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Lifespan: Why We Age and Why We Don't Have To

DAVID SINCLAIR
2019

There is no biological law that says we must age. I believe that aging is a disease. I believe it is treatable. I believe we can treat it within our lifetimes.

PART I: What We Know
  • The evolution of aging: 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 have inherited an advanced version of this survival circuit. But there is a trade-off. For this circuit within us, the descendant of a series of mutations in our most distant ancestors, is also the reason we age.
  • There is a singular cause of aging.
  • Science has since demonstrated 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. We can say with a high degree of confidence that aging isn’t caused by mutations in nuclear DNA.
  • Aging, quite simply, is a loss of information.
  • There are two types of information in biology:
    • The first type of information is digital. It is base 4, coded as adenine, thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA. Because DNA is digital, it is a reliable way to store and copy information.
    • The other type of information in the body is analog. Analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means. In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin.
  • 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. Unlike digital, analog information degrades over time. We can usually recover information from a scratched DVD. And if I am right, the same kind of process is what it will take to reverse aging.
  • The longevity genes I work on are called sirtuins. There are seven sirtuins in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body. Descended from gene B 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. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair. They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD. As we will see later, 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. Trading reproduction for repair, the sirtuins order our bodies to “buckle down” in times of stress and protect us against the major diseases of aging:
    • They mute the chronic, overactive inflammation
    • They prevent cell death and boost mitochondria
    • They go to battle with muscle wasting, osteoporosis, and macular degeneration.
  • Sirtuins aren’t the only longevity genes. Two other very well studied sets of genes perform similar roles. One of these is called target of rapamycin, or TOR, a complex of proteins that regulates growth and metabolism. The other is a metabolic control enzyme known as AMPK, which evolved to respond to low energy levels. These defense systems are all activated in response to biological stress.
  • 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. That’s called Hormesis. Hormesis is generally good for organisms, especially when it can be induced without causing any lasting damage.
  • The universal model of life and death: Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death.
  • Epigenomic noise was a likely catalyst of human aging. The ancestors of every living thing on this planet today evolved to sense DNA damage, slow cellular growth, and divert energy to DNA repair until it was fixed - what is called the survival circuit.
  • All of the symptoms of aging were being caused not by mutation but by the epigenetic changes that come as a result of DNA damage signals.
  • 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.
  • One of the best ways to predict whether someone will survive a disease is to take a look at how old he or she is when diagnosed. Aging makes you more likely to die. The older we get, the less it takes for an injury or illness to drive us to our deaths.
  • Current solutions, which are focused on curing individual diseases, are both very expensive and very ineffective when it comes to making big advances in prolonging our healthspans. Treating one disease at a time has little impact on lifespan.
  • I believe that aging is a disease. I believe it is treatable. I believe we can treat it within our lifetimes.
PART II: What We're Learning
  • Longevity diets: eating more vegetables, legumes, and whole grains, while consuming less meat, dairy products, and sugar.
  • Fasting - allowing our bodies to exist in a state of want, more often than most of us allow in our privileged world of plenty - is unquestionably good for our health and longevity. Studies demonstrated again and again that calorie restriction without malnutrition, or CR, leads to longevity for all sorts of life-forms.
  • In animal studies, the key to engaging the sirtuin program appears to be keeping things on the razor’s edge through calorie restriction - just enough food to function in healthy ways and no more. It engages the survival circuit, telling longevity genes to boost cellular defenses, keep organisms alive during times of adversity, ward off disease and deterioration, minimize epigenetic change, and slow down aging.
  • Human studies are confirming that once-in-a-while calorie restriction can have tremendous health results, even if the times of fasting are quite transient.
  • Study after study has demonstrated that heavily animal-based diets are associated with high cardiovascular mortality and cancer risk. When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly. There isn’t a single amino acid that can’t be obtained by consuming plant-based protein sources. Weight for weight, any given plant usually delivers limited amounts of amino acids.
  • When researchers studied the telomeres in the blood cells of thousands of adults with all sorts of different exercise habits, they saw a striking correlation: those who exercised more had longer telomeres. Exercise, by definition, is the application of stress to our bodies. It raises NAD levels, which in turn activates the survival network, which turns up energy production and forces muscles to grow extra oxygen-carrying capillaries. High-intensity interval training (HIIT) - the sort that significantly raises your heart and respiration rates - that engages the greatest number of health-promoting genes, and more of them in older exercisers. Your breathing should be deep and rapid at 70 to 85 percent of your maximum heart rate. Exercise turns on the genes to make us young again at a cellular level.
  • Exposing your body to less-than-comfortable temperatures is another very effective way to turn on your longevity genes. When the world takes us out of the thermoneutral zone our breathing patterns shift. The blood flow to and through our skin. Our heart rates speed up or slow down.
  • Colder temperatures could change the way the gene operated, through its ability to rev up brown adipose tissue. Also known as “brown fat,” this mitochondria-rich substance was, until recently, thought to exist only in infants. Now we know that it is found in adults, too, although the amount of it decreases as we age. Exercising in the cold, in particular, appears to turbocharge the creation of brown adipose tissue.
  • A bit of adversity or cellular stress is good for our epigenome because it stimulates our longevity genes.
  • There are no biological, chemical, or physical laws that say life must end. Yes, aging is an increase in entropy, a loss of information leading to disorder. But living things are not closed systems. Life can potentially last forever, as long as it can preserve critical biological information and absorb energy from somewhere in the universe.
  • The three main longevity pathways, mTOR, AMPK, and Sirtuins, evolved to protect the body during times of adversity by activating survival mechanisms. When they are activated, either by low-calorie or low-amino-acid diets, or by exercise, organisms become healthier, disease resistant, and longer lived. Molecules that tweak these pathways, such as rapamycin, metformin, resveratrol, and NAD boosters, can mimic the benefits of low-calorie diets and exercise and extend the lifespan of diverse organisms.
  • Xenohormesis: the idea that stressed plants produce chemicals for themselves that tell their cells to hunker down and survive. Plants have survival circuits, too, and we think we might have evolved to sense the chemicals they produce in times of stress as an early-warning system, of sorts, to alert our bodies to hunker down as well. The theory is also relevant to the foods we eat; plants that are stressed have higher concentrations of xenohormetic molecules that may help us engage our own survival circuits.
  • When resveratrol is combined with intermittent fasting, it can greatly extend both average and maximum lifespan even beyond what fasting alone accomplishes.
  • Young human cells taken out of the body and grown in a petri dish divide about forty to sixty times until their telomeres become critically short, a point discovered by the anatomist Leonard Hayflick that we now call the Hayflick limit. If you put telomerase into cultured skin cells, they don’t ever senesce. A very short telomere will lose its histone packaging, and, like a shoelace that’s lost an aglet, the DNA at the end of the chromosome becomes exposed. When we have lots of senescent cells in our bodies, it’s a clear sign that aging is getting a strong grip on us.
  • Thanks to the primordial survival circuit we’ve inherited from our ancestors, our cells eventually lose their identities and cease to divide, in some cases sitting in our tissues for decades. Zombie cells secrete factors that accelerate cancer, inflammation, and help turn other cells into zombies. Senescent cells are hard to reverse aging in, so the best thing to do is to kill them off. Drugs called senolytics are in development to do just that, and they could rapidly rejuvenate us.
  • We evolved senescence as a rather clever trick to prevent cancer when we are in our 30s and 40s. Senescent cells, after all, don’t divide, which means that cells with mutations aren’t able to spread and form tumors.
  • Antagonistic pleiotropy: the idea that a survival mechanism that is good for us when we are young is kept through evolution because this far outweighs any problems it might cause when we get older.
  • Old DNA retains the information needed to be young again.
  • We are analog, therefore we age. According to the Information Theory of Aging, we become old and susceptible to diseases because our cells lose youthful information. DNA stores information digitally, a robust format, whereas the epigenome stores it in analog format, and is therefore prone to the introduction of epigenetic “noise.”
  • Shannon proposed that information loss is simply an increase in entropy, or the uncertainty of resolving a message. His “noisy-channel coding theorem,” it is possible to communicate information nearly error free as long as you don’t exceed the channel capacity. But if the data exceeds the channel capacity or is subject to noise, which is often the case with analog data, the best way to ensure it makes it to the receiver is to store a backup set of data.
  • We know from cloning: if a lot of the epigenetic information is lost in old age, obscured by epigenetic noise, there must be information that tells the cell how to reset. This fundamental information, laid down early in life, is able to tell the body how to be young again - the equivalent of a backup of the original data.
  • To end aging as we know it, we need to find: An “observer” who records the original data The original “correction data” And a “correcting device” to restore the original signal.
  • The Information Theory of Aging predicts that it is a loss of epigenetic rather than genetic information in the form of mutations.
  • If we can fix the toughest-to-fix and regenerate the toughest-to-regenerate cells in our body, there’s really no reason to suspect we cannot regrow any type of cells our bodies need.
  • Eventually, every drug will be included in a huge and ever-expanding database of pharmacogenetic effects. It won’t be long before prescribing a drug without first knowing a patient’s genome will seem medieval.
  • There are more than a hundred companies just in the United States pursuing lightning-fast, superfocused DNA testing that can offer us early and accurate diagnoses of a vast range of ailments and even estimate our rate of biological aging.
  • In the near future, families will be monitored by biosensing wearables, small devices at home, and implants that will optimize our health and save lives by suggesting meals and detecting falls, infections, and diseases.
  • The more diseases we can vaccinate for, especially those that claim elderly people’s lives, such as flu and pneumonia, the more life expectancy will rise in the coming years.
  • When we inoculate the herd, it doesn’t just protect us individually, it protects the weakest among us: the young and the old.
  • In the future, when we need body parts, we might very well print them, perhaps by using our own stem cells, which will be harvested and stored for just such an occasion, or even using reprogrammed cells taken from blood or a mouth swab.
PART III: Where We're Going (The Future)
  • We often fail to acknowledge that knowledge is multiplicative and technologies are synergistic.
  • It is not an unreasonable expectation for anyone who is alive and healthy today to reach 100 in good health—active and engaged at levels we’d expect of healthy 50-year-olds today. One hundred twenty is our known potential, but there is no reason to think that it needs to be for the outliers.
  • The problem is not just population, it’s consumption. And it’s not just consumption, it’s waste. There is simply no economic model for a world in which people live forty years or more past the time of traditional retirement. The maximum sustainable human population is estimated at 8 billion or fewer people. And yes, by these estimates, we have either already met or will soon meet the maximum number of human beings our planet can sustain. If there were anything like a “natural” limit, the human population probably exceeded it tens of thousands of years ago, when our hunter-gatherer ancestors began to rely upon increasingly sophisticated water control systems and agricultural technologies to sustain and grow their numbers.
  • Humans are niche creators, we transform ecosystems to sustain ourselves.
  • Does Saving More Lives Lead to Overpopulation? The short answer is: No. It’s not the sort of exponential growth many people fret about.
  • Every aspect of job performance gets better as we age. It’s true that older people cannot work physically the same way they did when they were 20, but when it comes to management and leadership, it’s the opposite.
  • If you want a country in which your citizens flourish and that others envy, don’t reduce the retirement age or discourage medical treatments for the elderly, hoping to save money and make room for the young. Instead, keep your population healthy and productive, and destroy all barriers to education and innovation.
  • Research demonstrates that humans are a lot more humane when they’ve got more time.
  • Thanks to technologies, a prolonged, healthier human lifespan is inevitable.
  • Australia is leading the charge to define aging as a treatable disease.
  • There are two things that guide medical treatments more than anything else: age and economics.
  • 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. And so if we’re going to do the former, we have an absolute moral obligation to do the latter.
  • When it comes to the future health of our planet, people are overly preoccupied with the number of humans on Earth while ignoring the fact that consumption bears twice as much responsibility for pressure on resources and ecosystems as population growth.
  • Humans can live healthily and quite happily while consuming far less than most do in the developed world.

More about David's book can be found at www.lifespanbook.com



© 2020 Cedric Joyce