Lifespan

Now consider instead that you are a bird of prey at the top of the food chain. Because of this, your genes—well, actually, your ancestors’ genes—benefited from building a robust, longer-lasting body that could breed for decades. But in return, they could afford to raise only a couple of fledglings a year. Kirkwood’s hypothesis explains why a mouse lives 3 years while some birds can live to 100.5 (Location 397)

Denham Harman, a chemist at Shell Oil, was also thinking atomically, albeit in a different way. After taking time off to finish medical school at Stanford University, he 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.12 Harman spent the better part of his life testing the theory. I had the pleasure of meeting the Harman family in 2013. His wife told me that Professor Harman had been taking high doses of alpha-lipoic acid for most of his life to quench free radicals. Considering that he worked tirelessly on his research well into his 90s, I suppose, at the very least, it didn’t hurt. (Location 437)

Yet I believe that such an answer exists—a cause of aging that exists upstream of all the hallmarks. Yes, a singular reason why we age. Aging, quite simply, is a loss of information. (Location 520)

But there are two types of information in biology, and they are encoded entirely differently. The first type of information—the type my esteemed predecessors understood—is digital. Digital information, as you likely know, is based on a finite set of possible values—in this instance, not in base 2 or binary, coded as 0s and 1s, but the sort that is quaternary or base 4, coded as adenine, thymine, cytosine, and guanine, the nucleotides A, T, C, G of DNA. Because DNA is digital, it is a reliable way to store and copy information. Indeed, it can be copied again and again with tremendous accuracy, no different in principle from digital information stored in computer memory or on a DVD. DNA is also robust. When I first worked in a lab, I was shocked by how this “molecule of life” could survive for hours in boiling water and thrilled that it was recoverable from Neanderthal remains at least 40,000 years old.23 The advantages of digital storage explain why chains of nucleic acids have remained the go-to biological storage molecule for the past 4 billion years. The other type of information in the body is analog. We don’t hear as much about analog information in the body. That’s in part because it’s newer to science, and in part because it’s rarely described in terms of information, even though that’s how it was first described when geneticists noticed strange nongenetic effects in plants they were breeding. Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means. (Location 523)

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. (Location 548)

and even change them altogether. The longevity genes I work on are called “sirtuins,” named after the yeast SIR2 gene, the first one to be discovered. There are seven sirtuins in mammals, SIRT1 to SIRT7, and they are made by almost every cell in the body. When I started my research, sirtuins were barely on the scientific radar. Now this family of genes is at the forefront of medical research and drug development. (Location 584)

Up close, the epigenome is more complex and wonderful than anything we humans have invented. It consists of strands of DNA wrapped around spooling proteins called histones, which are bound up into bigger loops called chromatin, which are bound up into even bigger loops called chromosomes. 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.12 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. Every one of our cells has the same DNA, of course, so what differentiates a nerve cell from a skin cell is the epigenome, the collective term for the control systems and cellular structures that tell the cell which genes should be turned on and which should remain off. And this, far more than our genes, is what actually controls much of our lives. (Location 768)

Studies of identical twins place the genetic influences on longevity at between 10 and 25 percent which, by any estimation, is surprisingly low. (Location 796)

one universal model of life and death. It looked like this: Youth → broken DNA → genome instability → disruption of DNA packaging and gene regulation (the epigenome) → loss of cell identity → cellular senescence → disease → death. (Location 843)

CR 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.11 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. (Location 1616)

Note: Perfect timing for my health push

Hot dogs, sausage, ham, and bacon might be gloriously delicious, but they’re ingloriously carcinogenic, according to hundreds of studies that have demonstrated a link between these foods and colorectal, pancreatic, and prostate cancer.20 Red meat also contains carnitine, which gut bacteria convert to trimethylamine N-oxide, or TMAO, a chemical that is suspected of causing heart disease. (Location 1696)

Low levels of these amino acids correlate with increased lifespan26 and in human studies, a decreased consumption of branched-chain amino acids has been shown to improve markers of metabolic health significantly. (Location 1722)

The DNA in our cells holds about the same amount of data as a DVD, but in six feet of DNA that’s packed into a cell a tenth the size of a speck of dust. Together, all the DNA in our body, if laid end to end, would stretch twice the diameter of the solar system. (Location 2599)

As Shannon brilliantly showed in his “noisy-channel coding theorem,” it is possible to communicate information nearly error free as long as you don’t exceed the channel capacity. But if the data exceeds the channel capacity or is subject to noise, which is often the case with analog data, the best way to ensure it makes it to the receiver is to store a backup set of data. That way, even if some primary data are lost, an “observer” can send this “correcting data” to a “correcting device” to recover the original message. This is how the internet works. If data packets are lost, they are recovered and resent moments later, all thanks to Transmission Control Protocol/Internet Protocol (TCP/IP). As Shannon put it, “This observer notes the errors in the recovered message and transmits data to the receiving point over a ‘correction channel’ to enable the receiver to correct the errors.” Though it may sound like esoteric language from the 1940s, what dawned on me in 2014 is that Shannon’s “A Mathematical Theory of Communication” is relevant to the Information Theory of Aging. 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. (Location 2628)

I predict that cellular reprogramming in the body will first be used to treat age-related diseases in the eye, such as glaucoma and macular degeneration (the eye is the organ of choice to trial gene therapies because it is immunologically isolated). But if the therapy is safe enough to deliver into the entire body—as the long-term mouse studies in my lab suggest they might one day be—this may be in our future: 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, less even than what is commonly caused by a flu shot. The virus, which has been known to scientists since the 1960s, has been modified so it doesn’t spread or cause illness. 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, but that’s about it. Over the next month, your body would undergo a rejuvenation process as Waddington’s marbles were sent back to where they once were when you were young. 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. Your body would feel young again. Like Benjamin Button, you would f...

...eel 35 again. Then 30. Then 25. But unlike Benjamin Button, that’s where you would stop. The prescription would be discontinued. The AAV would switch off. The Yamanaka factors would fall silent. Biologically, physically, and mentally, you would be a couple of decades younger, but you’d retain all your knowledge, wisdom, and memories. (Location 2671)

If you were a member of the American upper middle class in the 1970s, you weren’t just enjoying a more affluent life, you had a longer one, too. Those in the top half of the economy were living an average of 1.2 more years than those in the bottom half. By the early 2000s, the difference had increased dramatically. Those in the upper half of the income spectrum could expect nearly six additional years of life, and by 2018, the divide had widened, with the richest 10 percent of Americans living thirteen more years of life than the poorest 10 percent.40 (Location 3630)