Lifespan

Once a marble has settled in Waddington’s landscape, it tends to stay there. If all goes well with fertilization, the embryo develops into a fetus, then a baby, then a toddler, then a teenager, then an adult. Things tend to go well in our youth. But the clock is ticking.

Every time there’s a radical adjustment to the epigenome, say, after DNA damage from the sun or an X-ray, the marbles are jostled—envision a small earthquake that ever so slightly changes the map. 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.

Each cell is succumbing to epigenetic noise. The tissue made up of thousands of cells is becoming a melange, a medley, a miscellaneous set of cells.

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.

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.

But we are not built this way. Evolution shapes both genomes and epigenomes only enough to ensure sufficient survival to ensure replacement—and perhaps, if we are lucky, just a little bit more—but not immortality. So our valley walls are only slightly sloped, and gravity isn’t that strong. A whale that lives two hundred years has probably evolved steeper valley walls and its cells maintain their identity for twice as long as ours do. Yet even whales don’t live forever.

I believe the blame lies with M. superstes and the survival circuit. The repeated shuffling of sirtuins and other epigenetic factors away from genes to sites of broken DNA, then back again, while helpful in the short term, is ultimately what causes us to age. Over time, the wrong genes come on at the wrong time and in the wrong place.

As we saw in the ICE mice, when you disrupt the epigenome by forcing it to deal with DNA breaks, you introduce noise, leading to an erosion of the epigenetic landscape. The mice’s bodies turned into chimeras of misguided, malfunctioning cells.

THE CHANGING LANDSCAPE OF OUR LIVES. The Waddington landscape is a metaphor for how cells find their identity. Embryonic cells, often depicted as marbles, roll downhill and land in the right valley that dictates their identity. As we age, threats to survival, such as broken DNA, activate the survival circuit and rejigger the epigenome in small ways. Over time, cells progressively move towards adjacent valleys and lose their original identity, eventually transforming into zombielike senescent cells in old tissues.

That’s aging. This loss of information is what leads each of us into a world of heart disease, cancer, pain, frailty, and death.

If the loss of analog information is the singular reason why we age, is there anything we can do about it? Can we stabilize the marbles, keeping the valley walls high and the gravity strong?

Yes. I can say with confidence that there is.

REVERSAL COMES OF AGE

Regular exercise “is a commitment,” says Benjamin Levine, a professor at the University of Texas. “But I tell people to think of exercise as part of personal hygiene, like brushing their teeth. It should be something we do as a matter of course to keep ourselves healthy.”[85 - If you’re a dedicated exerciser in middle age or an athlete in her fifties, chances are your heart is going to resemble that of someone much younger, several studies have revealed. Not so for the office worker who doesn’t exercise or someone who hits the gym or runs in the street on a sporadic basis. What isn’t clear, though, is whether commencing an aggressive exercise program in your middle years can turn around the effects of a sedentary lifestyle on the heart’s functioning and structure. G. Reynolds, “Exercise Makes the Aging Heart More Youthful,” New York Times, July 25, 2018, https://www.nytimes.com/2018/07/25/well/exercise-makes-the-aging-heart-more-youthful.html.]

I’m sure he’s right. Most people would exercise a lot more if going to the gym were as easy as brushing their teeth.

Perhaps one day it will be. Experiments in my lab indicate it is possible.

“David, we’ve got a problem,” a postdoctoral researcher named Michael Bonkowski told me one morning in the fall of 2017 when I arrived at the lab.

That’s seldom a good way to start the day.

“Okay,” I said, taking a deep breath and preparing for the worst. “What is it?”

“The mice,” Bonkowski said. “They won’t stop running.”

The mice he was talking about were 20 months old. That’s roughly the equivalent of a 65-year-old human. We had been feeding them a molecule intended to boost the levels of NAD, which we believed would increase the activity of sirtuins. If the mice were developing a running addiction, that would be a very good sign.

“But how can that be a problem?” I said. “That’s great news!”

“Well,” he said, “it would be if not for the fact that they’ve broken our treadmill.”

As it turned out, the treadmill tracking program had been set up to record a mouse running for only up to three kilometers. Once the old mice got to that point, the treadmill shut down. “We’re going to have to start the experiment again,” Bonkowski said.

It took a few moments for that to sink in.

A thousand meters is a good, long run for a mouse. Two thousand meters—five times around a standard running track—would be a substantial run for a young mouse.

But there’s a reason why the program was set to three kilometers. Mice simply don’t run that far. Yet these elderly mice were running ultramarathons.

Why? One of our key findings, in a study we published in 2018,[86 - “These findings have implications for improving blood flow to organs and tissues, increasing human performance, and reestablishing a virtuous cycle of mobility in the elderly.” A. Das, G. X. Huang, M. S. Bonkowski, et al., “Impairment of an Endothelial NAD

-H

S Signaling Network Is a Reversible Cause of Vascular Aging,” Cell 173, no. 1 (March 22, 2018): 74–89, https://www.cell.com/cell/pdf/S0092-8674(18)30152-1.pdf.] was that when treated with an NAD-boosting molecule that activated the SIRT1 enzyme, the elderly mice’s endothelial cells, which line the blood vessels, were pushing their way into areas of the muscle that weren’t getting very much blood flow. New tiny blood vessels, capillaries, were formed, supplying badly needed oxygen, removing lactic acid and toxic metabolites from muscles, and reversing one of the most significant causes of frailty in mice and in humans. That was how these old mice suddenly became such mighty marathoners.

Because the sirtuins had been activated, the mice’s epigenomes were becoming more stable. The valley walls were growing higher. Gravity was growing stronger. And Waddington’s marbles were being pushed back to where they belonged. The lining of the capillaries was responding as if the mice were exercised. It was an exercise mimetic, the first of its kind, and a sure sign that some aspects of age reversal are possible.

We still don’t know everything about why this happens. We don’t know what sorts of molecules will work best for activating sirtuins or in what doses. Hundreds of different NAD precursors have been synthesized, and there are clinical trials in progress to answer that question and more.

But that doesn’t mean we need to wait to take advantage of all that we’ve learned about engaging the epigenetic survival circuit and living longer and healthier lives. We don’t need to wait to take advantage of the Information Theory of Aging.

There are steps we can take right now to live much longer and much healthier lives. There are things we can do to slow, stop, and even reverse aspects of aging.

But before we talk about what steps we might take to combat aging, before I can explain the science-backed interventions that have the greatest promise for fundamentally changing the way we think about growing old, before we even begin to talk about the treatments and therapies that will be game changers for our species, we need to answer one very important question:

Should we?

THREE

THE BLIND EPIDEMIC

IT WAS MAY 10, 2010, AND LONDON WAS ABUZZ. CHELSEA FOOTBALL CLUB HAD just won its fourth national championship by devastating Wigan Athletic, 8–0, on the final day of Premier League play. Meanwhile, Gordon Brown announced that he would be stepping down as prime minister in response to a disastrous parliamentary result for his Labour Party, which had lost more than ninety seats in the previous week’s general election.

With the eyes of the English sports world on one part of London and the attention of the British political universe on another, the goings-on at Carlton House Terrace were missed by all but the most attentive observers of the president, council, and fellows of the Royal Society of London for Improving Natural Knowledge.

More simply known as the Royal Society, the world’s oldest national scientific organization was established in 1660 to promote and disseminate “new science” by big thinkers of the day such as Sir Francis Bacon, the Enlightenment’s promulgator of “the prolongation of life.”[87 - F. Bacon, Of the Proficience and Advancement of Learning, Divine and Human (Oxford, UK: Leon Lichfield, 1605). An original of this book sits on our mantelpiece at home, a gift from Sandra, my wife.] Befitting its rich scientific history, the society has held annual scientific events ever since. Highlights have included lectures by Sir Isaac Newton on gravity, Charles Babbage on his mechanical computer, and Sir Joseph Banks, who had just arrived back from Australia with a bounty of more than a thousand preserved plants that were all new to science.

Even today, in a post-Enlightenment world, most of the events at the society are fascinating if not world changing. But the two-day meeting that commenced in the spring of 2010 was nothing short of that, for gathered together on that Monday and Tuesday was a motley group of researchers who were meeting to discuss an important “new science.”

The gathering had been called by geneticist Dame Linda Partridge, bioanalytics pioneer Janet Thornton, and molecular neuroscientist Gillian Bates, all luminaries in their respective fields. The attendee list was no less impressive. Cynthia Kenyon spoke about her landmark work on a single mutation in the IGF-1 receptor gene that had doubled the lifespan of roundworms by activating DAF-16[88 - C. Kenyon, J. Chang, E. Gensch, et al., “A C. elegans Mutant That Lives Twice as Long as Wild Type,” Nature 366, no. 6454 (December 2, 1993): 461–64, https://www.nature.com/articles/366461a0.]—work that was first suggested by Partridge to be a worm-specific aberration[89 - L. Partridge and P. H. Harvey, “Methuselah Among Nematodes,” Nature 366, no. 6454 (December 2, 1993): 404–5, https://www.ncbi.nlm.nih.gov/pubmed/8247143.] but soon forced her and other leading researchers to confront long-held beliefs that aging could be controlled by a single gene. Thomas Nyström, from the University of Gothenburg, reported his discovery that Sir2 not only is important for genomic and epigenomic stability in yeast, it also prevents oxidized proteins from being passed on to young daughter cells.

Brian Kennedy, a former Guarente student who was about to assume the presidency of the Buck Institute for Research on Aging, explained the ways in which genetic pathways that had been similarly conserved in a diverse array of species were likely to play similar roles in mammalian aging. Andrzej Bartke from Southern Illinois University, former PhD adviser to Michael “Marathon Mouse” Bonkowski, talked about how dwarf mice can live up to twice as long as normal mice, a record. Molecular biologist María Blasco explained how old mammalian cells are more likely than young cells to lose their identity and become cancerous. And geneticist Nir Barzilai spoke of genetic variants in long-lived humans and his belief that all aging-related diseases can be substantially prevented and human lives can be considerably extended with one relatively easy pharmaceutical intervention.

Over the course of those two days, nineteen presenting scientists from some of the best research institutions in the world moved toward a provocative consensus and began to build a compelling case that would challenge conventional wisdom about human health and disease. Summarizing the meeting for the society later that fall, the biogerontologist David Gems would write that advances in our understanding of organismal senescence are all leading to a momentous singular conclusion: that aging is not an inevitable part of life but rather a “disease process with a broad spectrum of pathological consequences.”[90 - “Decelerated aging,” Gems wrote, “has an element of tragic inevitability: its benefits to health compel us to pursue it, despite the transformation of human society, and even human nature, that this could entail.” D. Gems, “Tragedy and Delight: The Ethics of Decelerated Ageing,” Philosophical Transactions of the Royal Society B: Biological Sciences 366 (January 12, 2011): 108–12, https://royalsocietypublishing.org/doi/pdf/10.1098/rstb.2010.0288.] In this way of thinking, cancer, heart disease, Alzheimer’s, and other conditions we commonly associate with getting old are not necessarily diseases themselves but symptoms of something greater.

Or, put more simply and perhaps even more seditiously: aging itself is a disease.

THE LAW OF HUMAN MORTALITY

If the idea that aging is a disease sounds strange to you, you’re not alone. Physicians and researchers have been avoiding saying that for a long time. Aging, we’ve long been told, is simply the process of growing old. And growing old has long been seen as an inevitable part of life.

We see aging, after all, in nearly everything around us and, in particular, the things around us that look anything like us. The cows and pigs in our farms age. The dogs and cats in our homes do, too. The birds in the sky. The fish in the sea. The trees in the forest. The cells in our petri dishes. It always ends the same way: dust to dust.