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

by David A. Sinclair

The circuit begins with gene A, a caretaker that stops cells from reproducing when times are tough. This is key, because on early planet Earth, most times are tough. The circuit also has a 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.

Cell a and b

But what makes M. superstes unique is that the gene B silencer has mutated 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.

M. superstes. Second function of b

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.

Main.

It is, in essence, a primordial survival kit that diverts energy to the area of greatest need, fixing what exists in times when the stresses of the world are conspiring to wreak havoc on the genome, while permitting reproduction only when more favorable times prevail.

The circuit

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.

antioxidant diet boosts enzymes

Over the past quarter century, researchers have increasingly honed their efforts in on addressing each of these hallmarks. A broad consensus formed that this would be the best way to alleviate the pain and suffering of those who are aging. There is little doubt that the list of hallmarks, though incomplete, comprises the beginnings of a rather strong tactical manual for living longer and healthier lives. Interventions aimed at slowing any one of these hallmarks may add a few years of wellness to our lives. If we can address all of them, the reward could be vastly increased average lifespans.

The hallmarks. But it might not be enough

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

Analog - Epigenome

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

Chromatin

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.

Main.SIR2.sirtuins

Descended from gene B in M. superstes, sirtuins are enzymes that remove acetyl tags from histones and other proteins and, by doing so, change the packaging of the DNA, turning genes off and on when needed.

Gene b

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.

NAD

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.

TOR gene and AMPK

Like that of sirtuins, mTOR activity is exquisitely regulated by nutrients. And like the sirtuins, 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.

TOR

The other pathway is a metabolic control enzyme known as AMPK, which evolved to respond to low energy levels.

AMPK.low energy

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 (I discuss this in chapter 4). That’s called hormesis.

Main.measures

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 (I discuss this in chapter 4). That’s called hormesis.

Hormesis.exercises

As they age, much like humans, 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. That makes them a pretty good place to start in the quest to understand aging.

Yeast experiment

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.

Control

Epigenetic noise causes the same kind of chaos. It is driven in large part by highly disruptive insults to the cell, such as broken DNA, as it was in the original survival circuit of M. superstes and in the old yeast cells that lost their fertility. And this, according to the Information Theory of Aging, is why we age. It’s why our hair grays.

The basic reason

The rDNA was in a state of chaos. The genome, it seemed, was fragmenting. DNA was recombining and amplifying, showing up on the Southern blot as dark spots and wispy circles, depending on how coiled up and twisted they were. We called those loops extrachromosomal ribosomal DNA circles, or ERCs, and they were accumulating as the mutants aged.

ERCs

The first testable prediction was if we put an ERC into very young yeast cells—and we devised a genetic trick to do that—the ERCs would multiply and distract the sirtuins, and the yeast cells would age prematurely, go sterile, and die young—and they did.

ERC into young cells. Cause of aging

His first experiment was to insert an extra copy of SIR2 into the genome of yeast cells to see if it could stabilize the yeast genome and delay aging. When the extra SIR2 was added, ERCs were prevented, and he saw a 30 percent increase in the yeast cells’ lifespan, as we’d been hoping. Our hypothesis seemed to be standing up to scrutiny: the fundamental, upstream cause of sterility and aging in yeast was the inherent instability of the genome.

And then SIR2 into the old cell.ERC prevented

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

And by artificially breaking the DNA in the cell and watching the cellular response, we showed why sirtuins move—to help with DNA repair.20 That turned out to be the second step of the survival circuit.21 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.

DNA damaging will lead to ERCs which distract Sir2

We 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 to the control of the epigenome and DNA repair. The others, 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.

7 SIRs

I had noticed that 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.

Lower amount of sugar

way back in primordium, the ancestors of every living thing on this planet today evolved to sense DNA damage, slow cellular growth, and divert energy to DNA repair until it was fixed—what I call the survival circuit.

Survival circuit

the sirtuins have since taken on a variety of new roles, not just as controllers of fertility (which they still are). They remove acetyls from hundreds of proteins in the cell: histones, yes, but also proteins that control cell division, cell survival, DNA repair, inflammation, glucose metabolism, mitochondria, and many other functions.

Sirtuin function

But what happens when there’s one emergency after another to tend to? Hurricane after hurricane? Earthquake after earthquake? The repair crews are away from home a lot. The work they normally do piles up.

the busy sirtuins can't be anywhere

one of the most important things they do while at home—reproducing—doesn’t get done. This form of hormesis, the original survival circuit, works fine to keep organisms alive in the short term. But unlike longevity molecules that simply mimic hormesis by tweaking sirtuins, mTOR, or AMPK, sending out the troops on fake emergencies, these real emergencies create life-threatening damage.

How does the SIR2 gene actually turn off genes? SIR2 codes for a specialized protein called a histone deacetylase, or HDAC, that enzymatically cleaves the acetyl chemical tags from histones, which, as you’ll recall, causes the DNA to bundle up, preventing it from being transcribed into RNA.

histone deacetylase, or HDAC

When the Sir2 enzyme is sitting on the mating-type genes, they remain silent and the cell continues to mate and reproduce.

In other words, 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:

Adding extra copy of Sir2

If the information theory is correct—that aging is caused by overworked epigenetic signalers responding to cellular insult and damage—it doesn’t so much matter where the damage occurs. What matters is that it is being damaged and that sirtuins are rushing all over the place to address that damage, leaving their typical responsibilities and sometimes returning to other places along the genome where they are silencing genes that aren’t supposed to be silenced.

Just to make sure, later we broke the DNA in other places, too, with the same results. Those breaks had induced a sirtuin response. When those fixers went to work, their absence from their normal duties and presence on other parts of the genome altered the ways in which lots of genes were being expressed at the wrong time.

Main. When too many damage happens. Aging happens. lost of information happens

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.

Epigenetic

Playing an integral role in the survival circuit, 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.35 In mammals, there are four DAF-16 genes, called FOXO1, FOXO3, FOXO4, and FOXO6.

DAF-16.longevity gene

worms become dauer when they are starved or crowded, hunkering down until times improve. Mutations that activate DAF-16 extend lifespan by turning on the worm defense program even when times are good.

DAF-16

Hidden within the sometimes byzantine way scientists talk about science are several repeating themes: low energy sensors (SNF1/AMPK), transcription factors (MSN2/DAF-16/FOXO), NAD and sirtuins, stress resistance, and longevity. This is no coincidence—these are all key parts of the ancient survival circuit.

Main

At the molecular level, what’s really going on as the marble rolls down the slope is that different genes are being switched on and off, guided by transcription factors, sirtuins and other enzymes such as DNA methyltransferases (DNMTs) and histone methyltransferases (HMTs), which mark the DNA and its packing proteins with chemical tags that instruct the cell and its descendants to behave in a certain way.

The code.how differences happen

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 percent a skin cell and 10 percent other cell types, all mixed up, with properties of neurons and kidney cells. The cell becomes inept at the things skin cells must do, such as making hair, keeping the skin supple, and healing when injured. In my lab we say the cell has ex-differentiated.

during constant "earthquakes" and "erosion"

As you’ll recall, the epigenome is inherently unstable because it is analog information—based on an infinite number of possible values—and thus it’s difficult to prevent the accumulation of noise and nearly impossible to duplicate without some information loss. The earthquakes are a fact of life. The landscape is always changing.

Cant stop. Analog

If the epigenome had evolved to be digital rather than analog, the valley walls would be the equivalent of 100 miles high and vertical, and gravity would be superstrong, so the marbles could never jump over into a new valley. Cells would never lose their identity. If we were built this way, we could be healthy for thousands of years, perhaps longer.

Digital

We had been feeding them a molecule intended to boost the levels of NAD, which we believed would increase the activity of sirtuins.

NAD increases the activity of sirtuins

To put yourself into an aged mind-set, try this little experiment. Using your nondominant hand, write your name, address, and phone number while circling your opposite foot counterclockwise. That’s a rough approximation of what it feels like.

Interesting

There are some simple tests to determine how biologically old you probably 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.

Indicator

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.

SRT

There’s a reason why hospitals and research institutions are organized in this way. Most of our modern medical culture has been built to address medical problems one by one—a segregation that owes itself in no small part to our obsession with classifying the specific pathologies leading to death. There was nothing wrong with this setup when it was established hundreds of years ago. And by and large, it still works today. But what this approach ignores is that stopping the progression of one disease doesn’t make it any less likely that a person will die of another.

The setup of different departments in hospital

the disability-adjusted life year, or DALY, which measures the years of life lost from both premature death and poor state of health. The Russian DALY is the highest in Europe, with twenty-five lost years of healthy life per person. In Israel, it is an impressive ten years. In the United States, the number is a dismal twenty-three.

the disability-adjusted life year, DALY

And overwhelmingly that advice comes down to eating more vegetables, legumes, and whole grains, while consuming less meat, dairy products, and sugar.

Food