📚 The Book in 3 Bullets

• The body responds to healthy stress by turning on longevity genes, so it’s good to be uncomfortable sometimes.

• There is no one conclusive reason to why we age. It is the culmination of many factors, ultimately it results in disruption to the epigenome.

• Humans are wildly ingenious. The increase in lifespan will result in a greater population initially, but we have to be able to engineer this planet and become more efficient for all of us to inhabit Earth.

📖 Summary & Notes

• The Error Catastrophe Hypothesis of aging postulated that mistakes made during the DNA-copying process lead to mutations in genes, including those needed to make the protein machinery that copies DNA.

• The Free Radical Theory of Aging blames aging on unpaired electrons that whiz around within cells, damaging DNA through oxidation, especially in mitochondria, because that is where most free radicals are stored.

  • This has not been substantiated though. Research shows that the positive health effects attainable from an antioxidant-rich diet are more likely caused by stimulating the body’s natural defenses against aging, including boosting the production of the body’s enzymes that eliminate free radicals, not as a result of the antioxidant activity itself.

• There’s not one single cause of aging, but there are many hallmarks of aging including:

  • Genomic instability caused by DNA damage

  • Attrition of the protective chromosomal endcaps, the telomeres

  • Alterations to the epigenome that control which genes are turned on and off

  • Loss of healthy protein maintenance, known as proteostasis

  • Deregulated nutrient sensing caused by metabolic changes

  • Mitochondrial dysfunction

  • Accumulation of senescent zombielike cells that inflame healthy cells (senescent cells are cells that cannot divide anymore)

  • Exhaustion of stem cells

  • Altered intercellular communication and the production of inflammatory molecules

• Epigenome - changes in gene expression due to alterations of DNA outside of the DNA sequence.

• Sirtuins are enzymes that remove acetyl tags from histones and other proteins and, by doing so, change the packaging of the DNA, turning genes off and on when needed.

• Sirtuins order our bodies to “buckle down” in times of stress and protect us against the major diseases of aging: diabetes, heart disease, Alzheimer’s, osteoporosis, and cancer. They mute chronic, overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma. They prevent cell death and boost mitochondrial function.

• Activating sirtuins can improve DNA repair, boost memory, increase exercise endurance, and help stay thin.

• The loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.

• Target of Rapamycin, or TOR, is a complex protein that regulates growth and metabolism. mTOR can signal cells in stress to hunker down and improve survival by boosting such activities as DNA repair, reducing inflammation caused by senescent cells, and perhaps its most important function, digesting old proteins.

• There are plenty of stressors that will activate longevity genes (sirtuins, mTOR, AMPK) without damaging the cell, including certain types of exercise, intermittent fasting, low-protein diets, and exposure to hot and cold temperatures. This is called hormesis.

• When hormesis happens, all is well. The little bit of stress that occurs when the genes are activated prompts the rest of the system to hunker down, conserve, and survive longer.

• Sirtuins stabilize human rDNA. By stabilizing human rDNA, sirtuins prevent cellular senescence.

• SIRT1, SIRT6, and SIRT7 are critical to controlling the epigenome and DNA repair. SIRT3, SIRT4, and SIRT 5 reside in mitochondria, where they control energy metabolism.

• Epigenetic noise is likely the catalyst of human aging. Epigenetic noise is a disruption in gene expression patterns, leading to decreases in tissue function and regenerative capacity.

• Sirtuins respond to epigenetic changes that come as a result of DNA damage signals. When damage is high, sirtuins are not home to perform their main function like endothelial wall integrity.

• When boosting NAD, it activates the SIRT1 enzyme, which improves capillary flow and microvasculature to supply more oxygen, remove lactic acid, and remove toxic metabolites from muscles. Boosting NAD activates sirtuins, and this makes the epigenome become more stable.

• Aging is not an inevitable part of life but rather a “disease process with a broad spectrum of pathological consequences.”

• Fasting allows our bodies to exist in a state of want and is good for our health and longevity.

• Calorie restriction without malnutrition leads to longevity for all sorts of life forms.

• The key to engaging sirtuin program appears to be through calorie restriction, just enough food to function in healthy ways, and no more. This engages our survival circuit, telling longevity genes to do what they have been doing since primordial times: boost cellular defenses, keep organisms alive during times of adversity, ward off disease and deterioration, minimize epigenetic change, and slow down aging.

• Mutations in IGF-1 and the IGF-1 receptor gene are associated with lower rates of death and disease and are found in abundance in females who tend to live past 100. These genes are closely related to longevity.

• There are nine essential amino acids that our bodies cannot make on their own and our cells need to sustain life. Studies show that heavily animal-based diets are associated with high CV mortality and cancer risk. Red meat contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease. When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly.

• Limiting your intake of amino acids can limit the activity of mTOR leading to more recycling of damaged proteins and increased longevity.

• Low levels of amino acids correlate with increased lifespan and have been shown to improve markers of metabolic health significantly.

• Leucine, an essential amino acid, when limited, has been shown to significantly reduce blood glucose levels, a key marker for improved health.

• Studies show that people who exercise more have longer telomeres. At least a half hour of jogging five days a week.

• Exercise raises NAD levels which turns on the survival network, which turns up energy production and forces muscles to grow extra oxygen-carrying capillaries. The longevity regulator AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise, irrespective of caloric intake, building new blood vessels, improving heart and lung health, making people stronger and live longer. Exercise essentially turns on the genes to make us young again at a cellular level.

• Being hungry is necessary for caloric restriction to work because hunger helps turn on genes in the brain that release longevity hormones.

• Sirtuins are switched on by the cold, which in turn activates protective brown fat in our back and shoulders.

  • Animals with abundant brown fat or subjected to shivering cold for three hours a day have much more of the mitochondrial, UCP-boosting sirtuin, SIRT3, and experience significantly reduced rates of diabetes, obesity, and Alzheimer’s disease.

  • Exercising in the cold, in particular, appears to turbocharge the creation of brown adipose tissue.

• Saunas can help drop heart disease, heart attacks, and all-cause mortality.

• Good stress to our bodies activates AMPK, turns down mTOR, boosts NAD levels, and activates sirtuins—to keep up with the normal wear and tear that comes from living on planet earth.

• Metformin mimics aspects of calorie restriction. But instead of inhibiting tOR, it limits the metabolic reactions in mitochondria, slowing down the process by which our cellular powerhouses convert nutrients into energy. Metformin also inhibits cancer cell metabolism, increases mitochondrial activity, and removes misfolded proteins.

• Metformin has been shown to reduce CV disease, cancer, frailty, and depression.

• Resveratrol, a powerful antioxidant, has been shown to protect mice from dozens of diseases.

• NAD is a central regulator of many major biological processes, including aging and disease. Without sufficient NAD, sirtuins don’t work efficiently, they can’t remove the acetyl groups from histones, they can’t silence genes, and can’t extend lifespan.

• A form of vitamin B3 called nicotinamide riboside, or NF, is a vital precursor of NAD. NR can extend lifespan by boosting NAD and increasing the activity of SIRT2.

• Small numbers of senescent cells can cause widespread havoc. They release cytokines that cause inflammation and attract macrophages that then attack the tissue. Inflammation is a driving force in heart disease, diabetes, and dementia.

• A class of pharmaceuticals called senolytics specifically kill senescent cells by inducing the death program that should have happened in the first place.

• Medicine will soon be able to detect cancers with a simple blood test and be able to stop the disease before it starts instead of just treating the ailment.

• United Nations predicts the population to plateau reaching about 11 billion people by 2100, then stop and drop from there.

Things to do to boost longevity

• Take 1 gram of NMN every morning, along with 1 gram of resveratrol, and 1 gram of metformin

• Take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin

• Keep sugar, bread, and pasta intake as low as possible

• Try to skip one meal a day

• Get blood drawn a few times a year and analyzed for dozens of biomarkers

• Exercise and use the sauna

• Ice baths

• Eat a lot of plants and try to avoid eating other mammals

• Don’t smoke and avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans

• Keep BMI between 23-25