Lifespan: Why We Age—and Why We Don't Have To

by David A. Sinclair

daffodils.”

Carpe diem.

alma mater,

stickybeak,

inquisitive,

curr...

wending

apocryphal

ostensibly

merest

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.

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.

The trio of biologists argued that we experience aging because the forces of natural selection required to build a robust body may be strong when we are 18 but decline rapidly once we hit 40 because by then we’ve likely replicated our selfish genes in sufficient measure to ensure their survival.

verbiage,

pleiotropy.”

Individuals don’t live forever because natural selection doesn’t select for immortality in a world where an existing body plan works perfectly well to pass along a body’s selfish genes.

alpha-lipoic acid

quench

rodents,

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.

cloisters

radicals

coalesce

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

senescent

Scientists have settled on eight or nine hallmarks of aging. Address one of these, and you can slow down aging. Address all of them, and you might not age.

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

In simple species, like ancient M. superstes and fungi today, epigenetic information storage and transfer is important for survival.

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.

“The Mathematical Theory of Communication”

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.

don’t have just a couple of genes that create a survival circuit, such as those that first appeared in M. superstes. Scientists have found more than two dozen of them within our genome. Most of my colleagues call these “longevity genes” because they have demonstrated the ability to extend both average and maximum lifespans in many organisms. But these genes don’t just make life longer, they make it healthier, which is why they can also be thought of as “vitality genes.”

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.

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. These critical epigenetic regulators sit at the very top of cellular control systems, controlling our reproduction and our DNA repair.

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.

autophagy.

meager

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

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.

remnants

oncogenes

Because our genes did not evolve to cause aging.

toiled

wisps

jolt

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.

The pianist that makes this happen is the epigenome.

Through a process of revealing our DNA or bundling it up in tight protein packages, and by marking genes with chemical tags called methyls and acetyls composed of carbon, oxygen, and hydrogen, the epigenome uses our genome to make the music of our lives.

agouti

They are not older, but they’ve clearly aged faster.