Why We Die: The New Science of Aging and the Quest for Immortality

by Venki Ramakrishnan

Philosopher Stephen Cave argues that the quest for immortality has driven human civilization for centuries. He classifies our coping strategies into four plans. The first, or Plan A, is simply to try to live forever or as long as possible. If that fails, then Plan B is to be reborn physically after you die. In Plan C, even if our body decays and cannot be resurrected, our essence continues as an immortal soul. And finally, Plan D means living on through our legacy, whether that consists of works and monuments or biological offspring.

The immortality merchants of today—the researchers who propose trying to extend life indefinitely and the billionaires who fund them—are really a modern take on the prophets of old, promising a long life largely free of the fear of encroaching old age and death. Who would have this life? The tiny fraction of the population who could afford it? What would be the ethics of treating or modifying humans to achieve this? And if it becomes widely available, what sort of society would we have? Would we be sleepwalking into a future without considering the potential social, economic, and political consequences of humans living well beyond our current life spans? Given recent advances and the enormous amount of money pouring into aging research, we must ask where this research is leading us, as well as what it suggests about the limits of human beings.

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.

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 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 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.

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.

mutations that increase life span reduce fecundity (the rate at which an organism produces offspring). Similarly, reducing the caloric intake of the daily food given to these organisms also increases life span and reduces fecundity.

the three biggest contributors have been modern sanitation and vaccines, which both prevented the spread of infection, and artificial fertilizers. Other significant innovations were antibiotics, blood transfusions (crucial for accidents and surgery), and sterilization of water and food by chlorination and pasteurization.

A few findings may surprise you: it recommends tea over coffee, reducing our intake of iron (often found in multivitamins), and flossing regularly. But many of the suggestions are what one might expect: eating moderately and healthily and avoiding fast food, processed meat, and excessive carbohydrate consumption, as well as exercising and maintaining a healthy weight, getting adequate sleep, reducing stress, staying mentally active, and having an optimistic outlook. It helps not to have diabetes, and having a close family member who lived to be over ninety is a big plus.

How could a thriving, vibrant city like Hampi have disintegrated and no longer exist? Throughout history, one of the fastest ways for a society to crumble was the breakdown of law and order resulting from a government’s loss of control due to civil unrest or a war. And just as with society, loss of control and regulation in biology leads to decay and death, not only of the cell but of the entire organism.

You could think of the process of life as an enormous program that somehow activates itself using the blueprint provided by DNA. The word blueprint is a convenient metaphor, but we should not take it too literally, because a blueprint implies a rigid manufacturing process that produces a strictly defined product. Unquestionably, DNA is the central hub for regulating the overall program of the cell. But I think of the cell

as more like a democracy than a dictatorship. Just as an ideal government is not autocratic but responsive to the needs of its people over time, DNA does not dictate the entire process. Rather, conditions in the cell and its environment decide which parts of the DNA are used, as well as how often and when.

WHEN A CELL SENSES SIGNIFICANT DNA damage, it triggers what is called the DNA damage response. This is not all good news: the damage response often has greater consequences for aging than the damage itself.

When we are stressed, our body produces much more cortisol—referred to as the stress hormone—which reduces telomerase activity.

As cells develop, they will methylate their DNA in the region of genes they want to shut down, and leave unmethylated those regions that contain genes they need to actively use. So cells that differentiate into skin cells will have a different methylation pattern from, say, neurons.

WE ALL KNOW THAT PEOPLE age at different rates. Some people look old at fifty, while others are remarkably youthful into their eighties. Some of this comes down to genetics, but aging can also be accelerated by stress and hardship. From the moment we are conceived, our cells don’t just acquire mutations in the DNA affecting the underlying code itself. They also acquire epigenetic marks. As we saw with the Dutch famine survivors, some of those marks are the result of environmental stress.

If we can overcome the technical problems, the possibilities are enormous and wide-ranging. Perhaps we could introduce new pancreatic cells that produce insulin in patients with diabetes, replace damaged heart muscles after a heart attack, or even regrow neurons in people who have suffered a stroke or a neurodegenerative disease like Alzheimer’s. The potential for such breakthroughs is why billions of dollars are being invested in stem cell research today.

If you stress or starve the cell, autophagy goes up.

autophagy is used both to ensure cells develop normally and to jettison defective proteins or aging structures, as well as to destroy bacteria and viruses. It has so many essential functions that when it fails even partially, we develop serious problems, from cancer to neurodegenerative diseases.

In rodents and other species, animals on CR lived 20–50 percent longer, as judged by both average life span and maximum life span. Moreover, they appeared to have delayed the onset of several diseases of aging, including diabetes, cardiovascular disease, cognitive decline, and cancer.

Most scientists working on aging agree that dietary restriction can extend both healthy life and overall life span in mice and also leads to reductions in cancer, diabetes, and overall mortality in humans. On a more granular level, limiting protein intake or even just reducing consumption of specific amino acids such as methionine and tryptophan (both of which are essential in our diets because our bodies don’t produce them) can confer at least some of the advantages of overall dietary restriction.

So why aren’t we all on CR diets? For the same reason that rich countries face an epidemic of obesity: we now live in a time of plentiful food, and we have not evolved to be abstemious. Moreover, caloric restriction is not without its drawbacks. It can slow down wound healing, make you more prone to infection, and cause you to lose muscle mass, all serious problems in old age. Among its other reported downsides are a feeling of being cold due to reduced body temperature, and a loss of libido. And, of course, a side effect that to most readers will seem blindingly obvious: people on calorically restricted diets feel perpetually hungry. In fact, animals on CR diets all revert to eating as much as possible when permitted.

We can now see how TOR is connected to caloric restriction. Under CR, there are fewer nutrients around, and TOR, recognizing that, can switch off protein synthesis and other growth pathways, and also green-light autophagy. We have already seen how important both controlling protein synthesis and clearing defective proteins and other structures through autophagy are to keep the cell working optimally, and to aging in general. But what if we didn’t need caloric restriction to reap its benefits—if we could inhibit a normal TOR and mimic its effects, with no change to the human diet? TOR was discovered precisely because it was the target of rapamycin. Might rapamycin be the long-sought pill that could imitate CR without our having to cut down on how much we eat?

TOR promotes cell growth, which is essential in early life. Later, however, it is unable to switch itself off even when the growth it drives becomes excessive, leading to cell deterioration and the onset of age-related diseases. They go on to suggest that while these pathways that cause aging cannot be completely switched off by a mutation (because that would be harmful or even lethal early in life), perhaps they can be inhibited by drugs such as rapamycin years later, when an uninhibited TOR becomes a problem after individuals have reached middle age.

A study of 2,700 Danish twins suggested that the heritability of human longevity—a quantitative measure of how much differences in genes account for differences in their ages at death—was only about 25 percent.

A second study, in humans, showed that diabetics on metformin lived longer not only than diabetics on other drugs but also longer than nondiabetics—a significant finding, since diabetes itself is a risk factor for aging and death.

Just as monetary currency increased trade and prosperity dramatically, enabling complex societies to evolve, and just as the energy currency of electricity allowed societies to become incredibly complex technologically, the efficient production of ATP allowed cells to become ever more complex and specialized. ATP is a small molecule and makes its way, as needed, all over the cell. It provides the energy for everything from making the components of the cell, to moving around parts of the cell, to enabling cells themselves to move. Our muscles use ATP to generate the power to contract. In our brain, ATP maintains the voltage across membranes in our neurons while they transmit electrical signals and fire impulses. The human body has to generate roughly its own weight in ATP every day, and the brain alone uses about a fifth of that. Just thinking uses hundreds of calories a day. And mitochondria provide nearly all of that ATP.

We inherit our mitochondria exclusively from our mothers because the sperm contributes none of its mitochondria to the fertilized egg. As a result, diseases due to defects in the mitochondrial genome are inherited entirely from the mother.

So you can think of damage to mitochondria from oxidation as a case of our cells rusting from within.

WHILE SCIENTISTS AND THE PHARMACEUTICAL industry strive to produce a pill that will combat mitochondrial dysfunction, there is a simple way to stimulate the production of new mitochondria, and it doesn’t have to cost a penny: exercise. Physical activity turns on some of the same pathways that stimulate mitochondrial production in tissues ranging from our muscles to our brain. Exercise too is an example of hormesis. Too much exercise can be harmful, and even moderate exercise can temporarily increase blood pressure, oxidative stress, and inflammation, all of which are potentially problematic. Yet as long as the amount of exercise is not so excessive as to injure us, which depends on our health and many individual factors, it is highly beneficial. One way it spurs mitochondrial function is by generating the reactive oxygen species produced by incomplete oxidation when we breathe, which, as discussed earlier in this chapter, can be beneficial in the right amounts. Of course, exercise does far more than that and benefits us in many ways: reducing stress, maintaining muscle and bone mass, countering diabetes and obesity, improving sleep, and strengthening immunity. Add to this list the healthful effects of fresh mitochondria.

The study concluded by saying that removal of senescent cells could prevent or delay aging disorders and extend healthy life. A few years later, the same team demonstrated that mice whose senescent cells were killed off were healthier in many ways than those in whom these cells were allowed to build up. Their kidneys functioned better, their hearts were more resilient to stress, they were more active, and they fended off cancers for longer. They also lived about 20–30 percent longer.

Apart from a gradual loss in the number of stem cells, there is a problem with the remaining stem cells. During much of our life, we have a healthy diversity of cells that have acquired different mutations, making us a mosaic of genomes. As we age, our stem cells acquire mutations, some of which cause them to proliferate more rapidly. These rapidly multiplying stem cells are not necessarily the best for regenerating tissues, but because they have a growth advantage, they outcompete their counterparts. Consequently, old age leaves us with stem cells that have all descended from just a few clones. Not only are they less effective, but—of greater concern—the clonal mutants themselves can become sources of cancer.

Parabiosis from young animals reduced the activity of genes that caused inflammation, whereas exercise increased the activity of genes that decline with age. Although they both stimulated growth of brain tissue, each stimulated different types of cells.

De Grey’s central idea is that if we can improve average life expectancy faster than we age—if, in other words, life expectancy increases by more than a year annually—we can hope to escape death altogether. He calls this “escape velocity.” To reach escape velocity, de Grey has a plan. Bucking the conventional wisdom of the biological community, he proposes that we can defeat aging if we crack seven key problems: (1) replenish cells that are lost or damaged over time, (2) remove senescent cells, (3) prevent stiffening of structures around the cell with age, (4) prevent mitochondrial mutations, for example by engineering mitochondria so that they don’t make any proteins themselves using their own genome but import them exclusively from the rest of the cell, (5) restore the elasticity and flexibility of the structural support to cells that stiffen with age, (6) do away with telomere lengthening machinery so that we don’t get cancer, and (7) figure out how to reengineer stem cells so that our cells and tissues don’t atrophy. He calls his program to solve these problems SENS: strategies for engineered negligible senescence.

Today there are more than 700 biotech companies focused on aging and longevity, with a combined market cap of at least $30 billion. Some

AGING RESEARCH TAPS INTO OUR primeval fear of death, with many people willing to subscribe to anything that might postpone or banish it. California tech billionaires, especially. Many of them made their money in the software industry, and because they were able to write programs to carry out rapid financial transactions or swap information of various sorts, they believe aging to be just another engineering problem to be solved by hacking the code of life. The pace of success in the software industry has made them impatient. They are used to making major breakthroughs in a couple of years, sometimes even a couple of months, and they underestimate the complexity of aging. They

“It is difficult to get a man to understand something when his salary depends on his not understanding it”?

the latest International Classification of Diseases by the World Health Organization (WHO) omitted aging. While many in the gerontology community were disappointed by this decision, others welcomed it because they worried that classifying aging itself as a disease could lead to inadequate care from physicians: rather than pinpoint the cause of a condition, they would simply dismiss it as an unavoidable consequence of old age.

It is conceptually easy to define mortality, but morbidity is much fuzzier. It is defined as a disease, but many chronic illnesses such as diabetes, high-blood pressure, or atherosclerosis can be treated with medication and people can lead perfectly normal and satisfactory lives. I take medication for high cholesterol and high blood pressure, which might be termed chronic diseases, but I can do most things I like, including bicycling and hiking. If you simply count diagnoses for diseases as morbidities, then you are not capturing a true picture of whether the person is living a reasonably healthy life or is decrepit, incapacitated, and suffering. Statistics regarding morbidities in old age must be looked at carefully.

For example, in the late eighteenth century, European women had about five children on average at a time when life expectancy was low due to high infant mortality, but that fertility rate now ranges from 1.4 to 2.6, depending on the country. Eventually the birth and death rates became roughly equal, and the population has stabilized at some new higher level. Over the course of the nineteenth and twentieth centuries, this happened in much of the West, as well as in many Asian countries such as Japan and South Korea.

Moreover, even after they can no longer do the job they did for much of their career and have to retire, older people can still be useful and productive in many ways for as much of the rest of their lives as possible. There is a lot of evidence that having a purpose in life reduces mortality from all causes as well as the incidence of stroke, heart disease, mild cognitive decline, and Alzheimer’s. And elderly professionals do have a wealth of experience and a deep knowledge of their field. They can be unparalleled sources of advice and mentorship; they can participate in civic activities. Peter Moore, whom I mentioned earlier, is a great example of someone who has retired from his professorship but still makes himself extremely valuable to the scientific community.

As always, the answer to problems created by technology seems to be even more far-fetched technology.

I AM NOT SURE THAT if we lived so much longer, we would be any more satisfied. Now that we live twice as long as we did a century ago, we still aren’t content with that entire extra life. Rather, we seem to be even more obsessed with death. If we live to be 120 or 150 years old, we will fret about why we can’t live to 300. The quest for life extension is like chasing a mirage: nothing will ever be enough short of true immortality. And there is no such thing. Even if we conquer aging, we will die of accidents, wars, viral pandemics, or environmental catastrophes. It may be simpler to accept that our life is limited.

This obsession with mortality is probably unique to humans. It is only the accidental evolution of our brain and consciousness, and our development of language to communicate our fears, that has made our species so fixated on the end. The writer and editor Allison Arieff has pointed out the irony that the same Silicon Valley culture that produces gadgets designed to be obsolete and discarded every few years seems to be obsessed with living forever. She quotes the writer Barbara Ehrenreich, “You can think of death bitterly or with resignation and take every possible measure to postpone it. Or, more realistically, you can think of life as an interruption of an eternity of personal nonexistence, and seize it as a brief opportunity to observe and interact with the living, ever-surprising world around us.” Arieff believes that our very humanness is intertwined with the fact of our mortality.