Lifespan

● 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.

Take stem cells, which have the potential to develop into many other kinds of cells: if we can keep these undifferentiated cells from tiring out, they can continue to generate all the differentiated cells necessary to heal damaged tissues and battle all kinds of diseases.

Meanwhile, we’re improving the rates of acceptance of bone marrow transplants, which are the most common form of stem cell therapy, and using stem cells for the treatment of arthritic joints, type 1 diabetes, loss of vision, and neurodegenerative diseases such as Alzheimer’s and Parkinson’s. These stem cell–based interventions are adding years to people’s lives.

Or take senescent cells, which have reached the end of their ability to divide but refuse to die, continuing to spit out panic signals that inflame surrounding cells: if we can kill off senescent cells or keep them from accumulating in the first place, we can keep our tissues much healthier for longer.

The same can be said for combating telomere loss, the decline in proteostasis, and all of the other hallmarks. Each can be addressed one by one, a little at a time, in ways that can help us extend human healthspans.

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.

As for pushing way past the maximum limit? Addressing these hallmarks might not be enough.

But the science is moving fast, faster now than ever before, thanks to the accumulation of many centuries of knowledge, robots that analyze tens of thousands of potential drugs each day, sequencing machines that read millions of genes a day, and computing power that processes trillions of bytes of data at speeds that were unimaginable just a decade ago. Theories on aging, which were slowly chipped away for decades, are now more easily testable and refutable.

Although it is in its early days, a new shift in thinking is again under way. Once again we find ourselves in a period of chaos—still quite confident that the hallmarks are accurate indicators of aging and its myriad symptoms but unable to explain why the hallmarks occur in the first place.

THE HALLMARKS OF AGING. 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.

It is time for an answer to this very old question.

Now, finding a universal explanation for anything—let alone something as complicated as aging—doesn’t happen overnight. Any theory that seeks to explain aging must not just stand up to scientific scrutiny but provide a rational explanation for every one of the pillars of aging. A universal hypothesis that seems to provide a reason for cellular senescence but not stem cell exhaustion would, for example, explain neither.

Yet I believe that such an answer exists—a cause of aging that exists upstream of all the hallmarks. Yes, a singular reason why we age.

Aging, quite simply, is a loss of information.

You might recognize that loss of information was a big part of the ideas that 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.

Because DNA is digital, it is a reliable way to store and copy information. Indeed, it can be copied again and again with tremendous accuracy, no different in principle from digital information stored in computer memory or on a DVD.

DNA is also robust. When I first worked in a lab, I was shocked by how this “molecule of life” could survive for hours in boiling water and thrilled that it was recoverable from Neanderthal remains at least 40,000 years old.[39 - The authors discovered mitochondrial DNA in a Neanderthal bone in Croatia that revealed older dates of survival than previously thought. T. Devièse, I. Karavanié, D. Comeskey, et al., “Direct Dating of Neanderthal Remains from the Site of Vindija Cave and Implications for the Middle to Upper Paleolithic Transition,” Proceedings of the National Academy of Sciences of the United States of America 114, no. 40 (October 3, 2017): 10606–11, https://www.ncbi.nlm.nih.gov/pubmed/28874524.] The advantages of digital storage explain why chains of nucleic acids have remained the go-to biological storage molecule for the past 4 billion years.

The other type of information in the body is analog.

We don’t hear as much about analog information in the body. That’s in part because it’s newer to science, and in part because it’s rarely described in terms of information, even though that’s how it was first described when geneticists noticed strange nongenetic effects in plants they were breeding.

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

The term epigenetics was first coined in 1942 by Conrad H. Waddington, a British developmental biologist, while working at Cambridge University. In the past decade, the meaning of the word 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. DNA in the cell isn’t flailing around disorganized, it is wrapped around tiny balls of protein called histones. These beads on a string self-assemble to form loops, as when you tidy your garden hose on your driveway by looping it into a pile. If you were to play tug-of-war using both ends of a chromosome, you’d end up with a six foot-long string of DNA punctuated by thousands of histone proteins. If you could somehow plug one end of the DNA into a power socket and make the histones flash on and off, a few cells could do you for holiday lights.

In simple species, like ancient M. superstes and fungi today, epigenetic information storage and transfer is important for survival. For complex life, it is essential. By complex life, I mean anything made up of more than a couple of cells: slime molds, jellyfish, worms, fruit flies, and of course mammals like us. 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.[40 - A. S. Adikesevan, “A Newborn Baby Has About 26,000,000,000 Cells. An Adult Has About 1.9 × 10

Times as Many Cells as a Baby. About How Many Cells Does an Adult Have?,” Socratic, January 26, 2017, https://socratic.org/questions/a-newborn-baby-has-about-26-000-000-000-cells-an-adult-has-about-1-9-10-3-times-.]

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.

That’s why a neuron doesn’t one day behave like a skin cell and a dividing kidney cell doesn’t give rise to two liver 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.

In the warm ponds of the primordial Earth, a digital chemical system was the best way to store long-term genetic data. But information storage was also needed to record and respond to environmental conditions, and this was best stored in analog format. Analog data are superior for this job because they can be changed back and forth with relative ease whenever the environment within or outside the cell demands it, and they can store an almost unlimited number of possible values, even in response to conditions that have never been encountered before.[41 - C. B. Brachmann, J. M. Sherman, S. E. Devine, et al., “The SIR2 Gene Family, Conserved from Bacteria to Humans, Functions in Silencing, Cell Cycle Progression, and Chromosome Stability,” Genes & Development 9, no. 23 (December 1, 1995): 2888–902, http://genesdev.cshlp.org/content/9/23/2888.long; X. Bi, Q. Yu, J. J. Sandmeier, and S. Elizondo, “Regulation of Transcriptional Silencing in Yeast by Growth Temperature,” Journal of Molecular Biology 34, no. 4 (December 3, 2004): 893–905, https://www.ncbi.nlm.nih.gov/pubmed/15544800.]

The unlimited number of possible values is why many audiophiles still prefer the rich sounds of analog storage systems. But even though analog devices have their advantages, they have a major disadvantage. In fact, it’s the reason we’ve moved from analog to digital. Unlike digital, analog information degrades over time—falling victim to the conspiring forces of magnetic fields, gravity, cosmic rays, and oxygen. Worse still, information is lost as it’s copied.

No one was more acutely disturbed by the problem of information loss than Claude Shannon, an electrical engineer from the Massachusetts Institute of Technology (MIT) in Boston. Having lived through World War II, Shannon knew firsthand how the introduction of “noise” into analog radio transmissions could cost lives. After the war, he wrote a short but profound scientific paper called “The Mathematical Theory of Communication” on how to preserve information, which many consider the foundation of Information Theory. If there is one paper that propelled us into the digital, wireless world in which we now live, that would be it.[42 - It is one of the most interesting and important papers I’ve ever read. C. E. Shannon, “A Mathematical Theory of Communication,” Bell System Technical Journal 27, no. 3 (July 1948): 379–423, and 27, no. 4 (October 1948): 623–66, http://math.harvard.edu/~ctm/home/text/others/shannon/entropy/entropy.pdf.]

Shannon’s primary intention, of course, was to improve the robustness of electronic and radio communications between two points. His work may ultimately prove to be even more important than that, for what he discovered about preserving and restoring information, I believe, can be applied to aging.

Don’t be disheartened by my claim that we are the biological equivalent of an old DVD player. This is actually good news. If Szilard had turned out to be right about mutations causing aging, we would not be able to easily address it, because when information is lost without a backup, it is lost for good. Ask anyone who’s tried to play or restore content from a DVD that’s had an edge broken off: what is gone is gone.

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.

A TIME TO EVERY PURPOSE

The Information Theory of Aging starts with the primordial survival circuit we inherited from our distant ancestors.

Over time, as you might expect, the circuit has evolved. Mammals, for instance, 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.”

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. They tell us to hunker down when the going gets tough, and they tell us to grow fast and reproduce fast when the going gets easier.

And now that we know these genes are there and what many of them do, scientific discovery has given us an opportunity to explore and exploit them; to imagine their potential; to push them to work for us in different ways. Using molecules both natural and novel, using technology both simple and complex, using wisdom both new and old, we can read them, turn them up and down, and even change them altogether.

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.