Contents

Part I: What We Know (The Past)

1. Viva Primordium

2. The Demented Pianist

3. The Blind Epidemic

Part II: What We’re Learning (The Present)

4. Longevity Now

5. A Bitter Pill to Swallow

6. Big Steps Ahead

7. The Age of Innovation

Part III: Where We’re Going (The Future)

8. The Shape of Things to Come

9. A Path Forward

Conclusion

Part I: What We Know (The Past)

1. Viva Primordium

Early Life

As the nucleic acids concentrate, they grow into polymers. These are the world’s first RNA molecules, the predecessors to DNA. When the pond refills, the primitive genetic material becomes encapsulated by fatty acids to form microscopic soap bubbles—the first cell membranes. Eventually the shallow ponds are covered with a yellow froth of trillions of tiny precursor cells filled with short strands of nucleic acids, which we now call genes.

Most of the protocells are recycled, but some survive and begin to evolve primitive metabolic pathways, until the RNA begins to copy itself. Now that life has formed, as fatty-acid soap bubbles filled with genetic material, they begin to compete for dominance (prey vs. predator).

The products of mutations, insertions, gene rearrangements, and the horizontal transfer of genes from one species to another—will create organisms with bilateral symmetry, stereoscopic vision, and even consciousness.

Repair and Survival Gene Circuits

The original circuit begins with gene A, which stops cells from reproducing when times are tough. On early planet Earth, most times are tough. The circuit also has gene B, which encodes for a “silencing” protein. This silencing protein shuts gene A off when times are good, so the cell can make copies of itself when, and only when, it and its offspring will likely survive. The genes themselves aren’t novel. Then, the gene B silencer mutates to give it a second function: it helps repair DNA. When the cell’s DNA breaks, the silencing protein encoded by gene B moves from gene A to help with DNA repair, which turns on gene A. This temporarily stops all sex and reproduction until the DNA repair is complete.

Cells that fail to pause while fixing a DNA break will almost certainly lose genetic material. This is because DNA is pulled apart prior to cell division from only one attachment site on the DNA, taking the rest of the DNA with it. If DNA is broken, part of a chromosome will be lost or duplicated. The cells will likely die or multiply uncontrollably into a tumor. Cosmic rays, which tear vulnerable DNA strands apart, will result in unmutated genes losing their genetic material.

Modern day humans carry an advanced version of the survival circuit that allows it to last for decades past the age of reproduction. While it is interesting to speculate why our long lifespans first evolved given the chaos that exists at the molecular scale, it’s a wonder we survive thirty seconds, our reproductive years, let alone reach the age of 80.

To Everything There Is a Reason

Immune T-cells continuously patrol our body, looking for rogue cells to identify and kill before they can multiply into a tumor. However, rogue cancer cells evolve ways to fool cancer-detecting T-cells so they can keep multiplying. The latest and most effective immunotherapies bind to proteins on the cancer cells’ surface. Although, fewer than 10 percent of all cancer patients currently benefit from immunotherapy.

Thanks to a combination of a BRAF inhibitor and immunotherapy, survival of melanoma brain metastases, one of the deadliest types of cancer, has increased by 91 percent since 2011. Between 1991 and 2016, overall deaths from cancer in the United States declined by 27 percent and continue to fall.

Medawar expounded on a nuanced theory called “antagonistic pleiotropy.” It says genes that help us reproduce when we are young don’t just become less helpful as we age, they can actually become detrimental when we age.

Thomas Kirkwood framed the question of why we age in terms of an organism’s available resources. Known as the “Disposable Soma Hypothesis,” it is based on the fact that there are always limited resources available to species—energy, nutrients, water. They therefore evolve to a point that lies somewhere between two very different lifestyles: breed fast and die young, or breed slowly and maintain your soma, or body.

Homo sapiens: Having capitalized on its relatively large brain and a thriving civilization to overcome the unfortunate hand that evolution dealt it—weak limbs, sensitivity to cold, poor sense of smell, and eyes that see well only in daylight and in the visible spectrum—this highly unusual species continues to innovate. It has already provided itself with an abundance of food, nutrients, and water while reducing deaths from predation, exposure, infectious diseases, and warfare. These were all once limits to it evolving a longer lifespan. 

Crisis Mode

Peter Medawar and Leo Szilard proposed that aging is caused by DNA damage and a resulting loss of genetic information. Because of the fact that nuclear transfer works in cloning, we can say with a high degree of confidence that aging isn’t caused by mutations in nuclear DNA.

Leslie Orgel proposed the “Error Catastrophe Hypothesis,” which postulated that mistakes made during the DNA-copying process led to mutations in genes, including those needed to make the protein machinery that copies DNA. The process increasingly disrupts those same processes, multiplying upon themselves until a person’s genome has been incorrectly copied into oblivion.

Denham Harman came up with the “Free Radical Theory of Aging,” which 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 generated.

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.

Aging and the diseases that come with it are the result of multiple “hallmarks” of aging:

• Genomic instability caused by DNA damage
• Attrition of the protective chromosomal endcaps, the telomeres
• Alterations to the epigenome that controls 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
• Exhaustion of stem cells
• Altered intercellular communication and the production of inflammatory molecules

If we can keep undifferentiated stem cells from tiring out, they can continue to generate all the differentiated cells necessary to heal damaged tissues and battle all kinds of diseases.

Meanwhile, we’re improving the rates of acceptance of bone marrow transplants, which are the most common form of stem cell therapy, and using stem cells for the treatment of arthritic joints, type 1 diabetes, loss of vision, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s.

Senescent cells, which have reached the end of their ability to divide but refuse to die, continuing to release inflammatory cytokines: if we can kill off senescent cells or keep them from accumulating, we can keep our tissues much healthier for longer.

The same can be said for combating telomere loss, the decline in proteostasis, and all of the other hallmarks. Each can be addressed one by one, a little at a time, in ways that can help us extend the human health span.

In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin. DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein called histones. 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, sometimes for decades, as in the case of individual brain neurons and certain immune cells.

Unlike digital information, analog information degrades over time—falling victim to magnetic fields, gravity, cosmic rays, and oxygen. Worse still, information is lost as it’s copied.

As cloning proves, our cells retain their youthful digital information even when we are old. To become young again, we just need to find some polish to remove the scratches (CD analogy).

A Time to Every Purpose

The Information Theory of Aging starts with the primordial survival circuit we inherited from our distant ancestors.

Over time the circuit has evolved. Scientists have found more than two dozen of them within our genome. Most of his colleagues call these “longevity genes” because they have demonstrated the ability to extend both average and maximum health and lifespans in many organisms. 

These genes form a surveillance network within our bodies, communicating between cells and organs by releasing proteins and chemicals into the bloodstream, monitoring and responding to what we eat, how much we exercise, and what time of day it is. They tell us to hunker down when the going gets tough, and they tell us to grow fast and reproduce fast when the going gets easier.

There are seven sirtuins (longevity genes) in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body. Sirtuins are enzymes that remove acetyl tags from histones and other proteins and 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. After a few billion years of advancement since the days of yeast, they have evolved to control our health, our fitness, and our very survival. They have also evolved to require nicotinamide adenine dinucleotide (NAD). 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: diabetes and heart disease, Alzheimer’s disease and osteoporosis, even cancer. They mute the chronic, overactive inflammation that drives diseases such as atherosclerosis, metabolic disorders, ulcerative colitis, arthritis, and asthma. They prevent cell death and boost mitochondria. They also prevent muscle wasting, osteoporosis, and macular degeneration. In studies on mice, activating the sirtuins improved DNA repair, boosted memory, increased exercise endurance, and helped the mice stay thin, regardless of what they ate.

Like sirtuins, scientists have found TOR—called mTOR in mammals—in every organism in which they’ve looked for it. Similar to sirtuins, mTOR activity is regulated by nutrients, and can signal cells in stress to hunker down and improve survival by boosting activities such as DNA repair, reducing inflammation caused by senescent cells, and digesting old proteins.

When all is well, TOR is a master driver of cell growth. It senses the number of amino acids that are available and dictates how much protein is created in response. When it is inhibited, it forces cells to divide less and to reuse old cellular components to maintain energy and extend survival (autophagy).

The other pathway is a metabolic control enzyme known as AMPK, which evolved to respond to low energy levels. It has also been highly conserved among species.

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. When hormesis happens, all is well. And, in fact, all is better than well, because the little bit of stress that occurs when the genes are activated prompts the rest of the system to hunker down, to conserve, to survive a little longer. That’s the start of longevity.

Then there are also hormesis mimicking molecules.

2. The Demented Pianist

Yeast of Eden

S. cerevisiae shares about 70% of our genes and like most humans, yeast cells are always either trying to eat or reproduce. As they age, they slow down and grow larger, rounder, and less fertile. But whereas humans go through this process over the course of many decades, yeast cells experience it in a week.

Sir2 is an epigenetic factor, an enzyme that sits on genes, bundles up the DNA, and keeps them silent. Sir2 achieves this via its enzymatic activity, making sure that acetyls don’t accumulate on the histones and loosen the DNA packaging. When sirtuins left the mating genes—the ones descended from gene A that controlled fertility and reproduction—the mutant cells turned on both male and female genes, causing them to lose their sexual identity, just as in normal old cells, but much earlier.

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.

The Recital

Sirtuins instruct the histone spooling proteins to bind up DNA tightly, while they leave other regions to flail around. In this way, some genes stay silent, while others can be accessed by DNA-binding transcription factors that turn genes on. Accessible genes are said to be in “euchromatin,” while silent genes are in “heterochromatin.” By removing chemical tags on histones, sirtuins help prevent transcription factors from binding to genes, converting euchromatin into heterochromatin.

Studies of identical twins place the genetic influences on longevity at between 10 and 25 percent which, by any estimation, is surprisingly low.

Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death.

They demonstrated that the redistribution of Sir2 to the nucleolus is a response to numerous DNA breakages, which happen as a result of extrachromosomal ribosomal DNA circles (ERCs) multiplying and inserting back into the genome or joining together to form super-large ERCs. When Sir2 moves to combat DNA instability, it causes sterility in old, bloated yeast cells.

• By demonstrating that if you add an ERC to young cells they age prematurely, they had crucial evidence that ERCs don’t just happen during aging, they cause it. And by artificially breaking the DNA in the cell and watching the cellular response, they showed why sirtuins move—to help with DNA repair.
• The DNA damage that gave rise to the ERCs was distracting Sir2 from the mating-type genes, causing them to become sterile, a hallmark of yeast aging.

Mammals have seven sirtuin genes that have evolved a variety of functions beyond what simple SIR2 can do. Three of them, SIRT1, SIRT6, and SIRT7, are critical for the control of the epigenome and DNA repair. SIRT3, SIRT4, and SIRT5 reside in mitochondria, where they control energy metabolism, while SIRT2 buzzes around the cytoplasm, where it controls cell division and healthy egg production.

Yeast cells fed with lower amounts of sugar were not just living longer, but their rDNA was exceptionally compact—significantly delaying the inevitable ERC accumulation, catastrophic numbers of DNA breaks, nucleolar explosion, sterility, and death.

The Survival Circuit Comes of Age

On average, each of our forty-six chromosomes is broken in some way every time a cell copies its DNA, amounting to more than 2 trillion breaks in our bodies per day. And that’s just the breaks that occur during replication. Others are caused by natural radiation, chemicals in our environment, and the X-rays and CT scans that we’re subjected to.

In mammals, the sirtuins have since taken on a variety of new roles, not just as controllers of fertility. They remove acetyls from hundreds of proteins in the cell: histones and also proteins that control cell division, cell survival, DNA repair, inflammation, glucose metabolism, mitochondria, and other functions.

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 controlling genes and making sure the cell retains its identity and optimal function.

Wherever epigenetic factors leave the genome to address damage, genes that should be off, switch on and vice versa. Wherever they stop on the genome, they do the same, altering the epigenome in ways that were never intended when we were born. Cells lose their identity and malfunction. Chaos ensues. The chaos materializes as aging. This is the epigenetic noise that is at the heart of our unified theory.

SIR2 codes for a specialized protein called a histone deacetylase (HDAC), that enzymatically cleaves the acetyl chemical tags from histones, which causes the DNA to bundle up, preventing it from being transcribed into RNA. When the Sir2 enzyme is sitting on the mating-type genes, they remain silent and the cell continues to mate and reproduce. But when a DNA break occurs, Sir2 is recruited to the break to remove the acetyl tags from the histones at the DNA. This bundles up the histones to prevent the frayed DNA from being chewed back further and to help recruit other repair proteins. Once the DNA repair is complete, most of the Sir2 protein goes back to the mating-type genes to silence them and restore fertility. That is, unless there is another emergency, such as the massive genome instability that occurs when ERCs accumulate in the nucleoli of old yeast cells.

The cell doesn’t make enough Sir2 protein to simultaneously silence the mating-type genes and repair broken DNA; it has to shuttle Sir2 between the various places on an “as-needed” basis. This is why adding an extra copy of the SIR2 gene extends lifespan and delays infertility: cells have enough Sir2 to repair DNA breaks and enough Sir2 to silence the mating-type genes.

They could age mice without affecting any of the most commonly assumed causes of aging. They hadn’t made their cells mutate, touched their telomeres, messed with their mitochondria, or directly exhausted their stem cells. Yet the ICE mice were suffering from a loss of body mass, mitochondria, and muscle strength and an increase in cataracts, arthritis, dementia, bone loss, and frailty. All of the symptoms of aging—the conditions that push mice, like humans, farther toward the precipice of death—were being caused not by mutation but by the epigenetic changes that come as a result of DNA damage signals.

Fruit of the Same Tree

Bristlecones are outliers in the biological world, but they are not unique in their defiance of aging. The freshwater polyp known as Hydra vulgaris has also evolved to defy senescence. Under the right conditions they have demonstrated a remarkable refusal to age.

DAF-16 encodes a small transcription factor protein that latches onto the DNA sequence TTGTTTAC and works with sirtuins to increase cellular survival when times are tough. In mammals, there are four DAF-16 genes, called FOXO1, FOXO3, FOXO4, and FOXO6.

He first encountered FOXO/DAF-16 in yeast, where it is known as MSN2, which stands for “multicopy suppressor of SNF1 (AMPK) epigenetic regulator.” Like DAF-16, MSN2’s job in yeast is to turn on genes that push cells away from cell death and toward stress resistance. They discovered that when calories are restricted MSN2 extends yeast lifespan by turning up genes that recycle NAD, thereby giving the sirtuins a boost.

Several repeating themes: low energy sensors (SNF1/AMPK), transcription factors (MSN2/DAF-16/FOXO), NAD and sirtuins, stress resistance, and longevity.

FOXO3 variants likely turn on the body’s defenses against diseases and aging, not just when times are tough but throughout life. If you’ve had your genome analyzed, you can check if you have any of the known variations of FOXO3 that are associated with a long life. For example, having a C instead of a T variant at position rs2764264 is associated with longer life.

The Landscape of Our Lives

Every time there’s a radical adjustment to the epigenome, such as after DNA damage from the sun or an X-ray, the marbles are jostled—envision a small earthquake that ever so slightly changes the map. Over time, with repeated earthquakes and erosion of the mountains, the marbles are moved up the sides of the slope, toward a new valley. A cell’s identity changes. A skin cell starts behaving differently, turning on genes that were shut off in the womb and were meant to stay off. Now it is 90% a skin cell and 10% other cell types. The cell becomes inept at the things skin cells must do, such as making hair, keeping the skin supple, and healing when injured. They call these cells ex-differentiated.

When you disrupt the epigenome by forcing it to deal with DNA breaks, you introduce noise, leading to an erosion of the epigenetic landscape.

Reversal Comes of Age

When treated with an NAD-boosting molecule that activated the SIRT1 enzyme, elderly mice’s endothelial cells were pushing their way into areas of the muscle that weren’t getting very much blood flow. New tiny blood vessels were formed, supplying badly needed oxygen, removing lactic acid and toxic metabolites from muscles, and reversing one of the most significant causes of frailty in mice and in humans.

The lining of the capillaries was responding as if the mice were exercised. It was an exercise mimetic.

3. The Blind Epidemic

The Mortal Breeze

Men who run middle-distance races, for instance, are fastest around the age of 25, no matter how hard they train after that. The best female marathoners can stay competitive well into their late 20s and early 30s, but their times begin to rise quickly after 40.

There are some simple tests to determine how biologically old you are. The number of push-ups you can do is a good indicator. If you are over 45 and can do more than twenty, you are doing well. The other test of age is the sitting-rising test (SRT). Sit on the floor, barefooted, with legs crossed. Lean forward quickly and see if you can get up in one move. A young person can. A middle-aged person typically needs to push off with one of their hands. An elderly person often needs to get onto one knee. A study of people 51 to 80 years found that 157 out of 159 people who passed away in 75 months had received less than perfect SRT scores.

When a child gets a cut on her foot, a noninfected wound will heal quite quickly. For an elderly person, a foot injury is not just painful but dangerous. For older diabetics, in particular, a small wound can be deadly: The five-year mortality rate for a foot ulcer in a diabetic is greater than 50 percent. That’s higher than the death rates for many kinds of cancer.

Small and large diabetic foot wounds rarely heal. They can look as though someone has taken an apple corer to the balls of both feet. The body doesn’t have enough blood flow and cell regeneration capacity, and bacteria thrive here.

Whack-A-Mole Medicine

The way doctors treat illness today “is simple,” wrote S. Jay Olshansky, a demographer at the University of Illinois. “As soon as a disease appears, attack that disease as if nothing else is present; beat the disease down, and once you succeed, push the patient out the door until he or she faces the next challenge; then beat that one down. Repeat until failure.”

The United States spends hundreds of billions of dollars each year fighting cardiovascular disease. But if we could stop all cardiovascular disease—every single case, all at once—we wouldn’t add many years to the average lifespan; the gain would be just 1.5 years. The same is true for cancer; stopping all forms would give us just 2.1 more years of life on average, because all other causes of death still increase exponentially.

One study found that 85-year-old men are diagnosed with an average of four different diseases, with women of that age suffering from five. Heart disease and cancer. Arthritis and Alzheimer’s. Kidney disease and diabetes. Most patients have several additional undiagnosed diseases, including hypertension, ischemic heart disease, atrial fibrillation, and dementia.

Cigarette smoke contains a chemical called benzo(a)pyrene, which binds to guanine in DNA, induces double-strand breaks, and causes mutations. The repair process also causes epigenetic drift and metabolic changes that cancer cells thrive on; in a process they’ve called geroncogenesis. The combination of genetic and epigenetic changes induced by years of exposure to cigarette smoke increases the chances of developing lung cancer about fivefold.

Even though 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. Such exponentially increasing odds also apply to heart disease. And diabetes. And dementia.

A Glorious Fight

According to The Merck Manual of Geriatrics, a malady that impacts less than half the population is a disease. But aging, of course, impacts everyone. The manual therefore calls aging an “inevitable, irreversible decline in organ function that occurs over time even in the absence of injury, illness, environmental risks, or poor lifestyle choices.” We used to say this about cancer, diabetes, and gangrene.

Maintaining proteostasis, preventing deregulation of nutrient sensing, thwarting mitochondrial dysfunction, stopping senescence, rejuvenating stem cells, and decreasing inflammation might all be ways to delay the inevitable.

Part II: What We’re Learning (The Present)

4. Longevity Now

Go Fast

Not malnutrition. Not starvation. These are not pathways to more years, let alone better years. But 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.

Cells fed with lower doses of glucose were living longer, and their DNA was exceptionally compact—significantly delaying the inevitable ERC accumulation, nucleolar explosion, and sterility.

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 than necessary. 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.

Caloric restriction (CR) works to extend the lifespan of mice, even when initiated at 19 months of age, but the earlier the mice start on CR, the greater the lifespan extension. What these and other animal studies tell us is that it’s hard to “age out” of the longevity benefits of calorie restriction, but it’s probably better to start earlier than later, perhaps after age 40, when things really start to go downhill, molecularly speaking.

The Periodic Table

Over the course of just three months, those who maintained the “fasting mimicking” diet lost weight, reduced their body fat, lowered their blood pressure, and lower levels of IGF-1. Mutations in IGF-1 and the IGF-1 receptor gene are associated with lower rates of death and disease and found in abundance in females whose families tend to live past 100.

We see that in some cases it doesn’t actually matter what they put into their bodies. They carry gene variants that seem to put them into a state of fasting no matter what they eat.

A popular method is to skip breakfast and have a late lunch (the 16:8 diet). Another is to eat 75 percent fewer calories for two days a week (the 5:2 diet). If you’re a bit more adventurous, you can try skipping food a couple of days a week (Eat Stop Eat), or as the health pundit Peter Attia does, go hungry for an entire week every quarter.

Amino Right

Heavily animal-based diets are associated with high cardiovascular mortality and cancer risk. Processed red meats are carcinogenic, according to hundreds of studies that have demonstrated a link between these foods and colorectal, pancreatic, and prostate cancer. Red meat also contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease.

From an energy perspective, there isn’t a single amino acid that can’t be obtained by consuming plant-based protein sources. The bad news is that, unlike most meats, weight for weight, any given plant usually delivers limited amounts of amino acids.

A body that is in short supply of amino acids overall, or any single amino acid for a spell, is a body under the very sort of stress that engages our survival circuits.

When 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.

Feeding mice a diet with low levels of methionine works particularly well to turn on their bodily defenses, to protect organs from hypoxia during surgery, and to increase healthy lifespan by 20 percent.

Methionine restriction causes obese mice to shed most of their fat. Even as the mice continued to eat as much as they wanted and shun exercise, they still lost about 70% of their fat in a month, while also lowering their blood glucose levels.

We can’t live without methionine. But we can do a better job of restricting the amount of it we put into our bodies. There’s a lot of methionine in beef, lamb, poultry, pork, and eggs, whereas plant proteins tend to contain low levels of that amino acid.

The same is true for arginine and the BCAAs, leucine, isoleucine, and valine, all of which can activate mTOR. Low levels of these amino acids correlate with increased lifespan and in human studies, a decreased consumption of branched-chain amino acids has been shown to improve markers of metabolic health significantly.

Studies in which leucine is completely eliminated from a mouse’s diet have demonstrated that just one week without it significantly reduces blood glucose levels, a key marker of improved health. So, a little leucine is necessary for muscle growth during good times, but it disengages the survival circuit.

Even if we eat a low-protein, vegetable-rich diet, we may live longer, but we won’t maximize our lifespans—because putting our bodies into nutritional adversity isn’t going to maximally trigger our longevity genes. We need to induce some physical adversity, too. If that doesn’t happen, we miss a key opportunity to trigger our survival circuits further.

Do Sweat It

Individuals who exercise more, e.g., a half hour of jogging five days a week, have telomeres that appear to be nearly a decade younger than those who live a more sedentary life.

Exercise raises NAD levels, which in turn activates the survival network, which turns up energy production and forces muscles to grow extra oxygen-carrying capillaries. The longevity regulators 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 extending telomeres. SIRT1 and SIRT6, for example, help extend telomeres, then package them up so they are protected from degradation.

One recent study found that those who ran four to five miles a week reduced their chance of death from a heart attack by 40% and all-cause mortality by 45%. 

Mayo Clinic researchers studying the effects of different types of exercise on different age groups found that although many forms of exercise have positive health effects, it’s high-intensity interval training (HIIT).

Your breathing should be deep and rapid at 70 to 85 percent of your maximum heart rate. You should sweat and be unable to say more than a few words without pausing for breath. This is the hypoxic response, and it’s great for inducing just enough stress to activate your body’s defenses against aging without doing permanent harm.

Many of the longevity genes that are turned on by exercise are responsible for the health benefits of exercise, such as extending telomeres, growing new microvessels that deliver oxygen to cells, and boosting the activity of mitochondria, which burn oxygen to make chemical energy.

The Cold Front

When the world takes us out of the thermoneutral zone, our breathing patterns shift, the blood flow to and through our skin changes, and our heart rates speed up or slow down.

Calorie restriction has the effect of reducing core body temperature.

Back in 2006, a team from the Scripps Research Institute genetically engineered some lab mice to live their lives a half degree cooler than normal, by inserting copies of the mouse UCP2 gene into its hypothalamus, which regulates the skin, sweat glands, and blood vessels. UCP2 short-circuited mitochondria in the hypothalamus so they produced less energy but more heat. That, in turn, caused the mice to cool down about half a degree Celsius. The result was a 20% longer life for female mice, the equivalent of about seven additional healthy human years, while male mice got an extension of 12%.

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

Chemicals called mitochondrial uncouplers can mimic the effects of UCP2, allowing protons to leak through mitochondrial membranes. The result is not cold, but heat as a by-product of the mitochondrial short circuit.

The sweet-smelling mitochondrial uncoupler called 2,4-dinitrophenol (DNP) was used for making explosives in the First World War, and it soon became apparent that employees exposed to the chemical were rapidly losing weight, with one employee even dying from overexposure. DNP ended up being sold as a weight loss pill and it actually worked. However, people ended up overdosing and dying, resulting in it being taken off the market.

Exercising in the cold, in particular, appears to turbocharge the creation of brown adipose tissue. Leaving a window open overnight or not using a heavy blanket while you sleep can help, too.

It’s probably better to change your lifestyle while you are young, because making brown fat becomes harder as you get older. If you choose to expose yourself to the cold, moderation will be key. Similar to fasting, the greatest benefits are likely to come for those who get close to, but not beyond, the edge.

Raising the temperature of yeast—from 30°C to 37°C, just below the limits of what they can sustain—turns on the PNC1 gene and boosts their NAD production, so their Sir2 proteins can work harder. What’s fascinating is not so much that these temperature-stressed cells lived 30% longer, but that the mechanism was the same as that evoked by calorie restriction. Because we are warm-blooded animals, our enzymes haven’t evolved a tolerance for large changes in temperature. You can’t just raise your core body temperature and expect to live longer.

A 2018 study conducted in Helsinki found that “physical function, vitality, social functioning, and general health were significantly better among sauna users than non-users,” although the researchers were correct to point out that part of the effect could be due to the fact that those who are sick or disabled don’t go to the sauna. Those who used a sauna with great frequency—up to seven times a week—enjoyed a twofold drop in heart disease, fatal hearts attacks, and all-cause mortality events over those who heat bathed once per week.

NAMPT, the gene in our bodies that recycles NAD, is turned on by a variety of adversity triggers, including fasting and exercise, which makes more NAD so the sirtuins can work hard at making us healthier.

Don’t Rock the Landscape

A bit of adversity or cellular stress is good for our epigenome because it stimulates our longevity genes. It activates AMPK, turns down mTOR, boosts NAD levels, and activates the sirtuins. When our sirtuins have to respond to many disasters— especially those that cause double-strand DNA breaks—these epigenetic signalers are forced to leave their posts and head to other places on the genome where DNA breaks have occurred. Sometimes they make their way back home. Sometimes they don’t.

The DNA damage that results from smoking keeps the DNA repair crews working overtime, and likely the result is the epigenetic instability that causes aging. The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke. 

In some places, the simple act of breathing is enough to do extra damage to your DNA. But it would also be wise to be wary of the PCBs and other chemicals found in plastics, including many plastic bottles and take-out containers. (Avoid microwaving these; it releases even more PCBs.) Exposure to azo dyes, such as aniline yellow, which is used in everything from fireworks to the yellow ink in home printers, can also damage our DNA. And organohalides—compounds that contain substituted halogen atoms and are used in solvents, degreasers, pesticides, and hydraulic fluid—can also wreak havoc on our genomes.

N-nitroso compounds are present in food treated with sodium nitrite, including some beers, most cured meats, and especially cooked bacon. In the decades since, we’ve learned that these compounds are potent carcinogens. What we’ve also come to understand is that cancer is just the start of our nitrate-treated woes, because nitroso compounds can inflict DNA breakage as well—sending those overworked sirtuins back to work some more.

Any source of natural or human-inflicted radiation, such as UV light, X-rays, gamma rays, and radon in homes (which is the second most frequent cause of lung cancer besides smoking) can cause additional DNA damage, necessitating the call-up of an epigenetic fix-it team.

You can’t avoid radon particles or cosmic rays unless you live in a lead box at the bottom of the ocean. And even if you were to move to a desert island, the fish you’d have to eat would likely contain mercury, PCBs, PBDEs, dioxins, and chlorinated pesticides, all of which can damage your DNA. In our modern world, even with the most “natural” lifestyle you can follow, this sort of DNA damage is inevitable.

5. A Bitter Pill to Swallow

Every second you are alive, thousands of glucose molecules are captured within each of your trillions of cells by an enzyme called glucokinase, which fuses glucose molecules to phosphorus atoms, tagging them for energy production. Most of the energy created is used by a multicomponent RNA and protein complex called a ribosome, whose primary job is to capture amino acids and fuse them with other amino acids to make fresh proteins.

Precise vibrating sockets on SIRT1 simultaneously clasp onto an NAD molecule and the protein it wants to strip the acetyls from, such as a histone or FOXO3. The two captured molecules immediately lock together, just before SIRT1 rips them apart in a different way, producing vitamin B3 and acetylated adenine ribose as waste products that are recycled back to NAD. The target protein has now been stripped of the acetyl chemical group that was holding it at bay. Now the histone can pack DNA more tightly to silence genes, and FOXO3 has had its shackles removed, allowing it to go turn on a defense program of protective genes.

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 World’s Greatest Easter Egg

It has become clear that rapamycin isn’t just an antifungal compound and it isn’t just an immune system suppressor; it’s also one of the most consistently successful compounds for extending life.

If you put 2,000 normal yeast cells into a culture, a few will remain viable after six weeks. But if you feed those yeast cells rapamycin, in six weeks about half will still be healthy. The drug will also increase the number of daughter cells mothers can produce by stimulating the production of NAD.

We’ve known for a long time that greater parental age is a risk factor for disease in the next generation. But when researchers from the German Center for Neurodegenerative Diseases inhibited mTOR in mice born to older fathers, the negative impact of having an old parent went away.

Longer-lived animals might not fare as well on it as shorter-lived ones do; it’s been shown to be toxic to kidneys at high doses over extended periods of time; and it might suppress the immune system over time. That doesn’t mean TOR inhibition is a dead end, though. It might be safe in small or intermittent doses—that worked in mice to extend lifespan and in humans dramatically improved the immune responses of elderly people to a flu vaccine.

Pennies for Prolonged Vitality

In mice, even a very low dose of metformin has been shown by Rafael de Cabo’s lab at the National Institutes of Health to increase lifespan by nearly 6%, though some have argued that the effect is due mostly to weight loss. Either way, that amounts to the equivalent of five extra healthy years for humans, the mice showed reduced LDL cholesterol levels and improved physical performance. In twenty-six studies of rodents treated with metformin, twenty-five showed protection from cancer.

Like rapamycin, metformin mimics aspects of calorie restriction. But instead of inhibiting TOR, it limits the metabolic reactions in mitochondria, slowing down the process by which they convert macronutrients into energy. The result is the activation of AMPK, an enzyme known for its ability to respond to low energy levels and restore the function of mitochondria. It also activates SIRT1. Among other beneficial effects, metformin inhibits cancer cell metabolism, increases mitochondrial activity, and removes misfolded proteins.

A study of more than 41,000 metformin users between the ages of 68 and 81 concluded that metformin reduced the likelihood of dementia, cardiovascular disease, cancer, frailty, and depression, and not by a small amount. In one group of already frail subjects, metformin use over the course of nine years reduced dementia by 4%, depression by 16%, cardiovascular disease by 19%, frailty by 24%, and cancer by 4%.

Even though not all cancers are suppressed (prostate, bladder, renal, and esophageal cancer seem recalcitrant), more than twenty-five studies have shown a powerful protective effect, sometimes as great as a 40% lower risk, most notably for lung, colorectal, pancreatic, and breast cancer.

Through the power of AMPK activation, it makes more NAD and turns on sirtuins and other defenses against aging as a whole—engaging the survival circuit upstream of these conditions, slowing the loss of epigenetic information and keeping metabolism in check, so all organs stay younger and healthier.

A small study of healthy volunteers claimed that the DNA methylation age of blood cells is reversed within a week and only ten hours after taking a single 850 mg pill of metformin. 

Nir Barzilai discovered several longevity gene variants in the insulin-like growth hormone receptor that controls FOXO3, the cholesterol gene CETP, and the sirtuin SIRT6, all of which seem to help ensure that some lucky people with Ashkenazi Jewish ancestry remain healthy beyond 100.

Stac it Up

In a series of papers, they reported that the cause of yeast aging was the movement of Sir2 away from the mating-type genes to deal with DNA breaks and a whole lot of ensuing genome instability. They showed that extra copies of the SIR2 gene could stabilize the rDNA and extend lifespan. They also linked genetic instability to epigenetic instability and found one of the world’s first true longevity genes.

The first SIRT1-activating compound, or STAC, was a polyphenol called fisetin, which helps gives plants such as strawberries and persimmons their color and is now known to also kill senescent cells. The second was a molecule called butein, which can be found in numerous flowering plants as well as a toxic plant known as the Chinese lacquer tree. Resveratrol has an overlapping structure – two phenolic rings connected by a bridge. It has also been shown to far outperform the previous two compounds.

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.

Resveratrol-fed yeast were slightly smaller and grew slightly slower than untreated yeast, getting to an average of thirty-four divisions before dying, as though they were calorie restricted. The human equivalent would be an extra 50 years of life. They saw increases in maximum lifespan, too—on resveratrol, they kept going past 35 (instead of the usual 25). They tested resveratrol in yeast cells with no SIR2 gene, and there was no effect. They tested it on calorie-restricted yeast, and saw no further increase in lifespan, suggesting that the same pathway was being activated; this was how calorie restriction was working.

Many other health-promoting molecules, and chemical derivatives of them, are produced in abundance by stressed plants; we get resveratrol from grapes, aspirin from willow bark, metformin from lilacs, epigallocatechin gallate from green tea, quercetin from fruits, and allicin from garlic.

Plants that are stressed have higher concentrations of xenohormetic molecules that may help us engage our own survival circuits. Look for the most highly colored ones because xenohormetic molecules are often yellow, red, orange, or blue. They tend to taste better. The best wines in the world are produced in dry, sun-exposed soil or from stress-sensitive varietals such as Pinot Noir, which contains the most resveratrol. The most delectable strawberries are those that have been stressed by periods of limited water supply. And as anyone who has grown leaf vegetables can attest, the best heads of lettuce come when the plants are exposed to a one-two combo punch of heat and cold.

They fed resveratrol to obese mice at one year of age and the mice stayed fat, but when they opened up the mice, the resveratrol mice looked identical to mice on a normal diet, with healthy hearts, livers, arteries, and muscles. They also had more mitochondria, less inflammation, and lower blood sugar levels. The ones they didn’t dissect wound up living about 20% longer than normal.

Resveratrol protects mice against a variety of cancers, heart disease, stroke and heart attacks, neurodegeneration, inflammatory diseases, and wound healing, and generally makes mice healthier and more resilient. They also discovered that when resveratrol is combined with intermittent fasting, it can greatly extend both average and maximum lifespan even beyond what fasting alone accomplishes. Out of fifty mice, one lived more than 3 years—in human terms, that would amount to about 115 years.

As it turned out, resveratrol wasn’t very potent and wasn’t very soluble in the human gut, two attributes that most medicines need to be effective at treating diseases.

STACs are many times more potent than resveratrol at stimulating the survival circuit and extending healthy lifespans in animals. They go by names such as SRT1720 and SRT2104, both of which extend the healthy lifespan of mice when given to them late in life. There are hundreds of chemicals that have been demonstrated to have an effect on sirtuins that are even more effective than resveratrol’s and some that have already been demonstrated in clinical trials to lower fatty acid and cholesterol levels, and to treat psoriasis in humans.

Another STAC is NAD, sometimes written as NAD+. NAD has an advantage over other STACs because it boosts the activity of all seven sirtuins. NAD is a product of the vitamin niacin, a severe lack of which causes inflamed skin, diarrhea, dementia, skin sores, and ultimately death. And because NAD is used by over five hundred different enzymes, without any NAD, we’d be dead in thirty seconds.

Without sufficient NAD, the sirtuins don’t work efficiently: they can’t remove the acetyl groups from histones, they can’t silence genes, and they can’t extend lifespan. They also noticed that NAD levels decrease with age throughout the body, in the brain, blood, muscle, immune cells, pancreas, skin, and even the endothelial cells that coat the inside of microscopic blood vessels.

They first discovered a gene called PNC1, which turns vitamin B3 into NAD. That led them to try boosting PNC1 by introducing four extra copies of it into the yeast cells, giving them five copies in total. Those yeast cells lived 50% longer than normal, but not if they removed the SIR2 gene. The cells were making extra NAD, and the sirtuin survival circuit was being engaged.

In the body, NR is converted into NMN, which is then converted into NAD. Give an animal a drink with NR or NMN in it, and the levels of NAD in its body go up about 25% over the next couple of hours, about the same as if it had been fasting or exercising.

NMN can protect against kidney damage, neurodegeneration, mitochondrial diseases, and an inherited disease called Friedreich’s ataxia.

They find NMN to be more stable than NR and see some health benefits in mouse experiments that aren’t seen when NR is used. But it’s NR that has been proven to extend the lifespan of mice. NMN is still being tested. So, there’s no definitive answer, at least not yet.

Fertile Ground

Anecdotal reports of restored menstruation and fertile horses are early but interesting indicators that NAD boosters might restore failing or failed ovaries. NMN is able to restore the fertility of old mice that have had all their eggs killed off by chemotherapy or have gone through “mousopause.”

The ovary is the first major organ to break down as a result of aging, in humans and animal models alike. 

NMN boosts NAD, and this boosts the activity of the SIRT2 enzyme, a human form of yeast Sir2 found in the cytoplasm. SIRT2 controls the process by which an immature egg divides so that only one copy of the mother’s chromosomes remains in the final egg in order to make way for the father’s chromosomes. Without NMN, or additional SIRT2 in old mice, their eggs were toast. Pairs of chromosomes were ripped apart from numerous directions, instead of exactly two. But if the old female mice were pretreated with NMN for a few weeks, their eggs looked pristine, identical to those of young mice.

Metformin is already widely used to improve ovulation in women with infrequent or prolonged menstrual periods as a result of polycystic ovary syndrome. Meanwhile, emerging research is demonstrating that the inhibition of mammalian target of rapamycin, or mTOR, may be able to preserve ovarian function and fertility during chemotherapy, while the same gene pathway plays an important role in male fertility, as a central player in the production and development of sperm.

Life with Father

His father takes metformin and NMN. After about 6 months, he became more energetic, mentally aware, and began to enjoy life more.

Come What May

By engaging our bodies’ survival mechanisms in the absence of real adversity, will we push our lifespans far beyond what we can today? And what will be the best way to do this? Could it be a souped-up AMPK activator? A TOR inhibitor? A STAC or NAD booster? Or a combination of them with intermittent fasting and high-intensity interval training? 

6. Big Steps Ahead

A very short telomere will lose its histone packaging and the DNA at the end of the chromosome becomes exposed. The cell detects the DNA end and thinks it’s a DNA break. It goes to work to try to repair the DNA end, sometimes fusing two ends of different chromosomes together, which leads to hypergenome instability as chromosomes are shredded during cell division and fused again, over and over, potentially becoming a cancer.

The other, safer solution to a short telomere is to shut the cell down. He believes this happens by permanently engaging the survival circuit. The exposed telomere, seen as a DNA break, causes epigenetic factors such as the sirtuins to leave their posts permanently in an attempt to repair the damage, but there is no other DNA end to ligate it to. This shuts cell replication down, similar to the way that broken DNA in old yeast distracts Sir2 from the mating genes and shuts down fertility.

Small numbers of senescent cells can cause widespread havoc. Even though they stop dividing, they continue to release cytokines that cause inflammation and attract immune cells called macrophages that then attack the tissue. Being chronically inflamed is unhealthy: just ask someone with multiple sclerosis, inflammatory bowel disease, or psoriasis. Inflammation is also a driving force in heart disease, diabetes, and dementia. It is so central to the development of age-related diseases that scientists often refer to the process as “inflammaging.” And cytokines also cause other cells to become zombie cells. When this happens, they can even stimulate surrounding cells to become a tumor and spread.

In animal models of disease, killing of senescent cells makes fibrotic lungs more pliable, slows the progression of glaucoma and osteoarthritis, and reduces the size of all sorts of tumors.

If DNA breaks happen too frequently or they overwhelm the circuit, human cells will stop dividing, then sit there in a panic, trying to repair the damage, messing up their epigenome, and secreting cytokines. This is the final stage of cellular aging. Cellular senescence would have been evolutionarily beneficial while young (and while the life expectancy was 50), preventing damaged cells from replicating, but not so much in old age.

Senolytics such as quercetin (in capers, kale, and red onion) and a drug called dasatinib may prove to be useful at killing them off.

The Hitchhiker’s Guide

LINE-1 retrotransposons, and their fossil remnants, make up about half of the human genome, what is often referred to as “junk DNA.” In young cells, these ancient “mobile DNA elements,” also known as retrotransposons, are prevented by chromatin from jumping out of the genome, then breaking DNA to reinsert themselves elsewhere. They have shown that LINE-1 genes are bundled up and rendered silent by sirtuins. But as mice age, and possibly us as well, these sirtuins become scattered all over the genome, having been recruited away to repair DNA breaks elsewhere, and many of them never find their way home. This loss is exacerbated by a drop in NAD levels. Without sirtuins to spool the chromatin and silence the transposon DNA, cells start to transcribe these endogenous viruses.

Over time, as mice age, the once silent LINE-1 prisoners are turned into RNA and the RNA is turned into DNA, which is reinserted into the genome at a different place. Besides creating genome instability and epigenomic noise that causes inflammation, LINE-1 DNA leaks from the nucleus into the cytoplasm, where it is recognized as a foreign invader. In response, the cells release even more immunostimulatory cytokines that cause inflammation throughout the body.

It may turn out that, as NAD levels decline with age, sirtuins are rendered unable to silence retrotransposon DNA. Perhaps one day, safe antiretroviral drugs or NAD boosters will be used to keep these jumping genes silent.

Vax to the Future

In 2018, scientists at Stanford University reported that they had developed an inoculation that significantly lowered the rates at which mice suffered from breast, lung, and skin cancer. By injecting the mice with stem cells inactivated by radiation and later adding a booster shot like those humans use for tetanus, hepatitis B, and whooping cough, the stem cells primed the immune system to attack cancers that normally would be invisible to the immune system. Other immuno-oncological approaches are making even greater strides. Therapies such as PD-1 and PD-L1 inhibitors, which expose cancer cells so they can be killed, and chimeric antigen receptors T-cell (CAR-T) therapies, which modify the patient’s own immune T-cells and reinject them to go kill cancer cells, are saving lives.

If we can use the immune system to kill cancer cells, it stands to reason that we can do that for senescent cells, too. Judith Campisi from the Buck Institute for Research on Aging and Manuel Serrano from Barcelona University believe that senescent cells, like cancers, remain invisible to the immune system by waving little protein signs that say, “No zombie cells here.”

Get With the Reprogram

Vaccines against senescent cells, CR mimetics, and retrotransposon suppressors are possible pathways to prolonged vitality, and work is under way already in labs and clinics around the world.

In Shannon’s drawing, there are three different components that have analogs in biology:

• The “source” of the information is the egg and sperm, from your parents.
• The “transmitter” is the epigenome, transmitting analog information through space and time.
• The “receiver” is your body in the future.

To end aging as we know it, we need to find three more things that Shannon knew were essential for a signal to be restored even if it is obscured by noise:

• An “observer” who records the original data
• The original “correction data”
• And a “correcting device” to restore the original signal

Shinya Yamanaka discovered that a set of four—Oct4, Klf4, Sox2, and c-Myc (Yamanaka factors)—could induce adult cells to become pluripotent stem cells, or iPSCs, which are immature cells that can be coaxed into becoming any other cell type. These four genes code for powerful transcription factors that each controls entire sets of other genes that move cells around on the Waddington landscape during embryonic development.

At age 30, you would get a week’s course of three injections that introduce a specially engineered adeno-associated virus, or AAV, which causes a very mild immune response. What this theoretical version of the virus would carry would be a small number of genes—some combination of Yamanaka factors, perhaps—and a fail-safe switch that could be turned on with a well-tolerated molecule such as doxycycline, an antibiotic that can be taken as a tablet, or, even better, one that’s completely inert.

Nothing, at that point, would change in the way your genes work. But when you began to see and feel the effects of aging, likely sometime in your mid-40s, you would be prescribed a month’s course of doxycycline. With that, the reprogramming genes would be switched on.

During the process, you’d likely place a drop of blood in a home biotracker or pay a visit to the doctor to make sure the system was working as expected. Over the next month, your body would undergo a rejuvenation process. Gray hair would disappear. Wounds would heal faster. Wrinkles would fade. Organs would regenerate. You would think faster, hear higher-pitched sounds, and no longer need glasses to read a menu. 

In a now-famous study from 2016, when Belmonte triggered the Yamanaka factors for just two days a week throughout the lifespan of a prematurely aging mouse breed called LMNA, the mice remained young compared to their untreated siblings and lived 40% longer. He’s shown that the skin and kidneys of regular old mice heal more quickly, too.

However, the Yamanaka treatment was highly toxic. If Belmonte overdid it by giving the mice the antibiotic for a few more days, the mice died. Serrano had also shown that the four-gene combo could induce teratomas.

Epigenetic reprogramming regrows optic nerves and restores eyesight in old mice. The Information Theory of Aging predicts that it is a loss of epigenetic rather than genetic information in the form of mutations. By infecting mice with reprogramming genes called Oct4, Sox2, and Klf4, the age of cells is reversed by the TET enzymes, which remove just the right methyl tags on DNA, reversing the clock of aging and allowing the cells to survive and grow like a newborn’s. How the enzymes know which tags are the youthful ones is a mystery. Solving that mystery would be the equivalent of finding Claude Shannon’s “observer,” the person who holds the original data.

When the DNA of the damaged neurons was examined, they seemed to be going through a very rapid aging program, one that was countered by the reprogramming factors. The neurons that received the reprogramming factors didn’t age, and they didn’t die. This is a radical idea but one that makes a lot of sense: severe cellular injury overwhelms the survival circuit and accelerates aging of the cell, leading to death, unless the clock is somehow reversed.

The biological information correcting device requires enzymes called ten-eleven translocation enzymes (TETs), which clip off methyl tags from DNA, the same chemical tags that mark the passage of the Horvath aging clock. This points to the DNA methylation clock as not just an indicator of age but a controller of it.

The TETs cannot just strip off all the methyls from the genome, for that would turn a cell into a primordial stem cell. We would not have old mice that can see better: we would have blind mice with tumors. How the TETs know to remove only the more recent methyls while preserving the original ones is a complete mystery.

Natural molecules stimulate the TET enzymes, including vitamin C and alphaketoglutarate, a molecule made in mitochondria that is boosted by CR and, when given to nematode worms, extends their lifespan, too.

7. The Age of Innovation

CAR T-cell therapy, in which doctors remove immune system cells from a patient’s blood and add a gene that allows the cells to bind to proteins on the patient’s tumor. Grown en masse in a lab and then reinfused into the patient’s body, the CAR T-cells go to work, hunting down cancer cells and killing them by using the body’s own defenses.

Checkpoint blockade therapy, quashes the ability of cancerous cells to evade detection by our immune systems. In this approach, drugs are used to block the ability of cancer cells to present themselves as regular cells, making it easier for T-cells to discriminate between friend and foe. This is the approach that was used, along with radiation therapy, by former president Jimmy Carter’s doctors to help his immune system fight off the melanoma in his brain and liver.

We can take single cells from a slice of a tumor, read every letter of the DNA in those cells, and look at the cells’ three-dimensional chromatin architecture. In doing so, we can see the ages of different parts of the tumor. We can see how it has grown, how it has continued to mutate, and how it has lost its identity over time. That’s important, because if you look at only one part of a tumor you could be missing the most aggressive part.

Through sequencing, we can even see what kinds of bacteria have managed to make their way into a tumor. Bacteria, it turns out, can protect tumors from anticancer drugs. Using genomics, we can identify which bacteria are present and predict which antibiotics will work against those single-celled tumor protectors.

Knowing Thyself

For most of medical history, our treatments and therapies have been based on what was best for males, thus hindering healthy clinical outcomes for females. 

Treatments that work through insulin or mTOR signaling typically favor females, whereas chemical therapies typically favor males, and no one really knows why.

For more than two hundred years, the drug digoxin from the digitalis family of plants has been used in small doses by doctors to treat failing hearts. Even under a doctor’s supervision, your chance of death if you are on digoxin increases by 29%, according to one study. His mother was particularly sensitive and it was accumulating in her heart.

The problem with healthcare isn’t how we pay for care; the problem is that we’ve set up doctors as the only conduits to diagnosis and often, in the case of primary care physicians, as the only people who can refer a patient to a specialist.

Soon, we will no longer have to wait for tumors to grow so big and so heterogeneously mutated that their spread is no longer controllable. With a simple blood test, doctors will be able to scan for circulating cell-free DNA, or cfDNA, and diagnose cancers that would be impossible to spot without the aid of computer algorithms optimized by machine learning processes trained on thousands of cancer patient samples. These circulating genetic clues will tell you not just if you have cancer but what kind of cancer you have and how to kill it. They will even tell you where in your body an otherwise undetectable tumor is growing, since the genetic (and epigenetic) signatures of tumors in one part of the body can be vastly different from those from other parts.

Moving Faster

Left untreated, Borrelia hides out in skin cells and lymph nodes, causing facial paralysis, heart problems, nerve pain, memory loss, and arthritis. It hides in a protective biofilm, making it extremely difficult to kill.

In Cambridge, Massachusetts, and Menlo Park, California, he’s helped gather infectious disease doctors, microbiologists, geneticists, mathematicians, and software engineers—to develop tests that can rapidly and unambiguously tell physicians what an infection is and how best to kill it, using “high-throughput sequencing.” The first step in this process is the extraction of nucleic acids from blood samples, saliva, feces, or spinal fluid. Because it adds cost and reduces sensitivity, the patient’s DNA is removed using innovative methods honed by the same scientists who extract ancient DNA from mummies—one of countless cases of one field of science benefiting another. Next, the samples are processed through agnostic DNA-sequencing technologies, meaning that the system is not looking for any one specific infectious agent but rather reading the genomes in the entire sample. That list is then scanned against a database of all known human pathogens at the strain level. The computer spits out a highly detailed report about what invaders are present and how best to kill them. The tests are as accurate as the standard ones, but they provide strain-level information and are pathogen agnostic. In other words, soon doctors won’t have to guess what to look for when ordering a test or what treatment will work best. They will know.

The Organ Grind

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. And because there won’t be competition for these organs, we won’t have to wait for things to go catastrophically wrong for someone else to get one—we’ll only have to wait for the printer to do its job.

Part III: Where We’re Going (The Future)

8. The Shape of Things to Come

The Hundred Years’ Warning

Our ancestors bred as fast as biology allowed, which was only slightly faster than the death rate. Humanity endured and scattered to all ends of the planet. It wasn’t until right around the time Christopher Columbus rediscovered the New World that we reached the 500-million-individuals mark, but it took just three hundred more years for that population to double. And today, with each new human life, our planet becomes more crowded, hurtling us toward, or perhaps further beyond, what it can sustain.

The Hundred-Year Politician

“Virtually every country in the world,” the United Nations reported in 2015, “is experiencing growth in the number and proportion of older persons in their population.” Europe and North America already have the largest per capita share of older persons; by 2030, according to the report, those over the age of 60 will account for more than a quarter of the population on both of these continents, and that proportion will continue to grow for decades to come.

Politicians seem opposed to stepping down in their 70s and 80s. More than half of the US senators running for reelection in 2018 were 65 or older. On average, members of the US Congress are 20 years older than their constituents.

We tend to tolerate a bit of bigotry among older people as a condition of the “age in which they grew up,” but perhaps also because we know we won’t have to live with it for long. Consider, though, a world in which people in their 60s will be voting not for another twenty or thirty years but for another sixty or seventy.

Social Insecurity

Individuals who make it to the age of 65 can count on about twenty more years of life. And as just about every social insurance doomsdayer can tell you, the ratio of workers to beneficiaries is an unsustainable three to one.

But by the 1980s, politicians on both sides of the political aisle had taken to calling Social Security the “third rail” of American politics: “Touch it, you’re dead.” At that time 15%of Americans were collecting Social Security. Today about 20% are. Today, people over the age of 65 make up 20 percent of the voting population and will grow by 60 percent by 2060, in addition to which they are about twice as likely as 18- to 29-year-olds to go to the polls.

What Divides Us Grows Greater

Most countries tax people when they die as a way to limit wealth accumulation over generations, but in the United States estate taxes weren’t initially designed to limit multigenerational wealth; they were imposed to finance wars. In 1797, a federal tax was imposed to build a navy to fend off a possible French invasion; in 1862, an inheritance tax was instituted to finance the Civil War. The 1916 estate tax, which was similar to present-day estate taxes, helped pay for World War I.

Thanks to tax loopholes, the percentage of rich American families who pay what were cleverly branded as “death taxes” decreased fivefold, providing the lowest cost for “dying rich” in modern times.

Unless aging is designated a medical condition, initially only the wealthy will be able to afford many of these advances. The same will be true for the most advanced biotracking, DNA sequencing, and epigenome analyses to permit truly personalized health care.

People, People, Glorious People

After our species was almost driven to extinction 74,000 years ago, up until 1900, the human population grew at a rate amounting to a fraction of a percent each year as we expanded to all habitable regions on the planet, breeding with at least two other human species or subspecies. By 1930, thanks to sanitation and decreases in child-mother mortality, our species was increasing its numbers at 1% each year. And by 1970, due to immunization and improvements in food production globally, the rate was 2% each year.

Over the past few decades, however, the rate of human population growth has been falling steadily—principally as women who have better economic and social opportunities, not to mention basic human rights, choose to have fewer children. Until the late 1960s, each woman on the planet had an average of more than five children.

By 2100, some researchers believe, the growth rate could fall as low as one-tenth of 1%. As this happens, United Nations demographers anticipate that our total global population will plateau, reaching about 11 billion people by the year 2100, then stop and drop from there.

In 1800, the global literacy rate was 12%, by 1900 it was 21%, and today it’s 85%.

The Long Race

Old people were revered in traditional cultures as sources of wisdom. Before written text, and long before the advent of digital information, elders were our only wellsprings of knowledge. That began to change when Johannes Gutenberg developed a press that led to the Printing Revolution. The subsequent Education Revolution, in the nineteenth and twentieth centuries, led to rates of literacy that grew to meet the availability of information. Elders were no longer the only sources of long-held information. Rather than being seen as an essential asset to a functioning society, the elderly came to be viewed as a burden.

A lot of people worry that young workers will be “crowded out” of jobs if no one ever retires. However, countries stagnate because they don’t innovate and don’t utilize their human capital, not because there aren’t enough jobs. This explains why countries with an earlier retirement age have a lower GDP.

The best way to create jobs for productive people of any age, even less skilled workers, is to build and attract companies that hire highly skilled ones. 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.

Unleashing the Army

Animal studies in his lab indicate that the window of female fertility could be extended by up to a decade. In the United States, 43% of women step away from their careers for a period of time, almost always to shoulder the burden of child rearing. Many never return to work. As a woman’s lifespan and fertility lengthens, the consequences of taking a break will be seen as relatively minor. By this century’s end, we will almost certainly look back with sadness at the world we currently inhabit, in which so many people, particularly women, are forced to choose between parenting and career success.

Many people in their 70s and 80s will reenter the workforce to do something they’ve always wanted to do, earning more than they ever did, or serving their communities as volunteers and helping raise their grandkids.

With the money saved by preventing expensive medical care, a retraining fellowship could be provided for a few years to allow people over 70 to go back to school and start the career they always wished they’d started but didn’t because they made the wrong decisions or life simply got into the way.

The Greatest of These

Perhaps when we’re not all so afraid of the ticking clock, we’ll slow down, we’ll take a breath, we’ll be stoic Samaritans.

When those years do come, how do we wish to spend them? Will we follow the perilous path that ultimately leads to a dystopian doom? Will we band together to create a world that exceeds our wildest utopian dreams?

9. A Path Forward

The evidence of the effectiveness of AMPK activators, TOR inhibitors, and sirtuin activators is deep and wide. On top of what we already know about metformin, NAD boosters, rapalogs, and senolytics, every day the odds increase that even more effective molecule or gene therapy will be discovered, as brilliant researchers around the world join the global fight to treat aging, the mother of all diseases.

All of that comes on top of the other innovations that are on track to further lengthen our lives and strengthen our health, such as senolytics and cellular reprogramming. Add to that the power of truly personalized care to keep our bodies running, prevent disease, and get ahead of problems that could be troublesome down the road. That’s not to mention the very easy steps we can all take right now to engage our longevity genes in ways that will provide us with more good years.

Invest Public Money to Tackle Aging, Now

It’s worth drilling down into the NIH budget to see which of the 285 diseases that are being researched get the most attention:

• Heart disease gets $1.7 billion for a disease that affects 11.7 percent of the population.
• Cancer gets $6.3 billion to impact 8.7 percent.
• Alzheimer’s disease gets $3 billion for a disease that impacts 3 percent—at most.

There are several ways to speed innovation to find and develop medicines and technologies that prolong healthy lifespan, but the easiest is also the simplest: define aging as a disease.

It’s Time to Insist on the Right to Be Treated

The quality of our medical care should not be predicated on age or income. A 90-year-old and a 30-year-old should be treated with the same enthusiasm and support.

Society should debate whether longevity medicines that don’t keep us healthier should ever be approved. If they were to be allowed, there would be even more elderly people with disease and disability, and, according to Goldman, health care spending in thirty years’ time would be 70 percent higher.

Australia now has reciprocal agreements with the United Kingdom, Sweden, the Netherlands, Belgium, Finland, Italy, Ireland, New Zealand, Malta, Norway, and Slovenia, which means that citizens from those countries can receive the same medical care in Australia as they can at home, and vice versa. Imagine an entire world like that.

We Should Be Able to Die Whenever We Want To

Heart disease at 50. Cancer at 55. Stroke at 60. Younger-onset Alzheimer’s at 65. Way too frequently, what is said at funerals is that someone left this life “way too early.” Or the diseases don’t kill, and the fight to beat them back again and again is a decades-long exercise in suffering.

It turns out that most people aren’t afraid of losing their lives; they are afraid of losing their humanity.

We Must Address Consumption with Innovation

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.”

Technology is already driving a global process of “dematerialization” that has replaced billions of tons of goods with digital products and human services. Thus, it is that wall-to-wall shelves dedicated to records and compact discs have been replaced by streaming music services; people who once needed vehicles for once-in-a-while travel now open an app on their phones to request a ride share; and entire wings of hospitals once used for storing patients’ records have been supplanted by handheld cloud-connected tablet computers.

There is nothing wrong with skepticism, but after thousands of studies, the evidence is irrefutable: if you believe climate change is a threat, you can’t say that GMOs are, because the evidence that GMOs are safe is stronger than the evidence that climate change is occurring.

Cas9, and now dozens of other DNA-editing enzymes from other bacteria, can alter plant genes with accuracy, without using any foreign DNA. They can create exactly the same kind of alterations that occur naturally. Using CRISPR is far more “natural” than bombarding seeds with radiation, a treatment that is not banned.

Longer, healthier lives will do us little good if we consume ourselves into oblivion. The imperative is clear: whether or not we increase human longevity, our survival depends on consuming less, innovating more, and bringing balance to our relationship with the bounty of our natural world.

We Need to Rethink the Way We Work

Skillbaticals, which might take the shape of a government-supported paid year off for every ten worked, might ultimately become cultural and even legal requisites, just as many of the labor innovations of the twentieth century have. In this way, those who are tired of “working harder” would be afforded every opportunity to “work smarter” by returning to school or a vocational training program paid for by employers or the government, a variation of the universal basic income that is being discussed in the United States and some countries in Europe.

Meanwhile, those who believe they are happy and secure in their careers can enjoy what has come to be known as “a mini-retirement”—a year off to travel, learn a language or musical instrument, volunteer, or refresh and reconsider the ways in which they are spending their lives.

We Need to Get Ready to Meet Our Great-Great-Grandkids

We will be accountable—in this life—for the decisions we made in the past that will impact the future. We will have to look our family members, friends, and neighbors in the eye and account for the way we lived before they came along.

We’re no longer going to be able to wait for prejudiced people to die; we’re going to have to confront them and work to change their minds. We can’t just allow the Anthropocene extinction to continue, we need to slow it dramatically and stop it altogether.

To build the next century, we’re going to have to figure out where everyone is going to live, how they are going to live, under what rules they are going to live. We’re going to have to ensure that the vast social and economic dividends we receive from prolonging people’s lives are spent wisely. We’re going to have to be more empathetic, more compassionate, more forgiving, and more just.

Conclusion

What Does David Do?

Not medical advice.

• 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into homemade yogurt) and 1 gram of metformin.
• A daily dose of vitamin D, vitamin K2, and 83 mg of aspirin.
• He tries to keep his sugar, bread, and pasta intake as low as possible. He gave up desserts at age 40.
• He tries to skip one meal a day or at least make it really small.
• Every few months, a phlebotomist comes to his home to draw blood, which he has analyzed for dozens of biomarkers. When his levels of various markers are not optimal, he moderates them with food or exercise.
• He tries to take a lot of steps each day and walk upstairs, and he goes to the gym most weekends with his son; they lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool.
• He eats a lot of plants and tries to avoid eating other mammals, even though they do taste good. If he works out, he will eat meat.
• He doesn’t smoke. He tries to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans.
• He tries to stay on the cool side during the day and when he sleeps at night.
• He aims to keep his body weight or BMI in the optimal range for health-span (23 to 25).

Supplements are far less regulated than medicines, so if he takes a supplement, he looks for a large manufacturer with a good reputation, seek highly pure molecules (more than 98 percent is a good guide), and look for “GMP” on the label, which means the product was made under “good manufacturing practices.” Nicotinamide riboside, or NR, is converted to NMN, so some people take NR instead of NMN because it is cheaper. Cheaper still are niacin and nicotinamide, but they don’t seem to raise NAD levels as NMN and NR do.

Some people have suggested NAD boosters could be taken with a compound that provides cells with methyl groups, such as trimethylglycine, also known as betaine or methylfolate. Conceptually, this makes sense—the “N” in NR and NMN stands for nicotinamide, a version of vitamin B3 that the body methylates and excretes in urine when it is in excess, potentially depleting cells of methyls—but this remains a theory.