“Old age is the supreme evil, because it deprives us of all pleasures,
leaving us only the appetite for them, and it brings with it all sufferings.
Nevertheless, we fear death, and we desire old age.”
Giacomo Leopardi (1798-1837)
Spoiler alert: this article is not going to answer the question in the title. I would be glad to if I could but, sadly, there still is no answer to it, despite much research and relevant new information. Instead I will discuss why ageing remains such an interesting and difficult problem in biology and why it still merits attention despite the frustrations of researching it.
I first started thinking about ageing as a young graduate student in 1965. That was not because of gloomy reflections about the passing of youth or the shortness of Life but was prompted by the interest of my advisor in it. He himself was still young, only 28 years old. Prior to discussing ageing with him, I think I had unthinkingly accepted it as just a fact of life, like the connection of sex to new babies or the need for food. Jon’s interest in ageing made me realise that it was a scientific question, a puzzle. I believe that his interest had been prompted by that of a friend of his, Robin Holliday, a distinguished molecular biologist himself, then only in his mid-30s. Robin’s curiosity, in turn, had been ignited by an idea of another distinguished scientist, Leslie Orgel. This is often how scientific subjects attract people to explore them, not through sudden inspiration (Newton’s falling apple, Archimedes inspiration in the bathtub) but via social interactions and talk. (We will return later to Leslie Orgel’s specific idea.)
How did all this early interest turn out? It is safe to say that, six decades later, despite all the new information and ideas, we are not much closer to an answer about the “cause” of ageing than we were then.1
Here are my reasons for revisiting the question of ageing now.
First, it remains intensely interesting precisely because it remains an unsolved major question. (Solved problems are inherently less intriguing than those that are not.) Second, it is of nearly universal interest. Except for people who die young, everyone develops at least some interest in ageing because, at some point, you realise that you are experiencing it. In contrast, some of the other big biological questions -- the way evolution works, when “personhood” begins, what consciousness is – do not attract such wide-spread interest.
Third, its exploration illustrates vividly why getting clear answers to big questions in biology is difficult, despite the intelligence, efforts, time, and energy so often put into investigating them. In recent times, people have often been adjured to “Follow the Science!”, such as that on climate change and Covid-19. That slogan means “Believe the new findings”. The reality is that scientific research only rarely delivers clear, simple answers at early stages. Instead the answers are often incomplete and provisional. By all means, follow the latest science but do not automatically believe any new conclusions. The history of senescence research is a cautionary tale in this respect; it is the history of one false dawn after another.
I have referred to “ageing” but if that word denoted only getting older, that is clocking up years as time went by, it would not be especially interesting. What makes it so is the process of deterioration that happens as we get older, which is more precisely designated as “senescence”. In this article, I will use “ageing” and “senescence” as synonyms.
The big question is: what are the causes of that deterioration? A second important one is: is there only one cause of senescence for animals? (Let us leave plants aside because they almost certainly follow different rules.) If so, why do different animals experience it at such different rates. A fruit fly typically dies of old age after 30 days or so but we humans typically do not experience old age, as a set of problems, until we are in our seventh to tenth decade. Even more, tortoises, if undisturbed, normally happily soldier on, without much apparent change, to become centenarians. If there is one basic process of ageing, is it enormously accelerated in fruit flies or tremendously retarded in humans and tortoises?
In this series, I have addressed big questions in single, long articles, with the idea of returning to the topics later and tackling different aspects; that is still my plan. Here, however, I am going to split up the treatment into three pieces: the first (this one) will set out the general issues in senescence research and try to explain why it is such a difficult problem. The second will focus on some of the big ideas offered to explain it. The third will deal with the two divergent aims that have developed in medical research for dealing with it. (Parts 2 and 3 will follow relatively soon but not immediately after this piece in the next two weeks.)
However, before getting into the science (and its difficulties), let us note the ways the problem of ageing affects us.
First of all, it is fundamental to how we view being alive. To ask why we age is to become entangled with the question of what it means to be alive and then to die, given that ageing is the inevitable prelude to death. Given that individual lives are finite, are they less meaningful by being so or does the process of being alive acquire more significance by having its time limits? If human beings lived indefinitely, or even for centuries (in good condition), our whole feeling about what it means to be alive would be different. It is not accidental that philosophers, starting with Plato, have wrestled with the significance of ageing for the meaning of life, long before biologists did.2
Second, beyond such general philosophical questions, we must deal as individuals with ageing, both practically and psychologically. Every older person has to develop coping strategies for the particular ageing-associated problems they experience. This is never easy. In addition, one struggles with the attitude one takes toward ageing and death: do we face them stoically, or with humour, or with fear, or with acceptance or with bitterness and regret? (For most people, there is probably a mix of feelings but one predominant feeling.) One’s attitude towards one’s own ageing is inextricably tied up with one’s own philosophical and religious beliefs about life and death, not on a lofty, Plato-like plane but a personal one.
Then there is the social dimension. Societies have to deal with the problems of the elderly because of the tremendous economic costs that age-related health problems bring with them. A disproportionate share of each country’s budget for medical care is necessarily devoted to the health problems of the elderly caused by senescence. That in turn entails potential political problems that have to be dealt with by political leaders.
Finally, the nature of senescence is a challenge to science: how do we get at the root causes of something as complicated, hidden and slow as ageing? Is it best regarded as a general process, which reveals itself in multiple manifestations and consequences, or are those external signs the actual process itself? To put it another way: how does one dissect out the primary or essential cause of ageing, if there is one, from its multiple effects? We have touched on this earlier in connection with one aspect of ageing, (The terrible tangle of Alzheimer’s disease) but looking at senescence as a general phenomenon does not make it simpler. Rather the reverse, it becomes more opaque.
The difficulty in determining whether there is a root cause of ageing lies in the complexity of the animal body, from fruit flies to mice, humans, lions and blue whales. Even many of the smaller invertebrates are already quite complicated, with brains, nervous systems, guts, etc. That biological complexity must be maintained in good order, to ensure continued healthy functioning. Yet even a slight sub-optimal functioning in anything – an animal’s liver, lungs, heart, blood, kidneys, gut, brain, peripheral nerves, anything in its body – will have knock-on effects, triggering some degree of dysfunction in one or more other parts of one’s body. And those events, in turn, cause more problems. In effect, whatever the root causes of senescence, it involves, inherently, a cascade of detrimental effects. This makes for a bewildering array of cause-effect relationships and a corresponding set of questions for the investigator. Where and how does the ageing process begin? Are there preferential initial weak points in this complex entity, the body? Or can any initial weak point start the process of senescence?
The start of the ageing process is subtle, hence difficult to explore. Gerontologists, scientists who study ageing, argue that senescence begins in humans about age 20, long before anyone that age feels they are “getting old”. The reason for this claim is that the human mortality rate (number of deaths per million people per year) begins to increase at that point and continues into the early 90s. Of course, few people die from old age in their 20s – we will come to the exceptions – or for a few decades later but one becomes more susceptible to illness, of many different kinds, at a rising rate. That increased susceptibility is part of and reflects the start of ageing.
Even in one’s early 20s, however, there are frequently indications, although they are not serious in terms of health consequences. These include the first facial wrinkles, hairline recession, the first grey hairs, and often having somewhat less energy when running or walking long distances. In other words, the ageing process has evidently begun long before its major consequences, the ones leading to discomfort, pain and death, begin to show up.
Hence, senescence is best seen as a long process, not as an end state, that is “old age” with physical feebleness and some attrition of one’s mental processes. Its initial mildness, when it begins, is welcome from an individual point of view. From a scientist’s, however, it is a problem. If we could detect the first underlying events in senescence (the molecular and cellular events that cause, for instance, the first grey hair and wrinkles), we would be on the way toward understanding the ageing process. The initial events in senescence, however, might not be identical for all people.
An analogous problem for scientific research is cancer. Its very earliest stages cause no detectable problems and therefore are nearly impossible to detect. There are many different kinds of cancer but they often show similar events and stages at later points. These are the well-known “hallmarks” of cancer, but they do not always show up in the same sequence. Something similar seems to be true of senescence: it’s hallmarks do not always show up in the same sequence and we know that different individuals experience different ones and with different degrees of severity.
Nevertheless, the shared features of ageing suggest that it is a process with its own rules or, at least, regularities. That thought leads on to the fact that there are broadly two ways to think about senescence. These are: 1) that it is, in some way, “programmed”, that is built into our biological make-up, or 2) that it is simply a process of cumulative wear-and-tear due to biological damage over lived time. Of the many ideas that have been proposed to be the mechanism of senescence, most fall into one category or the other (though a few combine elements of both).
Nevertheless, both ways of thinking about it and each individual hypothesis has to deal with two big facts about the different rates of ageing. First, any species of animal has a typical life-time, largely determined by its rate of senescence, but there is a maximum life time achieved by rare individuals. For humans, the typical life-time is on the order of 70-80 years though of course social and economic conditions affect average life-times. (In pre-industrial European countries, the typical life-time was in the 40s.) In contrast, the human maximum life-time appears to be about 120 years. These regularities are to be expected under the view that ageing is “programmed” although the big difference between the average human life-time and the maximum human life-time (120 years) is a difficulty for the program-view. For the “wear-and-tear” explanations of senescence, that difference is easier to accommodate since degrees of wear-and-tear will differ between people. There is more of an element of chance in it, hence more variability.
That variability in rate of ageing between people holds out the greatest hope for solving the problem of senescence. Changing its rate in a controlled way might provide clues to the underlying mechanism of senescence, if there is a single mechanism. The clues are tantalizing but have not delivered the explanatory pay-off that had been anticipated. Still, it is worth mentioning a few. By both environmental and genetic means, it is possible to either accelerate the speed of senescence or to slow it down. Let us give a few examples.
A major environmental modulator is termed “calorie restriction”. This is just what it sounds like: giving the animals less food, hence fewer calories, not to the point of starvation but a substantial reduction nevertheless. This can significantly extend life-time, on the order of 30% or more, a statistically significant amount. The problem is that this effect has been most convincingly shown only in two invertebrates, the roundworm Caenorhabditis elegans and the fruit fly Drosophila melanogaster, and one relatively short-lived mammal, the laboratory mouse. By the measures available, these extensions of life-span are accompanied by reduced signs of senescence. The mechanism is still debated but the more significant question is one already mentioned: is there one mechanism of senescence for all animals or different ones? Specifically, is senescence in animals with short life-times the same as in longer-lived (and often larger) animals? We do not know at present nor will the effect of calorie restriction be easy to test in long-lived animals.
Also, these questions relate to the question of whether the practical goal of senescence research should be is lifetime extension or simply producing healthier ageing, that is ageing without all of the typical side-effects that humans frequently experience. These goals are neither identical nor inseparably linked. (We will return to that question in part 3.)
It is genetic alterations, however, that have produced some of the most spectacular findings in altering the rates of ageing, both slowing it down and speeding it up. One set of genetic alterations that slow ageing are mutations in the insulin pathway, and these have been found in several very different animal species though not yet in humans. This result indicates connections between ageing and basic food metabolism but they are still unclear. (In part 2, we will return to this.)
The genetic changes that accelerate ageing are as interesting. One of the most spectacular of these is Werner’s syndrome, in which people who have this condition experience greatly accelerated aging, becoming indistinguishable from very elderly humans while still in their early teenage years. It is undoubtedly awful to experience for those afflicted with it. Intriguingly, the gene mutated is in a gene for an essential DNA repair enzyme. In a previous article (“On ‘existential threats’, radiation genetic damage, and biological resilience”), I discussed the importance of DNA repair in humans in surviving potentially deadly radiation from nuclear sources. The observations on Werner’s syndrome patients suggests that adequate DNA repair may be part of the mammalian defense against senescence. These observations do not imply that senescence is caused by the failure of DNA repair in ageing cells but are consistent with that possibility.
In the next article in this sub-series, we will explore some of the most interesting ideas proposed to explain ageing and attempt to give some sense of where the field stands now on this issue. We will start with the idea that particularly intrigued Leslie Orgel and Robin Holliday, mentioned at the beginning.
Supplementary reading:
da Costa, J.P., et al. (2016). A synopsis on ageing – Theories, mechanisms and future prospects. Ageing Res. Rev. 29:90-112.
A short but good review of the current state of the field.Medawar, P.B. (1952). An Unsolved Problem in Biology. H. K. Lewis Publishing.
This is a classic statement by the immunologist Peter Medawar. He was one of the best scientific writers of the 20th century and some years after this article, became a Nobel laureate. This book helped inspire research on senescence in the 1950s and ‘60s.Roper, M., et al. (2019). Senescence: still an unsolved problem. BioArXiv doi.org/10.1101/739730
An updated look at Medawar’s idea, with much new data on the diversity in senescence patterns. It is both a tribute to Medawar and a critique of his idea.
This is not just my personal opinion but the consensus in the field. See ref. 3 above.
Plato (428-347 BC) emphasized the positive side of getting older. He argued that old age brought the benefit of wisdom. A more pessimistic but commoner view, today but probably throughout human history, is that of Giacomo Leopardi cited in the epigraph.