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Book Notes: “Lifespan” by David Sinclair

Summary

Lifespan: Why We Age—and Why We Don’t Have To by David Sinclair (with Matthew LaPlante, 2019) is a book that will change your perspective on life, death, and aging. Sinclair's core thesis is that aging is a disease. This bucks conventional wisdom that views aging as an inevitable part of life. Frame aging as a disease and a world of possibilities arise: diseases can be prevented, treated, cured, and even eliminated. Since aging sits upstream of many maladies (e.g. cancer), solving aging might eliminate entire categories of downstream conditions. Better yet, a cure to aging offers the tantalizing benefit of extended healthspans (vitality and quality of life) in addition to extended lifespans—the latter is of little value without the former.

Lifespan is a scientific book by a reputable academic for the lay audience. Sinclair’s bona fides are legit: he is a professor of molecular genetics at the Harvard Medical School and a leading researcher in the field of aging. His laboratories have generated ground-breaking discoveries along with a steady pipeline of students who have gone on to produce even more cutting-edge research. The book’s claims might be overly ambitious, but the underlying science, while not yet definitive, is credible. The result? One of the most exhilarating reads I’ve enjoyed in a long time.

The basis for Sinclair's optimism centers on an idea called “the informational theory of aging.” It's an idea that might hold the key to curing the disease of aging. This theory, supported substantial scientific inquiry over the past 30 years, posits that aging is the result of a loss of information—specifically epigenetic information (non-DNA encoded information). Sinclair describes this information loss as analogous to a DVD. Over time, the surface of a DVD is scratched and damaged. These scratches obscure the underlying data and cause errors during playback. What is needed is a way to polish the disc and routinely repair or replace any of the missing information.

Fortunately, there are a number of biological mechanisms and cellular pathways that can accomplish this necessary “polishing” and repair. Sinclair’s own research efforts have long focused on a family of enzymes known as sirtuans (SIR2). Sirtuans play a key role in DNA repair (essential to maintaining health and vitality). In experiments with yeast, fruit flies, and mice, the introduction of additional sirtuans into test subjects resulted in startling metabolic and physiological changes along with increased lifespans. While more studies are needed, the current findings are promising: repair the damaged information and one can forestall and even reverse aging.

The book is divided into three parts: the past, the present, and the future. In Part I we learn about Magna superstes, a hypothetical primitive life-form, that evolved a very specific and advantageous genetic trait, “the survival circuit,” that improved cellular reproduction and DNA repair. This survival circuit has been inherited by modern humans and is manifest in the aforementioned sirtuans (along with other pathways like AMPK, mTOR, and others). Armed with the biological underpinnings from Part I, Part II demonstrates the myriad ways we can support, engage and amplify this survival circuit. Diet and exercise are key. In particular, calorie restriction and intermittent fasting are highlighted for their tremendous benefits (well substantiated in the scientific literature). There are also numerous molecules—organic compounds, pharmaceuticals, nutritional supplements—that can activate or amplify the effects of sirtuans and other DNA repair mechanisms. Part III considers the ethical and long-term implications of future therapies and breakthroughs. What are the economic, political, environmental, and social implications of a population where the median age is 150? Will longevity-technologies benefit all people or only the rich? Will longevity exacerbate climate change? Any new technology carries consequences accompanied by valid objections. It behooves us to consider these, along with potential remedies, early and often.

To say that I was awestruck by Lifespan would be an understatement. I live for ideas that teach me new ways to see the world and force me to reconsider my deep-seated assumptions. This book meets my very definition of a “mental pivot.” I have no idea if the “informational theory of aging” is the answer to longevity or just a stepping stone to a superior future theory (either way it's clear we are headed in the right direction). The author readily admits that more research, time, and inquiry is needed. Nevertheless, it’s exciting to see human curiosity and ingenuity working to answer these fundamental questions. There are books that you finish and barely think about and there are books that you finish and can’t stop thinking about. Lifespan is firmly in the latter category.

Pros: It’s hard to stop thinking about the ideas in this info-rich tome. Amazing combination of practical ideas and sky’s-the-limit thinking. The decision to pair a leading scientist with a professional writer and illustrator results in engaging and accessible descriptions of complex ideas. This is edge-of-your-seat scientific reading.

Cons: Occasional passages of acronym and jargon-soup will make your head spin. Fortunately, the authors counteract this with vivid analogies, clear explanations, and helpful illustrations and diagrams. It’s also worth noting that Sinclair has been criticized by the scientific community for being overly optimistic about the implications of his longevity research.

Verdict: 9/10


Highlights

Introduction: A Grandmother’s Prayer

  • I have come to see aging as a disease—the most common disease—one that not only can but should be aggressively treated.”
  • There are a host of small steps and habits that can be adopted now to slow, stop or reverse aging. The therapies and habits discussed in this book have a strong scientific basis.
  • Healthspan: The portion of life experienced without disease or disability. Any increases in lifespan must be attended by increases in healthspan (otherwise what is the point?).
  • “There’s also a difference between extending life and prolonging vitality. We’re capable of both, but simply keeping people alive—decades after their lives have become defined by pain, disease, frailty, and immobility—is no virtue.”

Part I: What We Know (The Past)
Chapter 1: Viva Primordium

  • Origins of life: Water pools adjacent warm thermal vents on earth. Organic molecules from meteorites or comets are dissolved in the pools. Cycles of wetting and drying at the edges of these pools result in chemical reactions.

    • Nucleic acids concentrate. These are basic chemical units (base, sugar, phosphate groups) that, when strung together form DNA or RNA. Phosphates and sugars link to form the DNA/RNA backbone. Bases bind in pairs (base pairs).
    • Nucleic acids grow into polymers. Polymers are long repeating chains of molecules. Polymers exhibit different properties depending on the types of molecules and how they are bonded.
    • Primitive genetic material is encapsulated in fatty acids when these prehistoric ponds are refilled forming the first cell membranes.
    • Some protocells evolve primitive metabolic pathways. Eventually, RNA copies itself. This marks the start of life: fatty-acid bubbles encasing genetic material.
  • Magna superstes (aka “great survivor”) a hypothetical evolutionary species that evolved a genetic “survival circuit” that was essential for all modern life.

    • Gene A: A “caretaker” that stops cells from reproducing in adverse conditions (e.g. during a drought, cellular reproduction is halted since energy, food, is scarce and the probability of survival is low). Me: I think of it as a "gate" whose default state is "shut," e.g. “no reproduction.”

    • Gene B: A gene that encodes a “silencing protein” that regulates Gene A. When it is safe to reproduce, Gene B deploys the silencing protein to Gene A. When Gene A is “silenced," reproduction occurs (the “gate” is opened).

      • Gene B evolves a critical secondary function: It helps repair DNA. When the silencing protein is deployed to repair broken DNA elsewhere in the DNA chain (or even in another cell), Gene A is not silenced (the gate is shut, cellular reproduction ceases while DNA is fixed).
      • The dual function of Gene B gives M.superstes an evolutionary edge: “A primordial survival kit that diverts energy to the area of greatest need...”
  • DNA damage can occur from both endogenous (internal) and exogenous (external) causes.

    • Internal: cellular replication/copying process errors.
    • External: pollution, radiation, x-rays, etc.
  • Sinclair posits that this survival circuit, descended from M.superstes, is also the reason why we age.

  • “Because all species are resource limited, they have evolved to allocate the available energy either to reproduction or to longevity, but not to both.”

  • Hallmarks of aging:

    • Genomic instability caused by DNA damage.
    • Telomere damage: Protective chromosomal endcaps (likened to aglets at the end of shoelaces—keeps the DNA from fraying at the ends. Like shoelaces these “wear out” over time).
    • Alternations to the epigenome that controls which genes are turned on and off (consider if the M.superstes survival circuit malfunctioned).
    • Proteostasis: loss of healthy protein maintenance.
    • Deregulated nutrient sensing caused by metabolic changes.
    • Mitochondrial dysfunction. Mitochondira, through cellular respiration, break down nutrients to create energy.
    • Accumulation of senescent zombielike cells that inflame healthy cells.
    • Exhaustion of stem cells—adaptive cells that can turn into specialized cells or divide to create more stem cells. Stem cells are used to replenish differentiated (specialized) cells in other parts of the body (e.g. skin cells, brain cells, etc.).
    • Altered intercellular communication and the production of inflammatory molecules.
  • “Address these hallmarks, and you can slow down aging. Slow down aging, and you can forestall disease. Forestall disease, and you can push back death.”

  • Aging, quite simply, is a loss of information.

  • Information theory of aging: Aging is the result of information loss over time (specifically: epigenetic information).

    • Epigenetic information: Non-DNA code information. Epigenetic marks tell proteins where and when to read the DNA.

    • Two types of biological information. Each type is encoded differently.

      • Digital information: Base 4, coded as adenine, thymine, cytosine, and guanine. The DNA nucleotides: A, T, C, G. Digital information can be reliably stored and copied with great accuracy.

      • Analog information: Commonly referred to as the epigenome. These are heritable traits that are not transmitted by genetic means.

        • Epigenetic information is stored in a structure called chromatin.
        • Cellular DNA is wrapped around protein balls called histones. (think of how a garden hose is wrapped in a loop).
        • “If the genome were a computer, the epigenome would be the software. It instructs the newly divided cells on what type of cells they should be and what they should remain...”
        • “Without epigenetic information, cells would quickly lose their identity and new cells would lose their identity too. If they did, tissues and organs would eventually become less and less functional until they failed.”
        • Analog information degrades over time due to external phenomena and information is lost when replicated.
  • Sirtuins: Enzymes that control longevity. They require NAD+ to function. There are 7 sirtuin genes in mammals (SIRT1, SIRT2, etc.).

    • NAD is nicotinamide adenine nucleotide. NAD facilitates critical chemical reactions including sirtuin function that regulates genes and causes DNA repair.
    • NAD levels are increased via healthy diet and exercise.
    • Sirtuins are descended from Gene B in M.superstes.
    • “These critical epigenetic regulators site at the very top of cellular control systems, controlling our reproduction and our DNA repair.”
    • Activating sirtuins promotes DNA repair, memory, endurance and regulates weight gain.
  • TOR: a complex of proteins that regulates growth and metabolism.

    • mTOR: the specific TOR complex found in mammals.
    • Similar to sirtuins, mTOR activity “can signal cells in stress to hunker down and improve survival by boosting such activities as DNA repair, reducing inflammation...and, perhaps its most important function, digesting old proteins.”
    • Rapamycin: A compound with immunosuppressant functions. Extends lifespan by inhibiting mTOR.
  • AMPK is anther metabolic control enzyme.

  • “There are plenty of stressors that will activate longevity genes without damaging the cell, including certain types of exercise, intermittent fasting, low-protein diets, and exposure to hot and cold temperatures.”

    • Hormesis: “A level of biological damage or adversity that stimulates repair processes that provide cell survival and health benefits.”
    • Hormesis-mimicking molecules: Drugs that can activate the body’s defense mechanisms without creating any damage.

Chapter 2: The Demented Pianist

  • Current state of science has uncovered genes can be as short as 21 base pairs. When the human genome was originally mapped, genes less than 300 base pairs were disregarded.

  • Genes impacting the symptoms of aging have been found, but Sinclair believes we won’t find an “aging gene”.

  • “Our genes did not evolve to cause aging.”

  • Humans and yeast are separated by a billion years of evolution and yet S. cerevisiae share 70% genetic code.

  • “Broken DNA causes genome instability...which distracts the Sir2 protein, which changes the epigenome, causing the cells to lose their identity and become sterile while they fixed the damage. Those were the analog scratches on the digital DVDs. Epigenetic changes cause aging.”

  • Epigenome analogy: “Think of our genome as a grand piano. Each gene is a key. Each key produces a note. And from instrument to instrument...each will sound a bit different...these are our genes. We have about 20,000 of them, give or take a few thousand.”

    • There are endless ways that the keys can be played together.
    • The pianist in this metaphor is the epigenome.
    • The size, shape, and condition of a piano dictate what a pianist can do. A concerto cannot be played on an 18-key toy piano. A piano out of tune, won’t sound good.
    • Using this analogy, errors are introduced when the pianist misses a key due to performance errors or errors in the music or instructions they are following. The piano is intact (as is the genome).
  • From Sinclair’s early yeast experiments, a sequential model for life and death emerged:

    • Youth
    • Broken DNA
    • Genome instability
    • Disruption of DNA packaging and gene regulation (epigenome)
    • Loss of cell identity
    • Cellular senescence
    • Disease
    • Death
  • “Adding in more copies of the sirtuin genes SIRT1 and SIRT6...increases the health and extends the lifespan of mice, just as adding extra copies of the yeast SIR2 gene does in yeast.”

  • Sirtuin analogy: “Think of sirtuins as the directors of a multifaceted disaster response corps, sending out a variety of specialized emergency teams to address DNA stability, DNA repair, cell survivability, metabolism, and cell-to-cell communication.”

  • “When sirtuins shift from their typical priorities to engage in DNA repair, their epigenetic function at home ends for a bit. Then, when the damage is fixed, and they head back to home base, they get back to doing what they usually do: controlling genes and making sure the cell retains its identity and optimal function.”

    • **Problems arise when there’s an endless sequence of emergencies and the repair crews (sirtuins) don’t return home. **
    • In this analogy, “work at home” piles up while emergencies are attended too.
  • “Wherever epigenetic factors leave the genome to address damage, genes that should be off, switch on and vice versa...cells lose their identity and malfunction. Chaos ensues...this is the epigenetic noise...”

  • Yeast cells don’t produce enough Sir2 protein to both repair broken DNA and silence reproductive genes (“Gene A”).

    • Introducing extra copies of the SIR2 gene extends lifespan and delays infertility.
    • Increasing Sir2 allows for simultaneous repair and cellular reproduction.
  • “If the information theory is correct...it doesn’t matter where the damage occurs. What matters is that it is being damaged and that sirtuins are rushing all over the place to address that damage, leaving their typical responsibilities and sometimes returning to other places along the genome where they are silencing genes that aren’t supposed to be silenced.”

  • “DNA-editing genes such as Cas9 and I-Ppol are nature’s gift to science.”

    • CRISPR genes (an immune system found in bacteria) allows scientists to “cut” DNA at precise locations in a genome.
    • For age-research, CRISPR was used to activate the survival/repair circuitry without killing the cell. By creating “sirtuin distractions” research teams could ascribe accelerated aging in mice to overloaded sirtuins that had abandoned their gene silencing functions.
  • Natural evidence that cellular age can be reset:

    • Bristlecone trees live thousands of years (half their genes are closely related to ours). Comparing young specimens with old specimens show negligible differences in function.
    • Some jellyfish species can completely regenerate from adult body parts (aka “immortal jellies”).
    • The Greenland shark does not reach sexual maturity until 150 years old. Individual specimens may live 500 years.
    • Bowhead whales are believed to live up to 200 years.
  • DAF-16/FOXO: “A gene control protein called a transcription factor that activates cell defense genes...” The equivalent in yeast is known as MSN2.

    • “When calories are restricted MSN2 extends yeast lifespan by turning up genes that recycle NAD, thereby giving the sirtuins a boost.”
  • Waddington’s Landscape: A biological metaphor that explains cellular identity. Marbles, representing stem cells, roll into bifurcating valleys where the marbles come to “rest.” Each valley represents a pathway for the cellular identity.

    • Exdifferentiation: The phenomenon whereby a cell loses its identity due to epigenetic noise. Using the Waddington’s Landscape metaphor, marbles get shuffled and “slip” into adjacent valleys, losing their identity and turning into senescent “zombie” cells.
  • As of publication, we don’t know what molecules are best for activating sirtuins nor their optimal dosage.

Chapter 3: The Blind Epidemic

  • “The more often a cause shows up on a death certificate, the more attention society gives to fighting it.”

  • “Age is sometimes considered an underlying factor at the end of someone’s life, but doctors never cite it as an immediate reason for death.”

  • Simple tests to determine how biologically old you are:

    • Push-ups: If you are over 45 and can do more than 20 pushups your vitality is good.
    • SRT Test (sitting-rising): Sit barefoot on the floor with legs crossed. Lean forward and stand up in a single motion. Young people and healthy older people can do this with no hands. Middle-aged people often need to push off with a hand. Elderly people often need to get to one knee first.
  • “Surviving cancer or heart disease doesn’t substantially increase the average human lifespan, it just decreases the odds of dying of cancer or heart disease.”

  • “Your chance of developing a lethal disease increases by a thousandfold between the ages of 20 and 70, so preventing one disease makes little difference to lifespan.”

  • “Smoking increases the risk of getting cancer fivefold, being 50 years old increases your cancer risk a hundredfold. By the age of 70, it is a thousandfold.”

  • Aging meets all criteria of being a disease, save one: it impacts more than 50% of the population.

    • The Merck Manual of Geriatrics defines maladies affecting less than half the population as diseases.
    • Because aging affects everyone, it is not considered a disease.
  • “The words, definitions, and framing we use to describe aging are all about inevitability.”

  • “Why would we choose to focus on problems that impact small groups of people if we could address the problem that impacts everyone?”

Part II: What We’re Learning (The Present)
Chapter 4: Longevity Now

  • Blue zones: Regions in the world exhibiting longer than average lifespans.

    • Examples: Okinawa, Japan; Nicoya, Costa Rica; Sardinia, Italy
    • Dietary commonalities: Eat more vegetables, less meat. Fresh food versus processed food.
  • Recommendation: Eat Less

    • Fasting has tremendous benefits that have been scientifically proven.

    • Caloric restriction (CR) is one strategy whereby a deficit between the recommended level and actual consumption is maintained (the goal is restriction, not malnutrition).

      • Restriction engages the survival circuit by boosting cellular defenses and minimizing epigenetic change.
      • A 1978 study of the Okinawan population found that school children consumed 66% fewer calories than mainland Japanese children. Adult Okinawans were found to take in 20% fewer calories than mainland Japanese.
      • 25% fewer calories than the typical recommendation are a good target, but studies have found even 12% restriction carries significant benefits.
      • Animal studies have shown that 30% reductions in middle-age can also yield tremendous benefits.
    • Intermittent Fasting (IF) is another approach to introducing dietary stressors through periodic nutritional scarcity.

      • IF practitioners eat normal portions but only during designated feeding windows. Instead of a normal 3 meals per day, an IF practitioner might eat 2 or only 1 meal per day.
      • Example: An 16:8 IF schedule means that 16 hours spent fasting and 8 hours are spent eating. For example, one fasts overnight from 8pm until 12 noon (skipping breakfast). Between the Noon and 8pm (an 8-hour window), food may be consumed.
      • Larger fasting windows are also possible, for example 18:6 and 20:4 are also common IF schedules.
      • IF doesn’t “rest” the body. Instead, it puts the body, at a cellular level, into a state of beneficial stress.
    • Even periodic CR and IF can prove beneficial (e.g. practice one week on and one week off).

    • Other approaches to fasting and calorie restriction:

      • The 5:2 diet: Eat 75% fewer calories for two days a week.
      • Eat Stop Eat: Skip food a couple of days a week.
      • Quarterly fasting: Go hungry for an entire week every 3 months (Peter Attia does this).
      • “Almost any periodic fasting diet that does not result in malnutrition is likely to put your longevity genes to work in ways that will result in a longer, healthier life.”
  • Recommendation: Amino acids are essential

    • Amino acids: The chemical building block of proteins. Chains of amino acids are strung together and folded into protein.

    • Protein: A string of amino acids folded into a three-dimensional structure. Proteins help cells grow, divide and function. Protein also satiates us.

    • Meat vs. plants:

      • Meat contains all nine of the essential amino acids but can be hard on our bodies.
      • “When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly.”
      • Plants deliver limited amounts of amino acids.
    • “When the enzyme known as mTOR is inhibited, it forces cells to spend less energy dividing and more energy in the process of autophagy, which recycles damaged and misfolded proteins.”

    • We want to keep mTOR from being activated too much and too often. Limiting intake of amino acids is one way to inhibit mTOR.

      • Low levels of methionine have been shown to activate cellular defenses in mice.
      • Meat has high levels of methionine whereas plant proteins have low levels.
      • Arginine, leucine, isoleucine, and valine can also activate mTOR. Low levels correlated with increased lifespan.
    • “Studies in which leucine is completely eliminated from a mouse’s diet have demonstrated that just one week without this particular amino acid significantly reduces blood glucose levels...” (Sinclair notes that a little is necessary).

  • Recommendation: Exercise

    • Exercise has many benefits at the cellular scale.

      • Studies show that people who exercise regularly have longer telomeres.
      • Exercise raises NAD levels which activates the survival network.
      • “Longevity regulators like AMPK, mTOR, and sirtuins are all modulated in the right direction by exercise.
    • “We don’t have to exercise for hours on end. One recent study found that those who ran four to five miles a week...reduce their chance of death from a heart attack by 40 percent and all-cause mortality by 45 percent.”

    • Exercise intensity is important when it comes to engaging longevity genes (i.e. walking is good but a brisk run is better).

      • Aim to raise heart and respiratory rate (HIIT is good for this).
      • Breathing should be deep and rapid at 70-85% of max heart rate.
      • Should be sweating and unable to speak more than a few words without pausing for breath (hypoxic response).
    • Diet and exercise are most effective when used in combination.

  • Recommendation: Cold temperatures

    • Exposing your body to uncomfortable temperatures activates longevity genes.

    • A byproduct of calorie restriction is that is reduces core body temperature.

    • A 2006 study in which mice were genetically engineered with a base temperature a half degree C lower lived 20% longer.

    • Cold temperatures “rev up” brown adipose tissue.

      • Brown fat is mitochondria-rich fat found in infants that decreases as we age.
      • White fat is normal fat that, in large quantities, leads to obesity.
    • Examples of cold exposure (to induce stress, NOT to induce hypothermia):

      • Exercise in the cold.
      • Wear fewer layers (e.g. skip the jacket).
      • Leave a window open or sleep with a light blanket.
      • Turn off the heater/thermostat.
      • Cryotherapy: Spend time in a superchilled box.
      • Cold showers
    • Heat may also be beneficial but in different ways (for example: saunas).

  • Recommendation: Keep the epigenome healthy

    • “We can’t prevent all DNA damage...but we do want to prevent extra damage.”

    • “Cigarettes, for starters. There aren’t many legal vices out there that are worse for your epigenome than the deadly concoction of thousands of chemicals smokers put into their bodies every day.”

    • DNA-damaging chemicals are a part of modern life: pollution, PCBs, plastics, take-out containers.

      • Avoid microwaving these containers which releases more PCBs.
      • Azo dyes (such as aniline yellow) can also damage DNA.
      • Organohalides used in solvents, degreasers, pesticides and hydraulic fluid can damage genomes.
      • N-nitroso compounds are present in foods with sodium nitrite (beers, cured meats and bacon). These are potent carcinogens.
    • Natural and human-inflicted radiation: UV light, X-rays, gamma rays, radon all damage DNA.

Chapter 5: A Better Pill to Swallow

  • Enzymes: “A protein made up of strings of amino acids that folds into a ball that can carry out chemical reactions that would normally take much longer or otherwise never happen.” (Sirtuins are enzymes).

  • Rapamycin is one of the most consistently successful compounds for extending life (an mTOR inhibitor).

    • 2000 yeast cells on a culture will mostly die out after 6 weeks.
    • Feed the same yeast cells rapamycin and half will still be healthy after 6 weeks.
    • Researchers are seeking other rapalogs, compounds similar to rapamycin, that have greater specificity and less toxicity.
  • Metformin is a molecule used to treat type 2 diabetes. It may be an effective longevity medicine by mimicking aspects of calorie restriction (by slowing down mitochondrial reactions).

  • STACs (aka SIRT1-activating compounds) are molecules that stimulate sirtuin activity.

    • Lower impact STACs (results insufficient for further research):

      • Fisetin is a STAC which gives strawberries and persimmons their color and has been shown to kill senescent zombie cells.
      • Butein is a STAC which is found in flowering plants.
    • Resveratrol is a STAC found in red wine. Stressed plants produce it.

      • Some believe resveratrol explains the “French paradox” (the phenomenon whereby French have low rates of heart disease despite a diet relatively high in saturated fats like butter and cheese).
    • NAD is a STAC that activates all seven sirtuins.

      • NR is the precursor to NAD. NR is converted into NMN which is then converted into NAD.
      • NMN is a compound found in avocado, broccoli and cabbage. NMN isn’t a regulated substance, it’s available as a supplement.
      • “Give an animal a drink with NR or NMN in it, and the levels of NAD in its body go up about 25 percent over the next couple of hours, about the same as if it had been fasting or exercising a great deal.”
    • Hundreds of other chemicals have demonstrated potential as STACs and many more remain unexplored and undiscovered.

  • “Researchers will continue to identify molecules that are better and better at promoting both reduction of epigenetic noise and a rejuvenation of cellular tissue.”

    • AMPK activator? TOR inhibitor? STAC or NAD booster? Combination of all these?

Chapter 6: Big Steps Ahead

  • Sinclair is optimistic that once we understand the regulators of aging, how we can change those regulators (with molecules like NMN, exercise, and diet), and that aging comprises a single disease, aging will be “easy to tackle.”

  • Sinclair notes that many of the biggest innovations have been simple and unsexy:

    • Example: We solved the majority of surgical infections by washing our hands with soap.
    • Example: We solved many infectious diseases with vaccines (an agent that resembles a disease-causing microorganism made from weakened or killed forms of the microbe, its toxins or one of its surface proteins).
  • Senescent “zombie” cells: Over time, cells lose their identities, cease to divide and sit in tissue for years, even decades—but they don’t die completely. Zombie cells secrete factors that cause inflammation and turn neighboring cells into zombies.

    • Reversing aging in senescent cells is difficult.

    • Senolytics are drugs that can be used to kill off zombie cells.

      • Quercetin is a senolytic found in capers, kale and red onions.
      • Dastanib is a chemotherapy treatment that can eliminate senescent cells.
      • Senomorphics are molecules that prevent zombie cells from releasing inflammatory molecules (rapamycin is a senomorphic).
    • CAR-T therapies modifies a patient’s T-cells and re-injects them to kill cancer cells. Some believe that this approach can also be used to kill zombie cells.

  • “The solution to aging could be cellular reprogramming, a resetting of the landscape—the way, for instance, that jellyfish have been shown to do by using small body fragments to regenerate polyps that spawn a dozen new jellies.”

  • Yamanaka factors:

    • A set of four genes that can induce adult cells to become any pluripotent stem cells—effectively allowing differentiated cells to become any other cell type.
    • Yamanaka factors can be used to “reset” the body’s epigenetic landscape.
    • Experiments with mice in which Yamanaka factors were triggered periodically throughout the lifespan of a mouse allowed the mice to live 40% longer. The downside: treatment was toxic and overdoing the dosage result in death or teratomas (gross tumors that mix several types of tissue).

Chapter 7: The Age of Innovation

  • Precision medicine: Next-generation therapies that account for personal data and genetics rather than “what works for most people most of the time.”

    • People don’t always respond to drugs in the same ways.
    • Males and females don’t always respond in the same ways.
  • “Now that we can detect the genetic signature of specific forms of cancer, using the place where you find the cancer as the only guide for what treatment to use is as ridiculous as categorizing an animal species based on where you’ve located it.”

  • Technological advances have brought the costs of reading an entire human genome (25,000 genes) to a few days and a hundred dollars.

  • DNA readouts can answer a number of questions which have broad healthcare implications:

    • What kind of cancer is this?
    • What infection do I have?
    • What foods should I eat?
    • What therapies will work best?
  • “Drug developers have figured this out. They are using genomic information to find new and revive failed drugs that work for people with specific genetic variations.”

    • Example: Gencaro which, if revived by the FDA, would become the first heart drug to require a genetic test.
    • “It won’t be long before prescribing a drug without first knowing a patient’s genome will seem medieval.”
  • Proteome: All the proteins that can be expressed by every type of cell. Like reading the genome, reading the proteome will facilitate precision medicine.

  • Biotracking: Technologies that monitor personal biological function (blood sugar levels, heart rate, blood pressure, etc.) will generate essential feedback for modifying diet, exercise, behavior and prescribed treatments.

Part III: Where We’re Going (The Future)
Chapter 8: The Shape of Things to Come

  • Many of Sinclair’s colleagues (1/3 by his estimate) take metformin or an NAD booster. Some also take low, intermittent doses of rapamycin.

  • Kevin Kelly (Wired founding editor) on the topic of new technologies and innovation: “Embrace things rather than try and fight them. Work with things rather than try and run from them or prohibit them.”

  • In 1798, Thomas Malthus, warned that advances in food production would yield unsustainable population growth and result in a Malthusian catastrophe. However, agricultural advances far outpaced what Malthus could imagine.

  • Population growth is attended by interconnected problems of consumption and waste. Climate change is also exacerbated by these problems.

  • “On average, Americans consume more than three times the amount of food they need to survive and about 250 times as much water.”

  • A short list of problems resulting from extended lifespans:

    • Longer cycles of conservative ideas—not just political but social and scientific.

      • Max Planck (physicist): “A new scientific truth does not triumph by convincing its opponents and making them see the light but rather because its opponents eventually die, and a new generation grows up that is familiar with it.” In other words, new ideas grow as the old guard and old ideas die off along with the people who held those beliefs.
      • In a world where people live longer, however, these old beliefs will live far longer than they have in the past.
    • Increased pressures on Social Security and other welfare systems.

      • When Social Security began, the ratio of workers to beneficiaries was 41:1. Today the ratio is 3:1 (which is becoming unsustainable).
      • Increased lifespans will require changes to the retirement age.
    • Wealth disparity could increase.

      • By living longer, the rich get richer (due to the power of compounding).
      • Estate taxes were originally designed to finance wars not to limit multigenerational wealth.
      • Depending on how future gene therapies and age-related treatments are financed, there’s a strong likelihood that those with financial means will continue to afford the latest and greatest possible treatments (thereby enhancing their advantages and earning potential).
  • Population growth doesn’t guarantee misery, disease and starvation. Sinclair citing the example of London cites that the problem isn’t “how many people lived in the city but how they lived in the city.” The London of the 1800s was riddled with disease, squalor, and poor sanitation with a population of 1 million. Today London has 9 million residents and far less death, disease and despair.

  • Humans are highly innovative and adaptable and have demonstrated an ability to improve their circumstances and respond to the problems of their time.

  • “Very few of the global carrying capacity models account for human ingenuity...it is easier not to see things coming than to see them, so we tend to extrapolate into the future directly from the way things are now.”

  • Erle C. Ellis (environmental scientist): “Our planet’s human-carrying capacity emerges from the capabilities of our social systems and our technologies more than from any environmental limits.”

  • “The only thing that seems unnatural—in that it has never happened in the history of our species—is to accept limitations on what we can and cannot do to improve our lives. We have always pushed against perceived boundaries; in fact, biology compels us to.”

  • Population growth has fluctuated:

    • Pre-1900 the human population grew < 1% annually.
    • By 1930, resulting from improved sanitation and infant-mortality rates, humanity grew at 1% annually.
    • By 1970, resulting from immunization and food production, humanity grew at 2% annually.
    • Today the growth rate is around 1% annually. Women have greater social and economic opportunities and fewer children are born.
  • Impact of death on population growth:

    • We tend to overestimate the impact.
    • Stopping all deaths results in an addition of 150k people each day (55M per year which is less than 1%). [me: Reminds me of Donella Meadow’s stock and flow models for population systems: inflows (births) are reinforcing loops which result in exponential growth, but deaths are balancing loops which result in steadier linear changes]
    • Reduced death does not result in exponential population growth. Population would grow slowly but not explosively in a world where people lived longer (and birth rate remained constant).
  • Increased lifespans could be a boon to the economy: workers with skills and experience that remain productive far longer (author is clear that ideal would be voluntary continued employment in this situation).

Chapter 9: A Path Forward

  • This chapter includes several recommendations that address the concerns raised in Chapter 8.

  • Recommendation: Greater public investment in age-related research.

    • Between 1940 and 2017, the US federal government was the biggest source of funding for basic scientific research in the nation.
    • National Institutes of Health started in 1901. Congressional funding is discretionary and subject to annual review.
    • Federal funding ensures that research isn’t solely driven by profit-motives.
    • Biology of aging receives less than 1% of total US research budget. This research is hamstrung by the fact that aging is not defined as a disease (similarly, obesity receives even less in funding despite its prevalence).
    • Most aging research is directed into the study of Alzheimer’s disease and hormone replacement therapy. Less than 3% goes to actual study of aging.
    • Public benefit: Nations that invest in aging research will reap health benefits for nation as well as reap rewards from patents and new treatments and technologies.
  • Recommendation: Allow medical treatments and therapies regardless of age.

    • “There are two things that guide medical treatments more than anything else: age and economics.”
    • Medical system is predicated on ageism: Young people don’t receive treatments that will help them when they are older. Old people don’t receive treatments used routinely on the young.
    • “Everyone should be entitled to treatments and therapies that improve quality of life, no matter what the date on his or her birth certificate.”
    • Example of the Australian universal healthcare system (enacted in the 1970s). Between 1970 and 2018, Australian men gained an extra 12 years of life on average.
    • Improved access to preventative medicine and universal healthcare results in a less costly and burdensome elderly population: old people are productive for longer and debilitating diseases like obesity, diabetes and disabilities are less prevalent.
    • The average American lifespan is 4 years shorter than that of Australia. The US spends 17% of its GDP on health care, double that of Australia.
    • Universal health is a positive-sum game: “When everyone is living longer and healthier, everyone does better.”
  • Recommendation: Give individuals greater control over end-of-life.

    • Streamline regulations that allow people to bring their lives to a peaceful end be it physician-assisted suicide, death with dignity, or elective euthanasia.
    • People must have the right to die on their own terms, including those with a terminal diagnosis or chronic illness.
    • “In my mind, there are few sins so egregious as extending life without health. This is important. It does not matter if we can extend lifespans if we cannot extend healthspans to an equal extent.”
  • Recommendation: Address consumption with innovation.

    • “The problem isn’t population; it is consumption.”
    • Dematerialization is one trend where digital products and services have reduced certain classes of physical products (e.g. compact discs, physical books, etc.).
    • Food, water, and energy pose significant consumption challenges.
    • GMOs have an essential role to play if we want to ensure that the world population is fed. We must maximize agricultural efficiency.
    • “There’s a tremendous need to figure out how to satiate the global demand for protein without the tremendous environmental costs of farmed animal meat.”
    • “Human ingenuity is not a zero-sum game.”
  • Recommendation: Rethink the way we work.

    • We take the 5-day workweek as a given, but it’s a recent innovation. Similarly, many other work-life assumptions are based on habit and tradition.
    • “The idea of connecting retirement to a person’s chronological age will be an anachronism soon enough.”
    • Skillbaticals: Idea in which a person, after a certain number of years of work, is subsidized for a period of time to acquire new skills and reenter the workforce.
    • Mini-retirements: Those with financial security can take a year off to travel, volunteer and refresh.
  • Recommendation: Adopt longer-range thinking.

    • The world’s biggest problem? “The future is seen as someone else’s concern.”
    • Instead of pushing problems and changes down the road to future (unseen) generations, longer lifespans will compel us to address those challenges, especially if our future selves are to be present in that world.

Conclusion

  • 2003 President’s Council on Bioethics submitted a report to the White House warning against research on aging because “it goes against the human grain and violates the purportedly orderly cycle of birth, marriage, and death.” The council further asserted that aging was natural and fighting aging might disconnect us from the cycle of life.”

  • Author refutes the 2003 recommendations: “If we truly believed that frailty was a requisite for meaningful life, we’d never mend a broken bone, vaccinate against polio, or encourage women to stave off osteoporosis by maintaining calcium levels and exercising.”

  • Sinclair reframes the argument: fighting aging is a fight against a disease.

  • 2018 WHO International Classification of Diseases includes a new disease code for aging: code MG2A. Beginning in 2022, countries can begin counting statistics of people who die from aging (e.g. senile debility and old age without mention of psychosis).

  • Sinclair offers a list of actions/habits he engages in (this does not constitute medical advice or a recommendation on part of the author):

    • Takes 1 gram of NMN per day.
    • Takes 1 gram of Resveratrol per day.
    • Takes 1 gram of metformin per day.
    • Takes vitamin D, vitamin K2, and 83 mg of aspirin daily.
    • Restricts carbohydrate intake (avoid sugar, bread, pasta, etc.).
    • Practices intermittent fasting (IF) daily. Usually by skipping breakfast and often lunch.
    • Runs quarterly blood panels to track biomarkers and adjust diet and exercise accordingly.
    • Walks every day (high step count) and exercises at the gym on weekends. Workouts consist of weights and jogging.
    • Takes ice plunges and spends time in saunas.
    • Increased ratio of plant:meat. Will eat meat when exercising.
    • Does not smoke.
    • Avoids microwaved plastic, UV exposure, X-rays, and CT scans.
    • Keeps ambient temperature cool throughout the day to keep his body on the cool side.
    • Maintains a BMI between 23-25.
  • Supplements not subject to strict regulations. Recommends large manufacturers with good reputation (look for the GMP label “good manufacturing practices”).

  • Regarding NMN: There’s a debate about whether NR (Nicotinamide riboside) or NMN is better. NR is converted to NMN and is also cheaper.



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