Whenever I walk along the streets of London, I never cease to be amazed by a city where millions of people can work, travel, and socialize so seamlessly. A complex infrastructure, and hundreds of thousands of people, all work in concert to make it possible: the London Underground and buses to move us around the city; the post office and courier services to deliver the mail and goods; the supermarkets that supply us with food; the power companies that generate and distribute electricity; and the sanitation services that keep the city clean and remove the enormous quantities of waste we produce. As we go about our business, it is easy to take for granted this incredible feat of coordination that we call a civilized society.

The cell, our most basic form of life, has a similarly complex choreography. As the cell forms, it builds elaborate structures like the parts of a city. Thousands of synchronized processes are required to keep it functioning. It brings in nutrients and exports waste. Transporter molecules carry cargo from where they are made to distant parts of the cell where they are needed. Just as cities cannot exist in isolation but must exchange goods, services, and people with surrounding areas, the cells of a tissue need to communicate and cooperate with neighboring cells. Unlike cities, whose growth is not always constrained, the cell needs to know when to grow and divide but also when to stop doing so.

Throughout history, cities were imagined by their inhabitants to be permanent. We don't go about our lives thinking that the city we live in will one day cease to exist. Yet cities and entire societies, empires, and civilizations grow and die just as cells do. When we talk about death, we aren't usually thinking about these other kinds of death: we mean as it occurs to each one of us as individuals. But it turns out to be tricky even to define an individual, let alone what we mean by its birth or death.

At the moment of our death, what exactly is it that dies? At this point, most of the cells in our body are still alive. We can donate entire organs, and they work just fine in someone else if transplanted quickly enough. The trillions of bacteria, which outnumber the human cells in our body, continue to thrive. Sometimes the reverse is also true: suppose we were to lose a limb in an accident. The limb would certainly die, but we don't think of ourselves as dying as a result.

What we really mean when we say we die is that we stop functioning as a coherent whole. The collection of cells that forms our tissues and organs all communicate with one another to make us the sentient individuals we are. When they no longer work together as a unit, we die.

Death, in the inevitable sense we are considering in this book, is the result of aging. The simplest way to think of aging is that it is the accumulation of chemical damage to our molecules and cells over time. This damage diminishes our physical and mental capacity until we are unable to function coherently as an individual being—and then we die. I am reminded of the quote from Hemingway's The Sun Also Rises, in which a character is asked how he went bankrupt and he replies, "Two ways. Gradually, then suddenly." Gradually, the slow decline of aging; suddenly, death. The process of aging can be thought of as starting gradually with small defects in the complex system that is our body; these lead to medium-sized ones that manifest as the morbidities of old age, leading eventually to the system-wide failure that is death.

Even then, it is hard to define exactly when this happens. Death used to mean when someone's heart stopped beating, but today cardiac arrest can often be reversed by CPR. The loss of brain function is now taken as a more direct sign of death, but there are hints that even that can sometimes be reversed. Differences in the precise legal definition of death can have very real consequences. Harvesting organs for donation from two persons in two different US states could be perfectly legal in one and murder in the other, even if they were both considered dead using identical criteria. A girl who was declared brain dead in Oakland, California, was considered alive by the standards of New Jersey, where her family lived. Her family petitioned and eventually had her body transported with its life support equipment to New Jersey, where she died a few years later.

If the precise moment of our death is ill-defined, so too is the moment of our birth. We exist before we emerge from the womb and take our first breath. Many religions consider conception to be the beginning of life, but conception too is a fuzzy term. Rather, there is a window of time after a sperm has made contact with the surface of an egg during which a series of events has to take place before the genetic program of the fertilized egg is set into motion. After that, there is a multi day window during which the fertilized egg undergoes a few divisions, and the embryo—now called a blastocyst—has to implant itself in the lining of the womb. Still later, the beginning of a heart develops, and only long after that, with the development of a nervous system and its brain, can the growing fetus sense pain.

The question of when life begins is as much a social and cultural question as it is a scientific one, as can be seen by the continuing debate over abortion. Even in many countries where abortion is legal, including the United States and the United Kingdom, it is a crime to grow embryos for research beyond fourteen days, which corresponds roughly to the time when a groove called the primitive streak appears in the embryo and defines the left and right halves. After this stage, the embryo can no longer split and develop into identical twins. Although we think of birth and death as instantaneous events—in one instant we come into existence and in another we cease to exist—the boundaries of life are blurry. The same is true of larger organizational units. It is hard to pinpoint the exact time when a city came into existence or when it crumbled.

Death can occur at every scale, from molecules to nations, but there are common features of the growth, aging, and demise of different entities. In every case, there is a critical moment when the component parts no longer allow the organic whole to function. Molecules in our cells work in a coordinated way to allow the cell to function, but they themselves can suffer chemical damage and eventually break down. If the molecules are involved in vital processes, their cells will themselves begin to age and die. Moving up the scale hierarchy, the trillions of cells in a human being carry out their specialized duties and communicate with one another to allow an individual to function. Cells in our body die all the time, with no adverse effects. In fact, during the growth of an embryo, many cells are programmed to die at precise points of development—a phenomenon called apoptosis. But when enough essential cells die, whether in the heart or the brain or some equally critical organ, then the individual can no longer function and dies.

We human beings are not so different from our cells. We carry out roles in groups: companies, cities, societies. The departure of one employee will not normally affect the functioning of a large company, and even less that of a city or a country, just as the death of a single tree says nothing at all about the viability of a forest. But if key employees, such as the entire senior management, were to leave suddenly, the health and future of the company would be in doubt.

It is also interesting to see that longevity increases with the size of the entity. Most of the cells in our body have died and been replaced many times before we ourselves die, while companies tend to have much shorter life spans than the cities in which they operate. The principle of safety in numbers has driven the evolution of both life and societies. Life probably began with self-replicating molecules, which then organized in closed compartments that we know as cells. Some of those cells then banded together to form individual animals. Then animals themselves organized into herds—or in our case, communities, cities, nations. Each level of organization brought greater safety and a more interdependent world. Today hardly any of us could survive on our own.

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Still, when we think of death, we are generally thinking about our own: the end of our conscious existence as an individual. There is a stark paradox about that kind of death: although individuals die, life itself continues. I don't mean just in the sense that our family, community, and society will all go on without us. Rather, it is remarkable that every creature alive today is a direct descendant of an ancestral cell that existed billions of years ago. So, although changing and evolving with time, some essence in all of us has lived continuously for a few billion years. That will continue to be true for every living thing for as long as life survives on Earth, unless we one day create an entirely artificial form of life.

If there is a direct line of succession from us to our ancient ancestors, then there must be something about each of us that doesn’t die. That something is information on how to create another cell or an entirely new organism, even after the original carrier of that information has died—just as the ideas and information here can persist in some form long after the physical copy of this book has deteriorated.

The information to continue life resides, of course, in our genes. Each gene is a section of our DNA, and is stored in the form of chromosomes in the nucleus, the specialized compartment that encapsulates genetic material in our cells. Most of our cells contain the same entire set of genes, known collectively as our genome. Every time our cells divide, they pass on the entire genome to each of the daughter cells. The vast majority of these cells are simply part of our body and will die with it. But some of our cells will outlive our body by developing into our children—the new individuals that make up the next generation. So what is special about these cells that allows them to live on?

The answer to this settled a raging controversy, one that came long before our knowledge of genes, let alone DNA. When people first began to accept that species could evolve, two opposing views emerged. The first, advanced by the Frenchman Jean-Baptiste Lamarck in the early nineteenth century, held that acquired characteristics could be inherited. For example, if a giraffe were to keep stretching its neck to reach higher branches for leaves to eat, its offspring would inherit the resulting longer neck. The second theory was natural selection, proposed by a pair of British biologists, Charles Darwin and Alfred Wallace. In this view, giraffes were variable, some with longer necks and others with shorter. Those with longer necks were more likely to find nourishment and thus be able to survive and have offspring. Progressively, with each generation, variants with longer and longer necks would be selected.

A relative outsider working in what was then the Malay Archipelago, thirty-five-year-old Alfred Wallace wrote to Darwin in 1858 expressing his ideas, not realizing that the older man had himself come to the same conclusion many years earlier. Because these ideas were so revolutionary, and had social and religious in-plications, Darwin had not yet summoned the courage to publish them, but the communication from Wallace spurred him into action. Darwin was at the heart of the British scientific establishment, and had he been less scrupulous, he could have simply ignored Wallace's letter and hurriedly published his book. Nobody would have ever known Wallace's name. Instead, Darwin arranged for himself and Wallace to make a joint presentation at the Linnean Society of London on July 1, 1858. The response to the lecture itself was relatively muted and had little immediate impact. In what was one of the worst pronouncements in the history of science, the society's president said in his annual address, "The year has not, indeed, been marked by any of those striking discoveries which at once revolutionize, so to speak, the department of science on which they bear." However, the lecture paved the way for the publication of Darwin's book On the Origin of Species the following year, which changed our understanding of biology forever.

In 1892, thirty-three years after Darwin's monumental tract was published, the German biologist August Weismann posited a neat rebuttal of Lamarck's ideas. Although humans have known for a very long time that sex and procreation were connected, it is only in the last 300 years that we discovered that the key event is the fusion of a sperm with an egg to start the process. The fertilization of an egg by a sperm results in the seemingly miraculous creation of an entirely new individual. The individual consists of trillions of cells that carry out nearly all of the functions of the body and die with it. They are known collectively as somatic cells, from soma, the Latin and Greek word for "body." The sperm and the egg, on the other hand, are germ-line cells. They reside in our gonads, which are testes in males and ovaries in females. And they are the sole transmitters of heritable information: our genes. Weismann proposed that germ-line cells can create the somatic cells of the next generation, but the reverse can never happen. This separation between the two kinds of cells is called the Weismann barrier. So if a giraffe stretches its neck, it might affect various somatic cells that make up its neck muscles and skin, but these cells would be incapable of passing on any changes to its offspring. The germ-line cells, protected in the gonads, would be impervious to the activities of the giraffe and any characteristics its neck acquired.

The germ-line cells that propagate our genes are immortal in the sense that a tiny fraction of them are used to create the next generation of both somatic and germ-line cells by sexual reproduction, which effectively resets the aging clock. In each generation, our bodies, or our soma, are simply vessels to facilitate the propagation of our genes, and they become dispensable once they have fulfilled their purpose. The death of an animal or a human is really the death of the vessel.

*

Why does death even exist? Why don’t we simply live forever? The twentieth-century Russian geneticist Theodosius Dobzhansky once wrote, "Nothing in biology makes sense except in the light of evolution." In biology, the ultimate answer to a question about why something occurs is because it evolved that way. When I first began to consider the question of why we die, I thought naively that perhaps death was nature's way of allowing a new generation to flourish and reproduce without having older ones hanging around to compete with it for resources, thus better ensuring the survival of the genes. Moreover, each member of a new generation would have a different combination of genes than its parents, and the constant reshuffling of life's deck of cards would help facilitate survival of the species as a whole.

This idea has existed at least since the Roman poet Lucretius, who lived in the first century BCE. It is appealing—but it's also wrong. The problem is that any genes that benefit the group at the expense of the individual cannot be stably maintained in the population because of the problem of cheaters. In evolution, a "cheater" is any mutation that benefits the individual at the expense of the group. For example, let us suppose there are genes that promote aging to ensure that people die off in a timely way to benefit the group. If an individual had a mutation that inactivated those genes and lived longer, that person would have more opportunity to have offspring, even though it did not benefit the group. In the end, the mutation would win out.

Unlike humans, many insects and most grain crops reproduce only once. Species such as the soil worm Caenorhabditis elegans, as well as salmon, produce lots of offspring in one big bang and die in the process, often recycling their own bodies as a form of suicide. This kind of reproductive behavior makes sense for worms, which usually live as inbred clones and are therefore genetically identical to their offspring. On the other hand, the reproductive behavior of salmon is a result of their life cycle: they have to swim thousands of miles in the ocean before returning to spawn. With little chance of surviving such a journey twice, they are better served by putting everything they can into breeding just once, using up their entire energy and even dying in the process, to produce enough offspring and maximize the chance that those offspring survive. For species that can reproduce multiple times, like humans, flies, or mice, it would not make genetic sense to die in the act of producing offspring to which they are only 50 percent related. In general, natural selection rarely acts for the good of species or even groups. Rather, nature selects for what evolutionary biologists call fitness, or the ability of individuals to propagate their genes.

If the goal is to ensure that our genes are passed on, why has evolution not prevented aging in the first place? Surely the longer humans survive, the more chance we have of producing offspring. The short answer is that through most of our history as a species, our lives were short. We were generally killed by an accident, disease, predator, or a fellow human before our thirtieth birthday. So there was no reason for evolution to have selected us for longevity. But now that we have made the world safer and healthier for us, why don't we just keep living on?

The solution to this puzzle began in the 1930s with two members of the British scientific elite, J. B. S. Haldane and Ronald Fisher. Haldane was a polymath who worked on everything from the mechanisms of enzymes to the origin of life. He was a socialist who late in life became disillusioned with Britain and emigrated to India, where he died. Fisher's fundamental contributions to statistics have propelled our understanding of evolution and also form the basis of randomized clinical trials that are used to test the efficacy of new drugs or medical procedures and have saved millions of lives. More than 50 years after his death in 1962, he became controversial for his views on eugenics and race. A stained glass window that portrayed one of Fisher's key ideas for the design of experiments was recently removed by Gonville and Caius College in Cambridge, where he was once a fellow, and its final disposition is still uncertain.

Around the same time, Fisher and Haldane independently came up with a revolutionary idea. A mutation that is harmful early in life, each realized, would be strongly selected against because those who carry it would not reproduce. However, the same could not be said for a gene that is deleterious to us only later in life, because by the time it causes harm, we will already have passed it on. For most of our history as a species, we would not have even noticed its harmful consequences, because long before these effects would be felt, we would have died. It is only relatively recently that we have become aware of the consequences of any mutations that are detrimental late in life. Huntington's disease, for example, primarily affects people over thirty, by which time, historically, most of them would have already reproduced and died.

Fisher's and Haldane's ideas explain why certain deleterious genes persist in the human population, but their relevance to aging was not immediately obvious. That understanding came when British biologist Peter Medawar, another brilliant and colorful figure, turned his attention to the problem. Medawar, born in Brazil, was most famous for his ideas of how the immune system rejects organ transplants and acquires tolerance. Unlike many scientists who focus narrowly on one area, Medawar, like Haldane, had widespread interests, and wrote books that were famous for their erudition and elegant writing. Many scientists of my generation grew up reading Advice to a Young Scientist (1981), which I found pompous, arrogant, thoughtful, engaging, and witty all at once.

Medawar proposed what has become known as the mutation accumulation theory of aging. Even if a person harbored multiple genetic mutations that didn’t noticeably impair health early on, in combination they brought about chronic problems later in life, resulting in aging.

Going one step further, the biologist George Williams suggested that aging occurs because nature selects for genetic variants, even if they are deleterious later in life, because they are beneficial at an earlier stage. This theory is called antagonistic pleiotropy. Pleiotropy is simply a fancy term for a situation in which a gene can exert multiple effects. So antagonistic pleiotropy means that the same gene could have opposite effects; with genes involved in aging, the effects could occur at different times, such as being helpful early in life and problematic later. For example, genes that help us grow early in life increase the risk of age related diseases such as cancer and dementia when we are old.

Similarly, the disposable soma hypothesis posits that an organism with limited resources must apportion them between investing in early growth and reproduction and prolonging life by continuously repairing wear and tear in the cell. According to biologist Thomas Kirkwood, who first proposed this theory in the 1970s, the aging of an organism is an evolutionary trade-off between longevity and decreased chances of passing on its genes through reproductive success.

Is there any evidence for these various ideas about aging? Scientists have experimented on fruit flies and worms, two favorite organisms because they are easy to grow in the laboratory and have short generation times. Exactly as these theories would predict, the mutations that increase life span reduce fecundity (the rate at which an organism produces offspring). Similarly, reducing the calorie intake of the daily food given to these organisms also increases life span and reduces fecundity.

Apart from the ethics of experimenting on humans, the two to three decades between generations is too long for a typical academic career, let alone the handful of years a graduate student or research fellow might stick around. But an unusual analysis of British aristocrats over the past 1,200 years shows that among women who survived beyond sixty (to weed out factors such a disease, accidents, and dying in childbirth), those with fewer children lived the longest. The authors argue that in humans too, there is an inverse relationship between fecundity and longevity, although, of course, as any harried parent knows, there could have been many other reasons why having fewer children extends life expectancy.

*

The increase in our life span over the last century brings us to another curious feature of aging that is almost unique to humans: menopause. With the exception of a few other species, including killer whales, most female animals can reproduce almost to the end of their lives, whereas women suddenly lose the ability in midlife. The abruptness of this change in women, as opposed to the more gradual decline in male fertility, is also strange.

You might think that if evolution selects for our ability to pass on our genes, it should want us to reproduce for as much of our lives as possible. So why do women stop reproducing relatively early in life?

This may be asking the wrong question. Our closest relatives, such as the great apes, all stop having babies about the same age that we do: the late thirties. The difference is that they generally die soon afterward. And for most of human history, most women too died soon after menopause, if not earlier. Perhaps the real question is not why menopause occurs so early in life but why women live so long afterward.

People cannot be sure they have reproduced in the sense of passing on their genes until their youngest child has become self-sufficient, and humans have a particularly long childhood during which they are dependent on their parents. Menopause may have arisen to protect women from the increased risk of childbirth in later age, keeping them alive longer to take care of the children they had already. This might also explain why men—who don't suffer such an increased risk—can be reproductive until much later in life. So perhaps menopause developed as an adaptation to maximize the chances of a woman's children growing up—and thus propagating her genes. This is the so-called good mother hypothesis. Indeed, the few species where females live well beyond their reproductive years are ones whose offspring require extended maternal care. However, even in these species, there is a gradual loss of fertility rather than the abrupt change brought on by menopause. For example, although the fertility of elephants declines with age, they, unlike humans, can continue to have offspring until very late in life. Similarly, while living beyond childbearing age has also been observed in chimpanzees, menopause actually occurs near the end of their life span.

The grandmother hypothesis for the origin of menopause takes the idea one generation further. Proposed by the anthropologist Kristen Hawkes, it argues that living longer makes sense if a woman helps in the care of her grandchildren, thus improving their survival and ability to reproduce. But others contend that it is rarely better for a woman to give up the chance to pass on half her genes through continuing to have her own children for the sake of improving the survival of grandchildren, who only carry a quarter of her genes.

Another idea, based on studying killer whales, one of the few species that, like humans, has true menopause and lives in groups, is that menopause is a way to avoid intergenerational conflict. In some species that breed in groups, reproduction is suppressed in younger females, who act as helpers to older, reproducing females. But in humans, there is little overlap: women stop breeding when the next generation starts to breed. Women would have no interest in helping their mother-in-law have more children, since they would not have any genes in common. But a woman who helps her daughter-in-law reproduce will help to bequeath a quarter of her genes to her grandchildren. So her best strategy may be to stop breeding and help her daughter-in-law breed instead.

It could also simply be that the number of eggs in a female evolved to match its average life span in the wild. Steven Austad, now at the University of Alabama in Birmingham, points out that menopause may not be adaptive at all in the sense of favoring mothering or grandmothering. It was only about 40,000 years ago that we became much longer lived than Neanderthals and chimpanzees. So perhaps there has just not been enough time for the aging of human ovaries to adapt to that increased life span. In the absence of hard experiments, scientists, especially evolutionary biologists, love to argue.

These theories of why we age depend on the idea of a disposable body being able to pass on its genes before it ages and dies. In doing so, the aging clock is somehow reset with each generation. Such theories should apply only to organisms where there is a clear distinction between parents and offspring. Certainly that distinction is true for all sexual reproduction. Sex evolved because it is an efficient mechanism to produce genetic variation in the offspring by generating different combinations of genes from each parent, allowing organisms to adapt to changing environments. In some sense, you could say that death is the price we pay for sex! While this may be a catchy statement, not all animals with a distinction between germ line and soma reproduce sexually, Moreover, scientists have found that even single-celled organisms such as yeast and bacteria age and die, as long as there is a clear distinction between mother and daughter cells.

The laws of evolution apply to all species, and all life forms are made up of the same substances. Biologists from Darwin onward have never ceased to be amazed that evolution, which is simply selecting for fitness—or the efficiency with which each species can pass on its genes—has given rise to the amazing variety of life forms on Earth. That variety includes a huge range of life spans, from those best measured in hours to those that may stretch more than a century. For human beings seeking to understand the potential limits of our own longevity, some surprising lessons can be learned from species across the animal kingdom. ♦

Excerpted from Why We Die by Venki Ramakrishnan. Reprinted by permission of HarperCollins. Copyright © 2024 by Venki Ramakrishnan.