have kids at 40 because historically childbirth has been very dangerous (~20% mortality rate). There are better ways for women to transition through menopause but also continue to have the right hormonal balance to protect against aging. Traditionally this has been estrogen replacement therapy and now other hormones are explored which can offer symptomatic relief. The dual use of estrogen in combination with the proper dose and balance of progesterone is super important. Women should measure estrogen and progesterone levels. The historical thought that supplementing can increase levels of cancer is due to the lack of understanding what the natural levels are. It’s important to know what the baseline levels are in the 30’s and 40’s. Women should measure these numbers particularly in the luteal phase (days 14-28 of a traditional cycle). Then physicians can help women match those levels in the late 40’s and beyond. Women need to talk to their physician about this. Those with breast cancer risk shouldn’t be pumping themselves with Estrogen, etc.
Skin is the largest organ in the body → 1/6th of our body weight. Skin pinch test → Lay hand on table, pinch skin and see how long takes to come down. If 30’s and 40’s less than 2 seconds, 50’s <10 seconds, 60’s 10-15 seconds, 70’s and over up to a minute and more. Epidurmal thinning starts happening with menopause. Skin is the primary organ to protect us, a barrier. In 70’s, 80’s and 90’s skin thickness is super important. David Armstrong, top surgeon for foot ulcers (40m Americans ~13%). If couple it with diabetes is problem. Need to keep feeling and thickness. Skin may age quicker due to DNA damage from the sun. â…“ of Australians have skin procedures. At Aussie beaches, free sunscreen, saves govt billions of dollars. Skin is full of senescent cells, if delete them get skin rejuvenation → ABT263 and rapamycin (not available yet for topical treatment) senelytic treatment reversed skin aging in the lab. A little bit of sunlight good for you (10-20 minutes) but over that, sunlight fuses cells and DNA can’t be read easily. Dr. Baroni looked for peptides that reversed the clock, by using one peptide in One Skin (about 20 seemed promising). They are trying to incorporate multiple peptides in future cream. One of downstream effects is that it makes collagen. RETIN-A, one of most important aspects for preventing and reversing fine lines in the skin. Retinoids boost the production of collagen, increase growth of epidemus, lower skin pigmentation, stimulate cell growth and lower lipids. Dries out skin though and makes it susceptible to sunlight. HOWEVER, it may be at the expense of long term health, as it crates an ‘abundance’ environment as opposed to autophagy. Vitamin C helps create collagen as well. Need to use proper moisturizer if use RETIN-A product, not get it in eyes, etc. Definitely don’t use every day and don’t use it when fasting… Rate of nail growth indicates how fast we’re aging; decreases ½% per year. Regarding anti-oxidants, there is no science which suggests it works. Resveratrol topical cream may help to boost sirtuins which helps. Sinclair working on cream to boost NAD in the skin. Hyaluronic Acid (HA) → hope is may prevent skin cancer. Injectable HA (long chain) may help to improve skin volume, while topical small chains may allow long chain-synthesis… Botox → inhibits neurotransmission → muscles will relax for 6-9 months and wrinkles go away. Not clearing out cellular senescence or reverse differentiation, but if look good → feel better, good for longevity, etc. Skin peels? Doesn’t change age. Microneedling could induce hormesis, which release repair factors, but not proven… Smoking HORRIBLE for skin, alcohol not great for skin either, western diet, high fat and sugar as well… Baldness → 600 genes in hair loss → no real age indicator… Why does hair loss occur? Stem cells get expelled, hair follicles shrink. Topical creams (rogaine) stimulates nitrous oxide production and slows hair loss mostly at the back of the head… Propecia, inhibits DHT (dihydrotestosterone), but may lower testosterone, increase depression, etc. but in low % so worth monitoring for those who really don’t like being bald... LLLT (low laser light therapy) stimulates hair growth, possibly due to mitohormesis (unclear yet). Possible overall wellness effects thus infrared sauna popularity increasing… PRP injections in many different places in the scalp has shown to help, likely due to a mixture of things, rejuvenating hair follicles… Stress can induce gray hair, yet it’s reversible. Melanocytes can recover function, create adversity memetic. Cyclosporine A + Minoxidil + Rapamycin combo may possibly help restore hair color down the road… Sinclair envisions a day where will take a pill, maybe 3, to get younger, hair will regrow, restore color, etc. In the meantime, get enough sleep, don’t stress, exercise, eat less and eat nutritious food.
Episode 7: The Science of Keeping the Brain Healthy
The body and mind are integrated and no one wants to stay healthy in the body and not the brain. Modern medicine has been good at keeping parts of the body healthy, but we’re not living better because the brain is still aging → why we need to HOLISTICALLY slow down the aging process. 6.2m Americans have Alzheimer’s and it will only increase if we don’t prevent brain aging. Sinclair believes if reverse aging in the brain, Alzheimer’s and other diseases of the brain will go away and people will recover memories. Further, all of us have cognitive decline as we age thus this will help reduce that decline. Aging is a result of ex-differentiation of cells → new idea of aging is not just random stuff going on → this begins at birth and before → we start as a stem cell that is fertilized → cells gain an identity or are given their specificity (brain cells, skin cells, etc.), everything that makes up our body (10’s of thousands of different cells), as certain genes are turned on throughout the genome through epigenetic signallers → the epigenome (computer that reads the software or genome/four chemical that are the instructions, “the reader of the compact disc”) is the regulator of the genome → the computer that reads that software/genome is the epigenome/reader of the compact disc (20,000 genes) → aging creates scratches on the genome/”CD” → epigenome/reader of the compact disc can’t read CD and play the right songs at the right time → brain cell starts to play the music of a skin cell of liver cell and doesn’t function as well (ex-differentiation) → AND WE GET DISEASES AS A RESULT (Alzheimer’s, etc.)... Luckily the brain is younger than the rest of the body. Can measure certain organs using the Horvath clock by measuring the methylation on the DNA → chemical called a methyl that’s added to the DNA and sticks there which prevents DNA from being read correctly. In the brain, cells are with us for the rest of our life, unlike the liver for example, which if cut piece out some can regrow… Avg. onset of dementia is 80 years old, so need to keep the brain young as we live longer. Volume of the brain reduces 5% per decade after the age of 40 → cognitive implications for all of us. Keeping the brain healthier, younger, comes down to the three longevity factors that respond to adversity → adversity memetics: 1) mTOR (low amino acid) 2) AMPK (low energy/glucose→ boost mitochondria which boost NAD, ) 3) Sirtuins, which require NAD, and can be activated by certain chemicals . They all work together; sirtuins can activate AMPK, AMPK can activate sirtuins and mTOR. They all protect the body in multiple ways, increase metabolism, repair DNA, clear out senescent cells, lower inflammation, among many other things. All three pathways play a role in autophagy, recycling proteins, which is incredibly important in the brain. In order for this to happen in the brain, we need deep cleansing, chaperone mediated autophagy and downregulating mTOR turns on those recycling pathways effectively. Changing diet to insure all three pathways are working in a way that will promote brain health. The sirtuins respond to a whole different variety of factors as opposed to AMPK and mTOR which are triggered specifically by low amino acids and glucose, respectively. There are seven sirtuins, the brain makes a lot of SIRT1 and SIRT6. SIRT1 seems to have the most important effect on the brain. NAD boosters have slowed the degradation of SIRT1 in mice. Mediterranean diet helps reverse aging of the brain, less amyloid beta, more gray matter, etc. The risk of dementia decreases with the degree of the Mediterranean diet. Resveratrol directly activates SIRT1 as does olive oil. Mediterranean and Okinawan diet tricks the body into thinking it is running out of food. If plant diet only, can be low in B12, B6 and B3, which are important. B vitamins make sure you have the methyls that are added and subtracted from the DNA that controls the DNA methylation clock, if deficient can screw up the epigenome which accelerates aging. Photo of the retina, if blood vessels are occluded, it’s a problem. Result of low B vitamins generally increases levels of homocysteine. Some Dr. 's want lower than 10 micromoles per liter; optimal B12 levels (avoid alcohol, smoking, etc.). High homocysteine increases methylation which screws up DNA and sirtuins can’t cope thus get older and build up inflammation, calcification of arteries instead of bones → increase probability of dementia and Alzheimer’s, etc. Dr. monitors accumulation by looking at the back of the retina, blood vessel lining. Proper brain health is critical to give brain fatty acids it needs → Salmon, Mackerel, and Sardines are the best natural source of Omega3’s (EPA and DHA). If eat fish, in good shape, if not, EPA (1g a day) and DHA supplement helps (ratio of 1.5x EPA to DHA). EPA and DHA shown to increase memory and counteract depression. Flaxseeds, walnuts, chia seeds for ALA (~10% of ALA gets converted to DHA and EPA). These Omega3’s actually form a structural component of the brain. These fats essentially become the membranes that wrap and protect the nerve cells. Oleic acid also important, component in olive oil and avocados. Exercise also important for brain health, increases blood flow and activates Sirtuins… 10 weeks of weight training in elderly increased BDNF which indicates brain age and regrowth of nerve cells… Metformin → good for brain health → Metformin fish study showed better memory/cognitive function → metformin disrupts electron transport chain → makes cells stronger → sends protein glut4 outside of the cell to suck more sugar out of the bloodstream → protects the body from the caramelization process that clogs arteries and ultimately speeds up dementia onset → 2017 Kearney and colleagues well-controlled metformin study on non Type2 diabetic patients, dementia IMPROVED. Larger 2019 study of diabetic patients on metformin had 55% reduced dementia incidence (A MASSIVE NUMBER)... NAD boosters (NMN) help brain activity. Jeffrey Milbrandt study demonstrated SARM1 enzyme gets turned on in nerve cells when they are damaged (as we age) which depletes NAD, so not only do we produce less NAD as we age, but SARM1 increases depletes existing… ALS → NR + Pterostilbene (Resveratrol with 3 methyls attached) slowed the progression of ALS. Essentially is a way of delivering Resveratorl with an NAD booster in pill form. Phase 2 now hoping patients continue to do better… NMN and SIRT1 activity help vascular flow critical to grow new blood vessels in the brain (in mice study)... Sleep → SIRT1 (enzyme activated by Resveratrol) and NAD up in the morn and down in the night helps the sleep cycle. NMN in the morn will also help jet lag, as does getting light in the morn (15 minutes outside at sunup helps circadian rhythm). 1 night of sleep deprivation increases amyloid beta production by 5%.
Episode 8: Biotracking, Age Reversal & Other Advanced Health Technologies
You can’t impact what you don’t measure! Our current healthcare model → wait till u get sick and then go to the doc. Technology is changing this obviously. Grail, can detect up to 50 cancers ($949) with a blood test before they become tumors and kill them years before they would show up and you would go to a Dr. When cancer cells begin to form, it begins releasing signallers, thus we can detect cancer in the bloodstream before tumors form… Ability to measure a heart’s function is coming shortly. FDA approved EKG, measures changes in heart rhythm (Apple watch now detects 98.3% of arrhythmia), may warn of heart attacks before they happen… Five metrics which Dr. Sinclair would like to monitor given only five, he then added the sixth: 1) glucose (Levels), 2) heart function, 3) inflammation (CRP: C-Reactive Protein), 4) cortisol (stress levels), 5) lactate (if body is able to deal with exercise), 6) blood oxygen (making sure get hypoxic) to stimulate hormesis… With societal adoption data issues (should be able to delete your data), there will be virus detection, etc… Viome tests biome (your gut) and gives custom supplements… Right now, Levels can tell what is bad to eat, Inside Tracker provides nutritional recommendations. Eventually, Sinclair envisions company/app will tell you where to go and buy what food, what restaurants to go to and what entrees to order… Eventually will be supplement machine in your home where pills will be made specifically for you, at the proper time of day, and will change as you evolve and biomarkers change… Eventually monitor will tell you better off running today, weights tomorrow, take today b/c cortisol levels too high, etc… Greg Fahey and Steve Horvath trials trying to reset the biological clock- epigenetic reset… Three genes (Och-4, Sox2, KLF4) turn on genetic programs to reset the age of the body. Inject a virus into the eye of a mouse- and the results were stunning. Retinal cells reset their age, genes were regulated properly. Cured blindness in mice, “Turning Back Time”. In the lab, can cure macular degeneration with this gene therapy, can shut down and stimulate neural connections in brain cells which suggests this type of gene therapy can cure Alzheimer’s… Currently, there doesn’t seem to be any downside to “resetting the epigenetic clock”, but we obviously don’t know for sure. If you go back too far in age, we could stimulate cancer. With gene therapy, irreversible, so better make sure it’s right… Make a mouse that typically lives two years, possibly ten or twenty… For those worried about too many humans, life extension should be a big GDP boost and we are approaching peak population. 17% of GDP also goes to HC, most of it wasteful… Right now, eat well, supplement, sleep well, and exercise well. Stimulate hormesis/adversity memetics, via exercise including hypoxia (out of breath), intermittent fasting, etc. Just around the corner, we’ll have things we can barely dream of!