Lifespan: The Revolutionary Science of Why We Age—and Why We Don't Have To

by David A. Sinclair

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. This makes sense, because while DNA is broken, sex and reproduction are the last things an organism should be doing.

It is superprimed for survival.

THE EVOLUTION OF AGING. A 4-billion-year-old gene circuit in the first life-forms would have turned off reproduction while DNA was being repaired, providing a survival advantage. Gene A turns off reproduction, and gene B makes a protein that turns off gene A when it is safe to reproduce. When DNA breaks, however, the protein made by gene B leaves to go repair DNA. As a result, gene A is turned on to halt reproduction until repair is complete. We have inherited an advanced version of this survival circuit.

But there is a trade-off. For this circuit within us, the descendant of a series of mutations in our most distant ancestors, is also the reason we age. And yes, that definite singular article is correct: it is the reason.

Eventually, the forces of natural selection hit zero. The genes get to move on. We don’t.

genes. And because all species are resource limited, they have evolved to allocate the available energy either to reproduction or to longevity, but not to both.

one, literally overcoming what evolution failed to provide.

Wilbur and Orville Wright could never have built a flying machine without a knowledge of airflow and negative pressure and a wind tunnel. Nor could the United States have put men on the moon without an understanding of metallurgy, liquid combustion, computers, and some measure of confidence that the moon is not made of green cheese.

The idea that mutation accumulation causes aging was embraced by scientists and the public alike in the 1950s and 1960s, at a time when the effects of radiation on human DNA were on a lot of people’s minds. But although we know with great certainty that radiation can cause all sorts of problems in our cells, it causes only a subset of the signs and symptoms we observe during aging,10 so it cannot serve as a universal theory.

In 1963, the British biologist Leslie Orgel threw his hat into the ring with his “Error Catastrophe Hypothesis,” which postulated that mistakes made during the DNA-copying process lead 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.11

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

longevity. 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.

Mitochondrial decline is certainly a hallmark of aging and can lead to organ dysfunction. But mutations alone, especially mutations in the nuclear genome, conflict with an ever-increasing amount of evidence to the contrary.

Arlan Richardson and Holly Van Remmen spent about a decade at the University of Texas at San Antonio testing if increasing free-radical damage or mutations in mice led to aging; it didn’t.

surprisingly simple to restore the function of mitochondria in old mice, indicating that a large part of aging is not due to mutations in mitochondrial DNA,...

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.

unlikely. The simplest explanation is that old animals retain all the requisite genetic information to generate an entirely new, healthy animal and that mutations are not the primary cause of aging.22

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

Researchers began to cautiously agree: address these hallmarks, and you can slow down aging. Slow down aging, and you can forestall disease. Forestall disease, and you can push back death.

Aging, quite simply, is a loss of information.

Szilard and Medawar independently espoused, but it was wrong because it focused on a loss of genetic information.

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.

The other type of information in the body is analog.

Today, analog information is more commonly referred to as the epigenome, meaning traits that are heritable that aren’t transmitted by genetic means.

epigenetics has expanded into other areas of biology that have less to do with heredity—including embryonic development, gene switch networks, and chemical modifications of DNA-packaging proteins—much to the chagrin of orthodox geneticists in my department at Harvard Medical School.

In the same way that genetic information is stored as DNA, epigenetic information is stored in a structure called chromatin.

Epigenetic information is what orchestrates the assembly of a human newborn made up of 26 billion cells from a single fertilized egg and what allows the genetically identical cells in our bodies to assume thousands of different modalities.24

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.

Without epigenetic information, cells would quickly lose their identity and new cells would lose their identity, too. If they did, tissues and organs would eventually become less and less functional until they failed.

But we can usually recover information from a scratched DVD. And if I am right, the same kind of process is what it will take to reverse aging.

As cloning beautifully 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. This, I believe, is possible.

Together, these genes form a surveillance network within our bodies, communicating with one another between cells and between 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.

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.

They have also evolved to require a molecule called nicotinamide adenine dinucleotide, or NAD. As we will see later, the loss of NAD as we age, and the resulting decline in sirtuin activity, is thought to be a primary reason our bodies develop diseases when we are old but not when we are young.

Sirtuins aren’t the only longevity genes. Two other very well studied sets of genes perform similar roles, which also have been proven to be manipulable in ways that can offer longer and healthier lives. One of these is called target of rapamycin, or TOR, a complex of proteins that regulates growth and metabolism.

mTOR activity is exquisitely regulated by nutrients.

mTOR can signal cells in stress to hunker down and improve survival by boosting such activities as DNA repair, reducing inflammation caused by senescent cells, and, perhaps its most important function, digesting old proteins.27

It senses the amount of amino acids that is available and dictates how much protein is created in response.

sort of like going to the junkyard to find parts with which to fix up an old car rather than buying a new one, a process called 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 and, as with sirtuins and TOR, we have learned a lot about how to control it.

These defense systems are all activated in response to biological stress.

Acute trauma and uncontrollable infections will kill an organism without aging that organism. Sometimes the stress inside a cell, such as a multitude of DNA breaks, is too much to handle. Even if the cell is able to repair the breaks in the short term without leaving mutations, there is information loss at the epigenetic level.

Here’s the important point: 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 h...

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.

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 (I discuss this in chapter 5).

The parts of the genome that were missing, generally overlapping sections of repetitive nucleotides, were just not considered important. These were areas of the code of life that were once derided as “junk DNA” and that are now a little better respected but still generally disregarded as “noncoding.” From the perspective of many of the best minds in science at the time, those regions were little more than the ghosts of genomes past, mostly remnants of dead hitchhiking viruses that had integrated into the genome hundreds of thousands of years ago. The stuff that makes us who we are, it was thought, had largely been identified, and we had what we needed to propel forward our understanding of what makes us human. Yet by some estimates, that genetic dark matter accounts for as much as 69 percent of the total genome,1 and even within the regions generally regarded as “coding,” some scientists believe, up to 10 percent has yet to be decoded, including regions that impact aging.

the original algorithms to detect genes were written to disregard any gene less than 300 base pairs long. In fact, genes can be as short as 21 base pairs, and today we’re discovering hundreds of them all over the genome.

Even once we have a complete code, though, there’s something we still won’t be able to find. We won’t be able to find an aging gene.

We have found genes that impact the symptoms of aging.