I heard the hype from the All In Pod which I listen to religiously.

Friedberg commented that all the Besties (i.e the other podcast hosts) were taking Metformin, and went on to describe why and recommend this book. I promptly forgot everything Friedberg said, but was intrigued enough to get the book, and it lived up to the hype.

David Sinclair has spent the last three decades studying aging, and is a pretty prolific guy:

He is a tenured professor of genetics, Blavatnik Institute, Harvard Medical School; co-director of the Paul F. Glenn Center for the Biology of Aging Research at Harvard; co-joint professor and head of the Aging Labs at the University of New South Wales in Sydney, Australia;

He has published more than 170 scientific papers, is a coinventor on more than 50 patents, and has cofounded 14 biotechnology companies in the areas of aging, vaccines, diabetes, fertility, cancer, and biodefense. He serves as co–chief editor of the scientific journal Aging, works with national defense agencies and with NASA

In this book he explains his research, his fundamental theory of aging around epigenomic damage, how we can activate our natural “longevity pathways”, why we should classify aging as a disease to be able to treat the upstream causes of so many diseases we’re playing “whack a mole” with, what his personal health regimen is, societal impacts if – as he predicts – we add at least 33 years to the median human lifespan in the next 50 years.

I was also struck about the amazing early results from compounds we seemed to have originaly found pretty randomly (eg rapamacyn on a volcanic island in Chile, metformin from lilac plant, resveratrol from grapes). How much faster will all this go when we can synthesize new compounds and test them at scale?

This book is already having an impact on me, I didn’t have breakfast.

Enjoy the notes

Also recommend

• Sinclair’s talk at Google, a 55min summary of his work
• Sinclair on Joe Rogan. Interesting to hear about the defensiveness from the scientific community in the early days, how his lab almost shut down due to lack of funding, but how he kept pushing and turned things around. Not the best format to learn about the science though

Why We Age

• Although the average life expectancy has been moving up, the limit has not. as long as we’ve been recorded history, we’ve known of people who reach the 100th year. Almost no-one reaches 115. Jeanne Calment only known person to have lived past 120, she died in 1997 aged 122.
• Past attempts at “universal fundamental theories” of why we age
  • It’s caused by DNA damage (mutation accumulation) – 50s and 60s
  • Issues in the DNA-copying process
  • Free radical theory of aging – DNA damage through oxydation
• But these did not explain all symptoms of aging, and antioxydants had disappointing results (didn’t stop it becoming a $3b industry) so couldn’t be fundamental theories
• Nowadays we think that aging is the result of multiple hallmarks:
  • Genomic instability caused by DNA damage
  • Attrition of the protective chromosomal endcaps, the telomeres
  • Alterations of the epigenome that controls which genes are turned on and off
  • Loss of healthy protein maintenance, known as proteostatis
  • Deregulated nutrient sensing caused by metabolic changes
  • Mitochondrial dysfunction
  • Accumulation of senescent zombielike cells that inflame healthy cells (senescent cells have permanently ceased reproduction)
  • Exhaustion of stem cells
  • Altered intercellular communication and the production of inflammatory molecules
• Address these “upstream hallmarks”, and we can slow down aging

Information Theory of Aging

• Sinclair and friends believe there is a cause that is upstream of all these hallmarks: a loss of information
• Genetic information, stored in DNA, is digital information (quaternary, ATCG) and is actually very well copied
• Epigenetic information, stored in a structure called chromatin, is analog information.
  • Enables cells to assume lots of different modalities (eg a nerve cell to be a nerve cell not a skin cell)
  • When cells lose their epigenetic info, causes all the above hallmarks of aging. Tissues and organs become less and less functional, our hair grays, skin wrinkles, joints ache etc.
  • It is this “analog” loss of information that causes aging, not the “digital” genetic information
• Our primordial survival circuit, turning cell reproduction on/off based on when it’s “safe” to do so
  • A 4-billion-year-old gene circuit in the first life-forms would have turned off reproduction while DNA was being repaired, providing a survival advantage. Gene A turns off reproduction, and gene B makes a protein that turns off gene A when it is safe to reproduce. When DNA breaks, however, the protein made by gene B leaves to go repair DNA. As a result, gene A is turned on to halt reproduction until repair is complete.
• We now have two dozen such “longevity/vitality pathways”
  • Sinclair works on sirtuins (a class of enzymes)
    • 7 sirtuins in mammals, and made by almost every cell in the body
    • They change the packaging of DNA and turns genes on/off when needed
    • They require a molecule called NAD. Belief that loss of NAD as we age is a reason our bodies develop diseases when we’re old but not when young
    • Activating surtuins in mice (published): improve DNA repair, boost memory, increase endurance, help them stay thin
  • Other longevity genes: rapamycin/TOR
    • Can signal cells in stress to “hunker down” and improve survival by boosting activities such as DNA repair, reduce inflamation, digest old proteins, when e.g you go hungry
    • Can also drive cell growth when eg lots of amino acids around
  • Other pathway: AMPK
    • Responds to low energy levels
• Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death.

What to do!

• Stressors / hormesis activate the above longevity pathways (sirtuins etc). These are:
• Intermittent fasting or calorie control
  • Skip 1 meal per day or 75% calorie intake
  • Sinclair says this is the #1 thing you can do
  • Very compelling results on rhesus monkeys since the 80s
  • (Inhibits mTOR, so cells spend less energy dividing and more energy recycling damaged and misfolded proteins)
• Vigorous exercise (70-85% of max heart rate)
  • Applies stress in the body, all longevity pathways modulated in the right direction, delays erosion of telomeres
• Low-protein diets
  • Heavily animal-based diets are associated with high cardiovascular mortality and cancer risk
  • Processed red meats especially bad (hot dogs, sausage, ham, bacon)
• Exposure to hot & cold temperatures

What not to do

• Smoking
  • The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke
• PCB and other chemicals in plastics
  • Plastic bottles, takeout containers (don’t microwave them)
  • Solvents, pesticides
• Radiation: UV light, X-rays, gamma rays, radon
  • Radon in homes is second most frequent cause of lung cancer. Particularly high in areas rich in granite
• High blood sugar
  • Believed to speed up the “epigenetic clock”

Meds

• Rapamycin
  • Compound discovered on the volcanic island of Rapa Nui 2,300 off coast of Chile
  • Suppressor of the immune system. Used during organ transplant to ensure immune system doesn’t fight back the new organ
  • Also successful for extending life in animals, not sufficiently tested in humans
  • Lots of research into similar “rapalogs” – similar compounds to rapamycin that inhibit TOR but with less toxicity
• Metformin
  • Originated from lilac plant
  • Type 1 diabetes, pancreas doesn’t produce enough of the hormones needed to alert the body to sugar, now widely treated by supplemental insulin
  • Type 2 diabetes, age-associated, pancreas able to make enough insulin but the body is deaf to it
  • Mid 1950s: French pharmacist & doctor demonstrated effectiveness of oral dimethyl biguanide for type 2 diabetes
  • Now it’s a drug called metformin, one of the most widely taken medicines on the globe, <$5/month
  • Doesn’t inhibit TOR like rapamycin, it limits metabolic reactions in mitochondria, activates AMPK enzyme and SIRT1, makes more NAD, removes misfolded proteins
  • Mounting evidence on longevity
    • 26 studies treating rodents with metformin, 25 showed protection from cancer
    • 41k humans, reduced likelihood of dementia, cardiovascular disease, cancer, frailty, depression
  • Nir Barzilai leading the push to regulate metformin for aging with the FDA
• Resveratrol
  • Found in grapes, and found in greater quantities in grapes that experienced stress! Plants go into xenohormesis (hunker down and survive) mode like us
  • May explain some of the aging benefits of wine
  • Very promising early results on longevity in animals
  • Research into other STACs (sirtuin-activating compounds)
• NAD & NMN
  • Boosts activity of all 7 sirtuins
  • Initially used as alcoholic fermentation enhancer
  • Nucotinamide riboside (NR) is a vital precursor to NAD, now sold as nutraceutical
  • NR -> NMN -> NAD
  • NR more stable, and has been proven to extend lifespan in mice
  • NMN still being tested, dozens of human trials underway
  • NMN might restore ovarian function… has done so in old horses…
• Senolytics
  • Drugs in development to help kill off zombie senescent cells in old tissues
  • James Kirkland at the Mayo Clinic: quercetin (found in capers, kale, red onions) and dastinib, used to kill off senescent cells in lab mice and extend their lifespan by 36%
  • Human trials started in 2018 to treat osteoarthritis and glaucoma (optic nerve damage)
• There has been a lot of serendipity in finding these molecules (eg lilac, grapes). Things will get a lot faster now that we can create and analyse synthetic molecules at scale
• Sinclair thinks about a third of his colleagues (not clear if direct colleagues or broader aging science community) take metormin or an NAD booster

Future gains

• Over the next 50 years we can expect following conservative increases to median lifespan (currently 80 years)
  • DNA monitoring: +10 years
  • People adopting better lifestyle & nutrition: +5 years
  • Molecules that bolster our survival cirtuit: +8 years
  • Reset epigenome, destroy senescent cells, replace parts of organs, etc: +10 years
  • Total: +33 years
• Other examples
  • Blood samples testing
  • DNA monitoring
  • Breathalyzer to tell you of immune diseases
  • Keystrokes on the keyboard to signal early Parkinson’s disease or multiple sclerosis

Societal impact

• Population growth
• Older constitutencies seem to support older politicians. Older politicians, slower societal change
• Social security / pensions liabilities strained
• Longevity drugs will likely have to be paid out of pocket initially (at least in US)… exacerbating inequalities
• Aging is not classified as a disease in most countries (WHO did add “old age” as disease code in 2018), so gets very small share of public funding. Yet it’s the upstream cause of a lot of stuff we spend a lot on (“whack a mole” medicine)
• Start talking about healthspan not lifespan (portion of our lives spent without disease or disability)

What Sinclair does

• I take 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into my homemade yogurt) and 1 gram of metformin.
• I take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin.
• I strive to keep my sugar, bread, and pasta intake as low as possible. I gave up desserts at age 40, though I do steal tastes.
• I try to skip one meal a day or at least make it really small. My busy schedule almost always means that I miss lunch most days of the week.
• Every few months, a phlebotomist comes to my home to draw my blood, which I have analyzed for dozens of biomarkers. When my levels of various markers are not optimal, I moderate them with food or exercise.
  • He also talks about using a company he co-founded called InsideTracker to get personalised guidance based on the blood tests
• I try to take a lot of steps each day and walk upstairs, and I go to the gym most weekends with my son, Ben; we lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool.
• I eat a lot of plants and try to avoid eating other mammals, even though they do taste good. If I work out, I will eat meat.
• I don’t smoke. I try to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans.
• I try to stay on the cool side during the day and when I sleep at night.
• I aim to keep my body weight or BMI in the optimal range for healthspan, which for me is 23 to 25.

Misc

• In the United States alone, each year, 82,000 elderly people have a limb amputated. That’s ten every hour. All this pain, all this cost, comes from relatively minor initial injuries: foot wounds. The older we get, the less it takes for an injury or illness to drive us to our deaths. We are pushed closer and closer to the precipice until it takes nothing more than a gentle wind to send us over. This is the very definition of frailty.
• When we toast to life, we should be toasting to enzymes
  • In each cell are a total of 75,000 enzymes like catalase,4 all thrown together, jostling around in a slightly salty sea. At the nanoscale, water is gelatinous, and molecular events are more violent than a category 5 hurricane, with molecules thrown together at speeds we would perceive as a thousand miles per hour. Enzymatic reactions are one-in-a-thousand events, but at the nanoscale one-in-a-thousand events can occur thousands of times a second, enough to sustain life.
• Right now there are over 100k people waiting for an organ transplant in the US. Road accidents are biggest source of organs, which will go to 0 with autonomous cars. Will we be able to figure out how to grow new organs fast enough?
• Nullius in Verba. Take nobody’s word for it. Royal Society motto. Love it.
• Michael Cooney from Sinclair’s lab is working with NASA to introduce DNA repair genes (from microcreatures called tardigrades) into human cells to help astronauts with protection from cosmic radiation and to slow aging