Lifespan Summary (8/10)

In Lifespan, Sinclair insists that aging is not a law of nature but a choice. There doesn’t have to be an upward limit to the human lifespan.

Why do we Age?

In any case, why do we age? If you don’t know, that’s okay. Many biologists don’t either. Doctors who specialize in aging (gerontologists) often don’t ask why we age but seek to treat the consequences.

It’s not just aging. In the 1960’s, even the fight against cancer was a fight against its symptoms. Until the second half of the twentieth century, it was accepted that organisms grow old and die for the benefit of species, an idea that dates back to Aristotle. Even modern people such as Elon Musk argue that old age hinders creative thinking and progress, and that death occurs for the good of humanity.

But Sinclair thinks this idea is totally false.

When it comes to longevity, individuals look out for themselves. Driven by their selfish genes, they try to breed for as long and as fast as they can – so long as it doesn’t kill them. In the 1950s, J. S. Haldane, Peter Medawar, and George C. Williams proposed important ideas about why we age. Humans, driven by their selfish genes, will press on and try to breed for as long and as fast as they can as long as it doesn’t kill them.

If our genes never want to die, why don’t we live forever? The three biologists argued that the forces of natural selection are strong when we are young but decline once we hit 40 because we’ve likely replicated our selfish genes enough to ensure their survival. Eventually, the forces of natural selection hit zero, the genes move on. We don’t.

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Disposable Soma Hypothesis

Kirkwood’s theory of evolution is that organisms 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. But a creature cannot breed fast and maintain a healthy and robust body – there isn’t enough energy to do both. Stated another way, any line of creature with a mutation that caused it to live fast soon ran out of resources and was thus deleted from the gene pool.

If you are a small prey animal, you will need to pass down your genetic material quickly. Gene combinations that promoted longevity did not stick around since your ancestors were unlikely to evade predation for long. But if you are on top of the food chain, your genes benefited from building a longer lasting body that could breed for decades. But in return, you could only afford to raise a couple of fledglings a year.

Claude Channon was an electrical engineer from MIT. He was disturbed by the problem of information loss. Having lived through the second World War, he knew that introducing “noise” into analog transmission could cost lives. After the war, he wrote a short but profound scientific paper called “The Mathematical Theory of Communication” on how to preserve information, which many consider the foundation of Information Theory.

This may be the one paper that propelled us into the digital, wireless world in which we now live. Shannon wanted to improve the robustness of electronic and radio communications between two points. More important than that, he discovered how to preserve and restore information, and Sinclair thinks this could be applied to aging.

It is unflattering to know that we may be the biological equivalent of an old DVD player, but this is good news. Information can be recovered from a scratched DVD. The same kind of process can reverse aging. Cloning proves that our cells retain their youthful digital information even when we are old. To become young again, we simply need to find polish to remove the scratches.

The Information Theory of Aging

“Longevity genes” are genes that have shown the ability to extend both average and maximum lifespans in many organisms. These genes don’t just make life longer, they make it healthier, which is why they’re called “vitality genes”. Together, these genes form a surveillance network within our bodies. They communicate with one another between cells and between organs by releasing proteins and chemicals.

Descended from gene B in M. superstes, sirtuins are enzymes that remove acetyl tags from histones and other proteins. These critical epigenetic regulators sit at the very top of cellular control systems. They have evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD.

Sirtuins prevent cell death and boost mitochondria, the power packs of the cell. Activating them can improve DNA repair, boost memory, increase exercise endurance, and keep mice thin, regardless of what they eat.

Sirtuins are turning out to be more amenable to manipulation than many other longevity genes. They are, it would appear, one of the first dominos in the magnificent Rube Goldberg machine of life. The key to understanding how our genetic material protects itself during times of adversity.

TOR, or target of rapamycin, is a gene that regulates growth and metabolism. Like sirtuins, It can signal cells in stress to hunker down and improve survival by boosting activities such as DNA repair and digesting old proteins. Two other well studied genes perform similar roles, mTOR and mTOR2, also have been proven manipulable.

Hormesis

Complementing these approaches are hormesis-mimicking molecules. Drugs in development and at least two drugs on the market can turn on the body’s defenses without creating any damage. It’s like making a prank call to the Pentagon. The troops and the Army Corps of Engineers are sent out, but there’s no war. In this way, we can mimic the benefits of exercise and intermittent fasting with a single pill.

We are now much closer to having a map of the complete sequence of our DNA. As of 2022 (after the release of this book), the human genome has been fully mapped.  But we still won’t be able to find an aging gene. We have only found genes that impact the symptoms of aging, and longevity genes that control the body’s defenses against aging and help slow aging through various interventions. But unlike the oncogenes that were discovered in the 1970s that have been useful in the battle against cancer, we haven’t found a single gene that causes aging. And we won’t. Our genes did not evolve to cause aging.

Over time, we accumulate DNA damage from the sun or an X-ray. Smoking accelerates the aging clock and makes you more likely to die than a nonsmoker (15 years earlier, on average). That is why we have fought it with legislation, taxes, and public health campaigns. We have done the same for cancer, investing billions of dollars’ worth of research. We know that aging makes you more likely to die, but we have accepted it as fate.

Consider this: 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.

Fasting

Blue Zones are areas where longevity is the highest.

There is ultimately no best diet for humans because of our differences. But we are similar enough to have commonalities. More vegies, less meat; fresh food, no processed food.

After twenty-five years of researching aging and having read thousands of scientific papers, if there is one piece of advice I can offer, one surefire way to stay healthy longer, one thing you can do to maximize your lifespan right now, it’s this: eat less.

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.

CR (caloric restriction) works to extend the lifespan of mice, even when initiated at 19 months of age, the equivalent of a 60- to 65-year-old human, 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.

If you’re interested in a long and healthy life, your diet probably needs to look a lot more like a rabbit’s lunch than a lion’s dinner. When we substitute animal protein with more plant protein, studies have shown, all-cause mortality falls significantly.

Exercise

We need to induce some physical adversity, too. If that doesn’t happen, we miss a key opportunity to trigger our survival circuits further.

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.

And according to one study funded by the Centers for Disease Control and Prevention and published in 2017, individuals who exercise more—the equivalent of at least 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.

But why would exercising delay the erosion of 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. 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, yes, extending telomeres.

Even about ten minutes of moderate exercise a day added years to their lives.35 35There is a difference between a leisurely walk and a brisk run, however. To engage our longevity genes fully, intensity does matter. 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)—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.

Cold

Cold activates longevity genes.

As with most things in life, it’s probably best to change your lifestyle when 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. Hypothermia is not good for our health. Neither is frostbite. But goose bumps, chattering teeth, and shivering arms aren’t dangerous conditions.

Heat

A more convincing study followed a group of more than 2,300 middle-aged men from eastern Finland for more than twenty years.

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. And there’s a lot of extra damage to be had out there.

Smoking

Cigarettes, for starters. There aren’t many legal vices out there that are worse for your epigenome than the deadly concoction of thousands of chemicals smokers put into their bodies every day. There’s a reason why smokers seem to age faster: they do age faster. 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. And although I’m not likely to be the first person you’ll hear this from, it nonetheless bears repeating: smoking is not a private, victimless activity.

The levels of DNA-damaging aromatic amines in cigarette smoke are about fifty to sixty times as high in secondhand as in firsthand smoke. If you do smoke, it is worth trying to quit. Don’t smoke? That’s great, but even without smoke there’s fire. In much of the developed world—and increasingly in the developing world as well—we’re practically bathing in DNA-damaging chemicals. In some places—cities with lots of people and lots of cars, especially—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.

Future Technologies

How long until we can destroy senescent cells, either by drugs or outright vaccination? How long until we can replace parts of organs, grow entire ones in genetically altered farm animals, or create them in a 3D printer? A couple of decades, perhaps. Maybe three. One or all of those innovations is coming well within the ever-increasing lifespans of most of us, though. And when that happens, how many more years will we get?

The maximum potential could be centuries, but let’s say it’s only ten years. That’s thirty-three years. At the moment, life expectancy in the developed world is a tad over 80 years. Add 33 to that. That’s 113 years, a conservative estimate of life expectancy in the future, as long as most people come along for the ride. And the advances we’ve already made are not going away That’s why, as we move faster and faster toward a Star Trek world, for every month you manage to stay alive, you gain another week of life.

Forty years from now, it could be another two weeks. Eighty years from now, another three. Things could get really interesting around the end of the century if, for every month you are alive, you live another four weeks.

Crispr

This might be the least considered societal advantage of prolonged vitality, and it might just be the greatest advantage of all. 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. The technology is colloquially known as CRISPR, for “clustered regularly interspaced short palindromic repeats,” which are the natural DNA targets of Cas9 cutting in bacteria. 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. That’s why the decision by the Court of Justice of the European Union in 2018 was so unexpected and upsetting to the United States. The court ruled in favor of Confédération Paysanne, a French agricultural union that defends the interests of small-scale farming, and eight other groups, to ban CRISPR-made foods.40The ruling defies science. It bans healthy foods that could relieve the environmental burden, increase the health of the poor, and allow Europe to cope better with global warming.

The ruling also scared developing nations away from CRISPR-modified crops; there they could make a positive impact both on people’s lives and on their land. The text of the ruling makes it clear that it was not a decision to protect consumers from the dangers of GMO; it was part of a global trade war to prevent US-patented products from entering the European Union.

What Does David Sinclair Do?

Save for “Eat fewer calories,” “Don’t sweat the small stuff,” and “Exercise,” I don’t give medical advice. I’m a researcher, not a medical doctor; it’s not my place to tell anyone what to do, and I don’t endorse supplements or other products. I don’t mind sharing what I do, though, albeit with some caveats:

This isn’t necessarily, or even likely, what you should do.

• I have no idea if this is even the right thing for me to be doing.

• While human trials are under way, there are no treatments or therapies for aging that have been through the sort of rigorous long-term clinical testing that would be needed have a more complete understanding of the wide range of potential outcomes.

Why take the risk of adverse side effects? The alternative is not pretty.

I take 1 gram (1,000 mg) of NMN every morning, along with 1 gram of resveratrol (shaken into my homemade yogurt) and 1 gram metformin.

• I take a daily dose of vitamin D, vitamin K2, and 83 mg of aspirin.

• I strive to keep my sugar, bread, and pasta intake as low as possible. I gave up desserts at age 40, though I do steal tastes. to skip one meal a day or at least make it really small. My busy schedule almost always means that I miss lunch most days of the week.

• Every few months, a phlebotomist comes to my home to draw my blood, which I have analyzed for dozens of biomarkers. When my levels of various markers are not optimal, I moderate them with food or exercise.

• I try to take a lot of steps each day and walk upstairs, and I go to the gym most weekends with my son, Ben; we lift weights, jog a bit, and hang out in the sauna before dunking in an ice-cold pool.

• I eat a lot of plants and try to avoid eating other mammals, even though they do taste good. If I work out, I will eat meat.

• I don’t smoke. I try to avoid microwaved plastic, excessive UV exposure, X-rays, and CT scans.

• I try to stay on the cool side during the day and when I sleep at night.

• I aim to keep my body weight or BMI in the optimal range for healthspan, which for me 23 to 25. About fifty times a day I’m asked about supplements. Before I answer, let me say that I never recommend supplements, I don’t test or study products, nor do I endorse them; if you see a product implying that I do, it’s certainly a scam.

Supplements are far, far less regulated than medicines, so if I do take a supplement, I look 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.”

Metformin

Metformin has been shown to extend lifespan in various organisms, including mammals (R,R).

In humans, we see that diabetics taking metformin actually live longer than healthy non-diabetics who obviously don’t take metformin (R). This was not the case for diabetics on other anti-diabetic drugs.

Taking metformin can, however, have side effects. In the short term, metformin can cause diarrhea and gastrointestinal discomfort, which often subsides after a few weeks. In the long term, metformin can reduce the uptake of vitamin B12.

Metformin probably works as a hormetic substance, meaning that it causes a little bit of damage to our cells so that our cells are put in a repair and protect modus. Metformin inhibits mitochondrial function, so the mitochondria will repair and protect themselves better.

Therefore, given exercise also “damages” the mitochondria somewhat (so that afterwards they will repair themselves, which is one of the health benefits of exercise), he does not combine metformin with exercise given that could put too much stress on the mitochondria. That is why Dr. Sinclair does not take metformin on the days he exercises.

Also, recent studies suggest that perhaps very old people should not take metformin, given metformin causes too much stress on already very old and very stressed mitochondria (R).

We wrote an article about natural alternatives for metformin here.

Furthermore, David Sinclair takes metformin in the evening, before going to bed. He says this because during the night, the body is already in a fasting state and metformin could further advance this state.

However, we would recommend taking metformin always before the largest meal (ideally 20 minutes before mealtime). This way, metformin can make the body more insulin-sensitive when it matters the most: during and in the hours after a meal, when mitochondria have to process the sugars and fats from the meal. This is also how metformin is ideally prescribed according to medical guideline.

Sources:

  • Lifespan, David Sinclair

"A gilded No is more satisfactory than a dry yes" - Gracian