3

Demystifying Aging

Aging has held us in a psychological stranglehold ever since we realized it existed, and that stranglehold remains intact to this day. I discussed in Chapter 2 the effect that this has on our willingness to think rationally about how terrible a thing aging is, and I explained why this irrationality used to have a valid psychological basis while there was no hope of combating aging, and also why it is now such a formidable obstacle.

There’s a complication, though. I’ve told you that we’ve recently reached the point where we can engage in the rational design of therapies to defeat aging; most of the rest of this book is an account of my favored approach to that design. But in order to ensure that you can read that account with an open mind, I need to dispose beforehand of a particularly insidious aspect of the pro-aging trance: the fact that most people already know, in their heart of hearts, that there is a possibility that aging will eventually be defeated.

Why is this a problem? Indeed, at first sight you might think that it would make my job easier, since surely it means that the pro-aging trance is not particularly deep. Unfortunately, however, self-sustained delusions don’t work like that. Just as it’s rational to be irrational about the desirability of aging in order to make your peace with it, it’s also rational to be irrational about the feasibility of defeating aging while the chance of defeating it any time soon remains low. If you think there’s even a 1 percent chance of defeating aging within your lifetime (or within the lifetime of someone you love), that sliver of hope will prey on your mind and keep your pro-aging trance uncomfortably fragile, however hard you’ve worked to convince yourself that aging is actually not such a bad thing after all. If you’re completely convinced that aging is immutable, by contrast, you can sleep more soundly.

The key qualification in what I’ve just said, of course, is the phrase “while the chance of defeating it any time soon remains low.” Once that chance becomes respectable, you’re better off doing your bit to increase it further—not just the actual laboratory work, of course, but also agitating, cajoling, helping others (not least those with influence over research funding) to awaken from their own pro-aging trance. Conversely, if the chance of aging being defeated is really tiny despite whatever you do, the cost-benefit balance of abandoning your comfort zone may tip the other way, in favor of applying the same irrationality to the existence of such a possibility as you may be doing in respect of the pros and cons of aging.

Therefore, in this chapter I’m going to describe what aging is in practical terms, so as to demystify it for you. By doing so I plan to show you that the popular presumption that aging is a phenomenon unlike all other health conditions, somehow beyond even the theoretical reach of medical technology, cannot be reconciled with established fact. Thus, by the end of this chapter I aim to have placed you in the awkward position of still wanting to believe (for your own peace of mind) that aging is immutable and thus not worth worrying about, but no longer actually being able to believe that. From that point on, my task will be the relatively easy one of explaining why our chances of defeating aging in the foreseeable future are not just non-zero, but high enough to justify my having broken your pro-aging trance in the first place. Justify, because once your pro-aging trance is no more, you—yes, you—can make a difference to how soon aging is defeated, and the fulfilment you will derive from that effort will far outweigh any comfort you may have found in your previous certainty that aging can never be combated.

The Illusory Boundary Between Aging and Disease

It used to be the case that people died of aging, but, if you believe what’s written on death certificates, these days they rarely do. The phrase “natural causes” was the accepted term for the cause of death when it occurred at an advanced age and in the absence of clearly defined pathology. These days, however, that’s considered inadequately informative, and coroners or their equivalent are encouraged to enter something more specific.¹

We all know, however, that quite a few people do indeed die in that way—not from a heart attack, not from pneumonia or influenza, not from cancer, not even from a stroke, but just peacefully, often in their sleep, because their heart simply stops. These relatively lucky people indisputably die of aging.

That brings me to the first of several times in this book when I must engage in the unpleasant business of exposing a serious distortion of the facts that has been perpetrated—often unintentionally, I realize—by a large number of senior researchers in the field of biogerontology, the study of how aging works. This distortion has by now been generally seen for the awful error that it was, but the disastrous consequences for the field are still being felt, and probably will be for many years to come. Through the 1950s, ’60s, and ’70s, while gerontology was making its big push for recognition as a legitimate biological discipline, rhetoric developed to the effect that the infirmities of aging should be viewed as separable into two distinct phenomena: on the one hand, age-related diseases, and on the other hand, “aging itself.” This distinction was publicly defended mainly on the basis that everyone has aging, whereas no age-related disease is universal. The motivation for this distinction, on the other hand, was purely pragmatic: by ring-fencing their area of work intellectually, gerontologists hoped to ring-fence it financially, too.

And ring-fence it they did, most notably with the creation (while President Richard Nixon was paying limited attention, so it is said) of the National Institute on Aging.² So far, so good. However, it’s not good enough. All gerontologists know full well that it’s no accident that age-related diseases are age-related: they appear at advanced ages because they are consequences of aging, or (to put it another way) because aging is no more and no less than the collective early stages of the various age-related diseases. Gerontologists knew this back then, too. Thus, they also should have seen back then that, by trumpeting the short-termist rhetoric that “aging is not a disease,” they were constructing an immense obstacle for themselves in the longer term: the response from policy makers that, well, if it’s not a disease, why should we spend money on combating it? The era of that backlash began decades ago and shows no sign of ending. Gerontologists these days point out over and over again that if we could just postpone aging even a little bit we would derive far more health benefits than would result from even the most decisive breakthroughs against specific diseases, but over and over again their paymasters fail to get the message.³ I maintain that it is overwhelmingly the inaccurate rhetoric of gerontologists, resulting from their misguided policy of previous decades, that has brought about such entrenched resistance to a simple, obvious and (within the field) universally agreed-upon truth about the potential value of postponing aging.

I told you just now that age-related diseases are merely consequences of aging; now I’ll tell you why we know that. In the process, I’ll also tell you why aging has the range of speeds that it does—within a single individual, and between individuals, and also between species.

Why Aging Doesn’t Need a Timer

The fact that a fair proportion of people die of natural causes, rather than of any specific disease, might at first sight imply that aging is a process independent of diseases: something that increases people’s vulnerability to disease (thus making diseases more common among the elderly) but that also kills us itself if no disease does so first. This is only partly correct. The elderly are indeed more vulnerable to infectious diseases, because one aspect of aging is the decline of the immune system. However, most diseases of old age have only a minor, if any, infectious component: they are mostly or wholly intrinsic. Take cancer, for example. A few types of cancer affect young people, but most types are never seen in people below the age of forty or so (except for people with very rare congenital DNA repair deficiencies). Some cancers are caused by viral infections—the best known of these is cervical cancer, caused by the human papilloma virus. But the major underlying cause of cancer is the simple accumulation over time of mutations in our chromosomes. Mutations are inevitable: they happen as a purely intrinsic side effect of our biology. The time they most often happen is when the DNA of our chromosomes is replicated during the process of cell division. The accumulation of mutations is, therefore, part of aging, and cancer is predominantly a consequence of aging—or, if you prefer, part of the later stages of aging.

Sounds pretty simple, doesn’t it? And yet, there is a pervasive presumption—one shared even by some biologists—that aging is some kind of mysterious phenomenon qualitatively different from any disease: something that has eluded, and thus may forever elude, biological elucidation. There are a few main reasons for this presumption, so I’ll briefly describe those reasons and why they’re wrong.

The first is that aging proceeds so much more slowly than specific diseases. So slowly, in fact, that we hardly notice its progression, whereas we are much more keenly aware of the more rapid development of conditions like cancer or diabetes. This is a conspicuous difference, but in fact it’s just what one would expect, because aging is a downward spiral. The more we age, the more our self-repair functions decline, so the less able our body is to stop us aging, so we age faster and faster. So it’s to be expected that the late stages of aging, the diseases, would go faster than the earlier stages.

Another thing that confuses people about aging is that it proceeds at very different rates in different species but at pretty similar rates in all members of a given species. This might be thought to imply that there is some kind of internal clock driving the process, which is set at different speeds in different species. The inference is that this clock is somehow immune to biomedical intervention, because changing its speed would require us to stop being human. But that’s not correct either, for two reasons. First, even if there were such a timer, we could in principle postpone the later stages of aging without changing the speed of the timer itself—I’ll be elaborating on this below. And second, if there were such a clock, why shouldn’t it be amenable to biomedical intervention anyway? The fact that organisms of the same species tend to age at the same rate is just one consequence of the fact that they’re genetically very similar to each other. It says nothing about what can or cannot be altered by biomedical technology.

Perhaps the most common reason for the belief that there is an “aging clock” is the fact that the various outcomes of aging (including age-related diseases) all tend to appear at more or less the same age in different individuals within a given species. Surely this must mean that there is indeed a central aging clock, which has ticked down enough to set these diseases on their way, right? No—and, again, this is for two main reasons.

First, this is exactly what one would expect if the debilities of old age were just the later stages of a multifaceted decay process, just so long as that system has one key feature: a rich degree of interconnection of the various chains of cause and effect. If lots of things are going quietly wrong throughout life, and their accumulation is feeding back on themselves and each other to accelerate them, they’ll necessarily all proceed at more or less the same rate and all “go critical” (explode into clinically identifiable disease) at about the same age. And that interconnectedness is, indisputably, indeed present in aging.

Second, if we think about the evolutionary basis of aging for a moment we can easily see that, even without much interconnection between the chains of events that lead to the various diseases of aging, we’d still expect to have them all emerge at roughly the same age. This is because, if we had genes that defended against one particular cause of death so well that everyone was dead from other causes before they died of that one, those genes would not be protected by evolutionary selection and would accumulate random, mild mutations from one generation to the next. Over evolutionary time, therefore, the quality of those genes would thereby sink down to the point where the disease they protected against occurred at the same age as all other age-related diseases.

Another common but incorrect reason for thinking that aging is somehow special is that it is “universal”—it happens to everyone. Well, yes: If you live long enough, you’ll exhibit signs of aging. But this is only a corollary of my earlier point about rates—that aging is really slow compared to age-related disease. Because age-related diseases progress from diagnosability to death rather quickly, many people die of one such disease before the others emerge, or at least while they are still too early-stage to have been diagnosed. But if those people hadn’t suffered the disease that killed them, they’d have lived long enough to suffer others. In fact, all the diseases of aging are universal in the sense in which the question ought to be asked: namely, you’ll definitely get them if you don’t get something else first.

Thus, in concluding this section I hope to have convinced you that aging is not something inherently mysterious, beyond our power to fathom. There is no ticking time bomb—just the accumulation of damage. Aging of the body, just like aging of a car or a house, is merely a maintenance problem. And of course, we have hundred-year-old cars and (in Europe anyway!) thousand-year-old buildings still functioning as well as when they were built—despite the fact that they were not designed to last even a fraction of that length of time. At the very least, the precedent of cars and houses gives cause for cautious optimism that aging can be postponed indefinitely by sufficiently thorough and frequent maintenance.

The Corollary That Even Most Experts Overlook

Everything I’ve explained above is well known to biogerontologists, the people who study aging. From the way that most biogerontologists go about exploring how to postpone aging, however, you might think they didn’t know this at all. People who work to combat specific diseases explore the way in which the disease progresses and look for ways to disrupt that pathway. In gerontology, however, the predominant modus operandi for designing interventions is to compare organisms that age at different rates—different species, or individuals of the same species in different conditions—and to come up with ways to copy or extrapolate those differences so as to make aging happen more slowly. This is effectively an a priori capitulation, not even trying to dissect and disrupt the process but rather treating it as a black box. It’s especially surprising when you bear in mind that biogerontologists certainly do work hard to dissect the aging process in order to understand it—just not in order to combat it. (Unfortunately, these two goals motivate different types of dissection.) Rather, the most promising ways to postpone aging are by disrupting the pathways underlying it, just as we do for specific diseases. Thus, since aging is just the accumulation of damage, we should be looking at ways to alleviate that accumulation. I’ll return to this in greater detail in the next chapter and beyond.

Why Fixing Aging Is Easier than Fixing Similarly Complex Machines

Now let’s move on to another reason that people often give for clinging to the belief that aging is inherently inaccessible to biomedical intervention. If aging is just damage, and the body is just a complex machine, it stands to reason that we can apply the same principles to alleviating the damage of aging as we do to alleviating damage to machines. But people sometimes point out that the body has a host of self-repair and self-maintenance processes, which machines basically don’t have, hence we’re not really machines at all. Thus, they claim, the maintainability of machines is no basis for confidence that the body is in principle similarly maintainable.

Well, I invite you to think about that logic for a moment. We have built-in repair and maintenance machinery. Why on earth would that make it harder to maintain our bodies in good working order? Clearly the opposite is the case: if our bodies are doing most of the job automatically, that leaves less for us to do with biomedical technology.

Let me stress that I’m not saying the task is easy. The body is a great deal more complicated than any man-made machine—and what’s more, we didn’t design it, so we have to reverse-engineer its workings in order to understand it well enough to keep it running. But that doesn’t change the above logic: the natural capacity for self-repair that we’re born with is our ally in the anti-aging crusade, not our enemy.

Postponed Aging in the Lab: No Longer Just Theory

By now I may have satisfied some readers that, indeed, aging is not a mystical phenomenon beyond the reach of mere, um, mortals. I’m well aware, however, that many people find theoretical arguments only modestly persuasive, even if no holes in those arguments seem evident. Such people—you, perhaps—feel altogether more comfortable with a conclusion if it is backed up by hard evidence. You’ll be pleased to discover, then, that for several decades scientists have been finding ways to lengthen the lives of various organisms in the laboratory. Best of all, they’ve done this not by extending those organisms’ period of declining vigor at the end of life, nor (by and large) by keeping them immature for longer, but by extending the period of peak health and vigor between maturity and frailty.

One highly robust life-extension technique was discovered over twenty years ago by a young Canadian researcher named Michael Rose, who is now a professor at the University of California, Irvine. Rose is an evolutionary biologist, and at that time he already had a thorough knowledge of the ways in which evolution optimizes a species’ longevity for its ecological niche. He realized that it might be possible to breed longer lived organisms, rather in the vein of the Howard families in Robert Heinlein’s Lazarus Long books, by maintaining them over many generations and only allowing those with the longest lives (actually, strictly speaking the longest reproductive lives) to contribute to the next generation. It would take many more generations than Heinlein described, but Rose was working with fruit flies, which reach maturity only a week after their own conception. And it worked, spectacularly: Rose was eventually able to achieve average lifespans twice those in his starting population.⁴

This approach, impressive though it was, has a fundamental and rather relevant limitation—a limitation that has probably not escaped you. Specifically: it can’t be applied to you, only to your great-great-great…great-grandchildren. Rose knew this, too, of course, and more recently he’s been working hard to identify the genetic, and thence molecular, basis for this life extension with a view to eventual therapies that might work on those of us unfortunate enough to be already alive. But thus far, all he has are long-lived distant descendents of short-lived flies.

Luckily, other laboratory life-extension successes have not shared this drawback. The first and best-known way to delay aging in the laboratory was discovered way back in the 1930s by a researcher named Clive McCay, working with laboratory mice.⁵ It is called calorie restriction—or sometimes dietary restriction, energy restriction or food restriction. It’s an extraordinarily simple concept: If you feed rodents (or, in fact, a wide variety of other animals) a bit less than they would like, they tend to live longer than if they have as much food as they want. This is not simply because such animals tend to overeat given the chance and become obese: animals that “eat sensibly” and maintain a constant body weight throughout most of their lives still live less long than those given less food.

The next researcher (not counting Rose) to take the postponement of aging a major leap forward was a geneticist working with a third, almost equally widely studied, model organism: the nematode worm Caenorhabditis elegans. His name is Tom Johnson. He was not, strictly speaking, the discoverer of the phenomenon I will describe here—that honor goes to one of his coworkers—but he spearheaded the work on it for some years and that work has become identified with him, so I’ll focus on him for the moment. What Johnson and his colleagues discovered and researched was a mutation in a single, identified gene, which on its own—without any of the sustained selective pressure employed by Rose—added at least 50 percent to the youthful adult lifespan of his worms.⁶ This was an immense breakthrough, because single genes can be modified in the test tube and then introduced into the body by gene therapy: either germline gene therapy, which affects only the recipient’s descendents, or somatic gene therapy, which affects the organism that receives the treatment. Somatic gene therapy for humans is still taking its baby steps, but there is widespread confidence that it’ll work well eventually. And human germline gene therapy raises ethical concerns (though there are technical approaches to avoiding these). But as a proof of principle, the postponement of aging by a single, defined genetic alteration is vastly closer to clinical applicability than something accomplished by selection over many generations and affecting an unknown number of genes.

Perhaps because of this, and also partly because of the experimental methods involved, Johnson’s result initiated a massive surge in attempts to identify genetic alterations to lab animals that would delay their aging. This surge actually took a few years to get going, but when a second laboratory (that of Cynthia Kenyon at the University of California San Francisco) identified a mutation in a different gene, also in nematodes, that extended their lives even more than Johnson’s mutation did, the topic became one of the hottest in the whole of biology.⁷ Kenyon and other top biogerontology researchers have been able to publish nearly all their best work in the very top few journals ever since—journals that scientists in most fields are lucky to publish in even a couple of times in their whole career.

Johnson’s and Kenyon’s mutations were in different genes, but these genes participate in largely the same range of metabolic processes. In particular, they help to mediate an alternative developmental trajectory that normal, nonmutant nematodes can follow, termed the dauer pathway. When a nematode larva follows the dauer pathway, it suspends its development for a period than can last much longer than the entire lifetime of a nematode that follows the normal, non-dauer trajectory. What, you may ask, triggers this developmental choice? And what “restarts” development and the resumption of the path toward normal nematode adulthood? Well, it just so happens that the usual trigger for entry into the dauer pathway is starvation, and that exit from dauer is stimulated by the presence of food. In other words, the dauer pathway is neither more nor less than nematodes’ extreme version of rodents’ response to calorie restriction.

Since Johnson’s and Kenyon’s breakthroughs, many other mutants have been discovered—not only in nematodes but also in fruit flies and mice—that have extended lifespans, and nearly all of these mutations have also disrupted genetic machinery that mediates the sensing or metabolism of nutrients. In general, the mutations confer a delay of aging at most equal to that achievable by simply restricting calorie intake.⁸ A few publications have appeared in the past few years reporting life extension in mice caused by reducing oxidative stress,⁹,¹⁰,¹¹ but I am currently cautious about the reproducibility of these findings, because a huge number of other attempts to postpone mouse aging in the laboratory in that way has failed.

At this point, therefore, I can point to a pretty compelling, double-whammy argument that aging is worth trying to tackle. On the one hand we should in principle be able to postpone aging by a large degree; moreover, we have actually done so in the laboratory. This is surely great cause for optimism that we will do so in the clinic in the not-too-distant future.

Isn’t it?

Well, I would hardly have written this book if that were not indeed my ultimate conclusion. However, the operative word here is “ultimate.” Before closing this chapter, I must explain why calorie restriction and its genetic emulation are not, in fact, pointers to the most promising route to combating human aging.

Calorie Restriction and Its Emulation: A False Dawn

Do you know any perfectionists?

I do—and I always have, because my mother is one. I certainly wouldn’t be where I am today without my mother, and that includes her influence on me as well as her sheer hard work and determination to give me the best start in life. But there are certain ways in which her influence on me was to show me a bad example, and her perfectionism is perhaps the most extreme such case. I feel that in many ways it has prevented her from achieving what she might have in her life, so I’ve never let myself become a perfectionist—and I’ve certainly never regretted that.

What’s wrong with perfectionism? We all know the main problem with it: Perfectionism takes time. Most people are interested in getting things done, and there are many circumstances in which a quick and dirty job is the best policy, because the advantages of the “quick” outweigh the disadvantages of the “dirty.” There are certainly other circumstances in which the balance is reversed, though—where a more painstaking approach is to be preferred; hence, the ideal is to have good intuition and judgment for how much attention to detail is appropriate in any particular case.

You may think that the above two paragraphs are a remarkably dramatic digression, so let me surprise you by bringing my chain of reasoning straight back to calorie restriction and its limitations in just a single sentence. The life-extending response to nutrient deprivation is neither more nor less than the expression of an organism’s genetically programmed intuition regarding the appropriate degree of attention to detail that it should exercise with regard to its day-to-day molecular and cellular functioning—and, because that’s all it is, it’s not amenable to substantial enhancement by foreseeable biomedical technology.

Some elaboration is in order, so here goes.

I’ve explained, earlier in this chapter, that there are no genes for aging in most species, simply because genes only survive if they confer enough benefit (and thereby enjoy enough selective pressure for their survival) to outweigh the constant stream of random mutations that all genes experience over evolutionary time, and a gene can’t confer any benefit if it only mediates a process that would happen anyway. The only species in which aging is actively driven by genetic machinery are those (such as salmon) in which there is some reason to age and die rapidly—something that does not happen by default to a machine that was running well for a long time previously. Slow aging, the sort that we see in nearly all species, is the default scenario, so no genes causing it can survive.

What we most certainly do have genes for, by contrast, is the panoply of interacting processes that turns each of us from a single cell into a fertile adult and that maintain our vigor and fertility until an age at which (in the wild) we’re very likely to have succumbed to starvation, predation, and so on. Now, what does that have to do with perfectionism? Well, the reason we have genes to keep us going until we’re very likely to have been killed is because the longer our fertile lives continue, the more progeny we’ll have time to have, so the greater the chance that our genes will be passed to future generations.

But what about the other end of our fertile life—the beginning? The same applies: the sooner we achieve sexual maturity, the more offspring we’ll have time to produce before we die. But here’s the problem: the beginning and end of fertile life are not independent of each other. Growth from a single cell to a fertile adult is a process as complex as any known, and mistakes always happen during its execution. You can probably see the light at the end of this logical tunnel now: The organism has a choice between doing a quick and dirty job of its growth, leading to early fertility but sloppy construction, or a more perfectionist job that delays sexual maturity but creates a more smooth-running machine in the end. And a more sloppily constructed animal will on average live less long—partly because it may be less able to defend itself against predators, famine, and such like, but also because the molecular and cellular damage that it laid down during its headlong rush to maturity has effectively given it a head start in the aging process. There’s abundant evidence that this is not just a reasonable idea but is also actually borne out in nature: for example, when you compare different species that are same size, the one that matures later tends to be the longer-lived.

So now: What does this have to do with calorie restriction, dauers, and the related genetic manipulations that I surveyed earlier in this chapter? Well, it’s actually very simple. In a famine, there are two big problems with passing on your genes. Firstly, gestation consumes a lot of energy, which of course comes from food. And secondly, whatever offspring you do succeed in having during a famine are very likely to die of starvation before they can have their own offspring, which is no better for the survival of your genes than if you hadn’t had any offspring in the first place. Thus, the advantage (in terms of your genetic heritage) of maturing quickly is less during a famine than when food is plentiful. But wait: the disadvantage of maturing quickly, namely the increased risk of death that results from being sloppily constructed, is unaltered! In fact, that risk may in some cases be amplified: If the duration of a particular famine is a large fraction of the species’s lifespan, the period late in life when the well-constructed, late-aging animals are the only ones left to procreate will be the only period when successful procreation can occur. In that case, the benefit of being well constructed (i.e., the drawbacks of being sloppily constructed) will be greater in a famine of that duration than when food is plentiful throughout life.

Thus, famine shifts the happy medium toward favoring a more painstaking development process. And since famines are unpredictable events, occurring at irregular intervals, it’s not possible for evolution to determine a species’ ideal degree of perfectionism in advance: each individual organism must have the ability to respond to its situation. Furthermore, famines have always been like that, ever since organisms started eating other organisms. It’s therefore no surprise that, everywhere we look in nature, we find the genetic machinery to respond to a famine early in life by slowing or suspending growth.

You may know that nutrient deprivation in adulthood often has the same effect to a milder extent, a phenomenon that doesn’t seem to be explained by what I’ve just told you. Indeed, there may not be such clear-cut evolutionary reasons why adult-onset calorie restriction postpones aging at all. But there don’t need to be, because genetic programs that exist for one time or circumstance are often activated unnecessarily in situations that are similar. Think, for example, of the fact that startling someone causes a mild adrenaline rush, something that exists to facilitate escape from life-threatening situations.

Finally I must explain why the logic I’ve outlined here implies that manipulating these nutrient-sensing pathways isn’t the most promising way to postpone human aging. I actually have three reasons.

First, the degree of life extension that has been obtained thus far in various species exhibits a disheartening pattern: it works much better in shorter-lived species than in longer-lived ones. Nematodes, as I mentioned above, can live several times as long as normal if starved at the right point in their development; so can fruit flies. Mice and rats, however, can only be pushed to live about 40 percent longer than normal. This pattern led me, a few years ago, to wonder whether humans might even be less responsive than that, and I quickly realized that there is indeed a simple evolutionary reason to expect just such a thing.¹² It’s a consequence of the fact that the duration of a famine is determined by the environment and is independent of the natural rate of aging of the species experiencing it.

Second, the adjustment of metabolism that organisms undergo when food is scarce causes only a slowdown in the accumulation of molecular and cellular damage, not a repair of damage that already happened. I’ve already told you that the key “Eureka moment” in my development of SENS was when I realized that repairing the damage of aging (before it progresses into disease) might be simpler than preventing it—but even setting that realization aside, repair is bound to be preferable, simply because any feasible therapy (whether to repair damage or to prevent it) will be only partial. That’s to say, repair therapies will repair some but not all damage, and prevention therapies will slow but not halt the accumulation of damage. Why does this mean that repair is preferable? The logic is quite simple. In broad terms, if you take a middle-aged person and halve the rate of their subsequent aging, you’ll double their remaining lifespan, but that might mean adding only 20 percent to their total lifespan. By contrast, if you take that same person at the same age and apply a therapy that halves their accumulated damage, and apply that same therapy periodically for the rest of their life, you’ll roughly double their total lifespan (because their accumulating damage will only consist of the types of damage that your therapy can’t repair), which means increasing their remaining lifespan (from the point when you first applied the therapy) by a factor of maybe four or five! So prevention-oriented approaches simply don’t aim high enough.

But there’s a third reason why I don’t think nutrient sensing is the most promising target for biomedical intervention in aging, and I would say it’s the most decisive. The reason it’s been so incredibly easy to extend the lifespans of so many organisms by this one trick is because it’s an evolved response to environmental conditions. The machinery that mediates that response is fantastically complex and poorly understood, just like the rest of our biology, but we can manipulate it easily despite that complexity, because its initial step—the sensing of nutrient availability—is simple. Just as you don’t need to understand how your computer works to turn it on and off, we also don’t need to understand the process of how nutrient deprivation is translated into the adjustment of masses of interacting metabolic pathways in order to turn that process on and off. But therein lies the show-stopping problem. You may not need to understand how your computer works in order to turn it on and off, but in order to make it do things that it does not already contain the hardware and software to do, you have to understand a lot more. And if the new functionality requires software that hasn’t yet been written or can’t be installed, you have to understand a huge amount more, enough to write that software yourself. The human body is, in that sense, like a computer into which new software can’t be installed—it’s very versatile, but that versatility cannot be extended by the same methods that merely elicit the existing versatility. Therefore, we can be sure that there is a fixed degree of life extension that can be achieved by manipulating the nutrient sensing pathway—whether by calorie restriction (CR) itself, or by drugs that trick the body into thinking it’s being starved, or by genetic changes that flip the same switch. As I explained a couple of paragraphs ago, I think that ceiling is very modest, maybe only a two-to-three-year extension; some of my colleagues think it may be as much as twenty to thirty years—but it’s still a ceiling. We will never be able to exceed that fixed degree of life extension by such means, however hard we try.

Not Good Enough—But Better than Nothing

I want to end this chapter on a positive note, though. Even though nutrient sensing can only extend life by a fixed maximum amount, and even though it may be a rather small amount, that’s still better than nothing! Also, there’s a very general finding in laboratory life-extension experiments that animals with some kind of mildly life-shortening genetic problem benefit more from the therapy or regime than congenitally longer-lived individuals. That’s quite likely to apply to calorie restriction (CR) in humans, too—which means that doing CR (or taking safe CR-mimicking drugs, as and when they appear) may be a good insurance policy against unknown congenital vulnerabilities. For these reasons, I strongly support the work that many of my colleagues in biogerontology are doing to squeeze the most we can out of that route to life extension.

But in closing, I want to bring you back firmly to the theme of this chapter. Once upon a time, aging was a truly mysterious phenomenon, but that time has passed. We can now reason about the aging of the human body in just the same way, and with just the same confidence, as we can reason about the aging and decay of simple machines. We know why different organisms age at different rates, whether that be because of different genes or different environments. We know that our genes are our allies, not our foes, in our war against aging—that they exist to postpone aging, not to cause it, and we only age because those life-preserving genetic pathways are not comprehensive.

Now—can you still tell yourself, with a straight face, that aging is too mysterious to try to tackle? You may have just one straw to clutch at in your effort to perpetuate your pro-aging trance: you may be telling yourself that the devil is in the detail, detail that I have not yet provided. I’ll be snipping that straw in Chapter 4.