What, then, of another mammal? A warm-blooded, milk-producing, live-birth-giving cousin?
Back in 2007, aboriginal hunters in Alaska caught a bowhead whale that, when butchered, was found to have the head of an old harpoon embedded in its blubber. The weapon, historians would later determine, had been manufactured in the late 1800s, and they estimated the whale’s age at about 130. That discovery sparked a new scientific interest in Balaena mysticetus, and later research, employing an age-determining method that measures the levels of aspartic acid in the lens of a whale’s eye, estimated that one bowhead was 211 years old when it was killed by native whalers.
That bowheads have been selected for exceptional longevity among mammals should perhaps not be surprising. They have few predators and can afford to build a long-lived body and breed slowly. Most likely they maintain their survival program on high alert, repairing cells while maintaining a stable epigenome, thereby making sure the symphony of the cells plays on for centuries.
Can these long-lived species teach us how to live healthier and for longer?
In terms of their looks and habitats, pine trees, jellyfish, and whales are certainly very different from humans. But in other ways, we’re very similar. Consider the bowheads. Like us, they are complex, social, communicative, and conscious mammals. We share 12,787 known genes, including some interesting variants in a gene known as FOXO3. Also known as DAF-16, this gene was first identified as a longevity gene in roundworms by University of California at San Francisco researcher Cynthia Kenyon. She found it to be essential for defects in the insulin hormone pathway to double worm lifespan. 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. If you suspect that we scientists sometimes intentionally complicate matters, you’d be right, but not in this case. Genes in the same “gene family” have ended up with different names because they were named before DNA sequences were easily deciphered. It’s similar to the not uncommon situation in which people have their genome analyzed and learn they have a sibling on the other side of town.36 DAF-16 is an acronym for dauer larvae formation. In German, “dauer” means “long lasting,” and this is actually relevant to this story. Turns out, 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.
I first encountered FOXO/DAF-16 in yeast, where it is known as MSN2, which stands for “multicopy suppressor of SNF1 (AMPK) epigenetic regulator.” Like DAF-16, MSN2’s job in yeast is to turn on genes that push cells away from cell death and toward stress resistance.37 We discovered that when calories are restricted MSN2 extends yeast lifespan by turning up genes that recycle NAD, thereby giving the sirtuins a boost.38
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.
But what about FOXO genes in humans? Certain variants called FOXO3 have been found in human communities in which people are known to enjoy both longer lifespans and healthspans, such as the people of China’s Red River Basin.39 These FOXO3 variants likely turn on the body’s defenses against diseases and aging, not just when times are tough but throughout life. If you’ve had your genome analyzed, you can check if you have any of the known variations of FOXO3 that are associated with a long life.40 For example, having a C instead of a T variant at position rs2764264 is associated with longer life. Two of our children, Alex and Natalie, inherited two Cs at this position, one from Sandra and one from me, so all other genes being equal, and as long as they don’t live terribly negative lifestyles, they should have greater odds of reaching age 95 than I do, with my one C and one T, and substantially greater than someone with two Ts.
It’s worth pausing to consider how remarkable it is that we find essentially the same longevity genes in every organism on the planet: trees, yeast, worms, whales, and humans. All living creatures come from the same place in primordium that we do. When we look through a microscope, we’re all made of the same stuff. We all share the survival circuit, a protective cellular network that helps us when times are tough. This same network is our downfall. Severe types of damage, such as broken strands of DNA, cannot be avoided. They overwork the survival circuit and change cellular identity. We’re all subject to epigenetic noise that should, under the Information Theory of Aging, cause aging.
Yet different organisms age at very different rates. And sometimes, it appears, they do not age at all. What allows a whale to keep the survival circuit on without disrupting the epigenetic symphony? If the piano player’s skills are lost, how is it possible for a jellyfish to restore her ability?
These are the questions that have been guiding my thoughts as I have considered where our research is headed. What might seem like fanciful ideas, or concepts straight out of science fiction, are firmly rooted in research. Moreover, they are supported by the knowledge that some of our close relatives have figured out a workaround to aging.
And if they can, we can, too.
THE LANDSCAPE OF OUR LIVES
Before most people could even fathom the idea of mapping our genome, before we had the technology to map a cell’s entire epigenome and understand how it bundles DNA to turn genes on and off, the developmental biologist Conrad Waddington was already thinking deeper.
In 1957, the professor of genetics, from the University of Edinburgh, was trying to understand how an early embryo could possibly be transformed from a collection of undifferentiated cells—each one exactly like the next and with the exact same DNA—to the thousands of different cell types in the human body. Perhaps not coincidentally, Waddington’s ponderings came in the dawning years of the digital revolution, at the same time that Grace Hopper, the mother of computer programming, was laying the foundation for the first widely used computer language, COBOL. In essence, what Waddington was seeking to ascertain was how cells, all running on the same code, could possibly produce different programs.
There had to be something more than genetics at play: a program that controlled the code.
Waddington conceived of an “epigenetic landscape,” a three-dimensional relief map that represents the dynamic world in which our genes exist. More than half a century later, Waddington’s landscape remains a useful metaphor to understand why we age.
On the Waddington map, an embryonic stem cell is represented by a marble at the top of a mountain peak. During embryonic development, the marble rolls down the hill and comes to rest in one of hundreds of different valleys, each representing a different possible cell type in the body. This is called “differentiation.” The epigenome guides the marbles, but it also acts as gravity after the cells come to rest, ensuring that they don’t move back up the slope or hop over into another valley.
The final resting place is known as the cell’s “fate.” We used to think this was a one-way street, an irreversible path. But in biology there is no such thing as fate. In the last decade, we’ve learned that the marbles in the Waddington landscape aren’t fixed; they have a terrible tendency to move around over time.
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