You’re Looking Very Well

by Lewis Wolpert

  In 1881 August Weismann delivered an important lecture on ageing at the University of Freiburg. It was the first attempt to explain ageing in terms of Darwinian evolution and the behaviour of cells. He was convinced that immortality would be a useless luxury and of no value to an organism, and that the cause of ageing would be a limitation of cells’ ability to reproduce. He regarded ageing as adaptive, as it helped get rid of decrepit old individuals who competed for resources with others in their group. This was wrong, as we shall see. He nevertheless recognised the important principle that once an individual had successfully reproduced and cared for their offspring, it ceased to be of any value to the species. He also made clear that the germ-line cells which give rise to eggs and sperm must not be subject to ageing, for if they were, the species would die out. It was another 60 or so years before there were further attempts to understand the evolution of ageing.

  Jean-Martin Charcot, a famous neurologist at the Pasteur Institute, also promoted the study of old age, which he recognised as being neglected. His lectures on the medicine of old age, Clinical Lectures On Senile And Chronic Diseases, aroused scientific interest in the field, and became available in English translation in 1881. They had a big influence, as Charcot saw old age as the simultaneous enfeebling of function and a special set of degenerative diseases, and these needed to be distinguished. Elie Metchnikoff, a Russian who went to the Pasteur in Paris in 1888, continued Charcot’s work and coined the term gerontology in 1903. Geronte is French for ‘man’ and has nothing to do with ageing but it remains with us as a name for the science of ageing.

  Metchnikoff won a Nobel prize for showing how certain cells in our bodies defend us against invaders like bacteria, by eating them and dead material, a process known as phagocytosis, and he saw old age as cellular involution in which cell decay outbalances cell growth. He believed ageing was due to bacterial toxins released from the intestine, and that Bulgarians lived especially long lives because they ate yogurt. He thus touted yogurt as an anti-ageing medicine. Based on his theory, he drank sour milk every day. George Edward Day (1815–72) wrote a common-sense book from the physician’s perspective on ageing in 1848. He complained that other physicians had little interest in caring for the ills of the aged. That refrain still rang true during the first few years of the twentieth century.

  Modern geriatrics was born with the invention of the word ‘geriatrics’ by Ignatz Leo Nascher from the Greek word geras for age. Nascher was born in Vienna in 1863, graduated as a pharmacist and then obtained his medical degree from New York University. He wrote a number of articles on geriatrics and a 400-page book, published in 1914, Geriatrics: The Diseases of Old Age and Their Treatment. He described ageing as a process of cell and tissue degeneration. He thought, mistakenly, that all our cells except for the brain were replaced as we aged. A major problem for him was how to distinguish between diseases in old age and diseases of old age. His interests in geriatrics and his development of treatments for older people almost certainly came from visits to Austria, where the care of elderly people was blossoming at the time. He retired at the age of 66.

  Nascher’s interest in geriatrics is a bit strange as it contrasted wildly with his contemporary William Osler, the famous Canadian physician who was chairman of medicine at Johns Hopkins in Baltimore. Osler appeared to be remarkably ageist, as shown in his final address, called ‘The Fixed Period’, in which he stated that men over 40 years, beyond the golden age of 25 to 40, were relatively useless. Men over 60 years were considered absolutely useless, and chloroform was not a bad idea for this age group. This address is said to have been responsible for a number of suicides.

  While there were scientific studies on child development, ageing was still largely ignored in the early twentieth century. The psychologist G. Stanley Hall was a founding father of psychology as a science. His major work was on child development, but, concerned about his own ageing, he wrote a book about ageing, Senescence, in 1922. He interviewed some elderly adults and found that their attitudes towards death changed as they aged. This was the first analysis of the changing attitudes and thinking linked to ageing:

  How different we find old age from what we had expected or observed it to be; how little there is in common between what we feel toward it and the way we find it regarded by our juniors; and how hard it is to conform to their expectations of us! They think we have glided into a peaceful harbor and have only to cast anchor and be at rest.

  It was Peter Medawar in 1952 who pointed out that environmental factors progressively reduce an individual’s lifespan, and natural selection would ensure that the good genes that support reproduction act early, and the bad ones that prevent reproduction much later. This was a major advance and it later became the basis for Tom Kirkwood’s disposable soma theory, which recognised that just a small amount of energy was devoted to repair of ageing processes as compared to reproduction, growth and defence. The theory also claims that ageing is due to the accumulation of damage to the body, and that long-living organisms devote more to repair.

  Perhaps the greatest impetus for the modern ‘merchants of immortality’ came from Leonard Hayflick’s finding that there were just a finite number of times a fibroblast cell could divide when placed in culture. This eventually became known as the ‘Hayflick Limit’. The original article by Hayflick was rejected by the Journal of Experimental Medicine with a scathing letter from the editor that stated, in part, ‘The largest fact to have come from tissue culture research in the last fifty years is that cells inherently capable of multiplying, will do so indefinitely if supplied with the right milieu in vitro.’ It was eventually published in Experimental Cell Research in 1961.

  If Nascher was the father of geriatrics, Marjory Warren was its mother—particularly in relation to care of the aged. She worked at the Isleworth Infirmary, which in 1935 took over responsibility for an adjacent workhouse to form the West Middlesex County Hospital. During 1936 Dr Warren systematically reviewed the several hundred inmates of the old workhouse wards. Many of the patients were old and infirm, and she matched care to their needs. She initiated an upgrading of the wards, thereby improving the morale of both patients and staff. She advocated creating a medical speciality of geriatrics, providing special geriatric units in general hospitals, and teaching medical students about the care of elderly people. Among her innovations was to enhance the environment and emphasise increased motivation on the part of the patient.

  Before the Second World War there had been little interest in old peoples’ mental or physical health. Joseph Sheldon, while working at the Royal Hospital in Wolverhampton, undertook a survey of 583 old people sponsored by the Nuffield foundation, which he published in his book The Social Medicine of Ageing in 1948. He found that over 90 per cent were living at home and many had severe problems with respect to care. He introduced home physiotherapy and promoted environmental modifications to prevent falls, which were all too common. Old-age psychiatry was only recognised as a speciality by the Department of Health in 1989. Now, of the 1700 patients each GP typically has, about 6 per cent are over 75 and 2 per cent over 80. There will be around six consultations a year for the over-65s, so old age is quite a burden for GPs.

  The first chair for geriatrics in the world was the Cargill Chair at Glasgow University, awarded to Dr Ferguson Anderson in 1965. Alex Comfort, more famous perhaps as a novelist and for writing The Joy of Sex, was a great propagandist for research on ageing. His early research was on ageing in the fruit fly Drosophila and thoroughbred horses. He then attempted to determine biomeasures of physiological ageing.

  In the US the first head of the Unit on Aging within the Division of Chemotherapy at the National Institutes of Health, Nathan Wetherwell Shock, was appointed in 1940. In 1948, the gerontology branch was moved to be under the National Heart Institute. An attempt was made to have an Institute of Ageing established with Heart as a subsidiary, but this failed, as a physician to the Senate stated, ‘We don’t need research on Ageing. All we nee
d to do is go into the library and read what has been published.’ This contrasts with Nathan Wetherwell Shock’s own viewpoint, enunciated just before his death in 1989: ‘I would remind you that we were formed and nurtured in the firm belief that the biological phenomenon we call “ageing” was worthy of scientific pursuit. We have achieved some degree of success. I would caution, however, that our future will be determined only, and only, by the quality of our scientific research on understanding the basic mechanisms of ageing processes.’ In 1974, Congress granted authority to form the National Institute of Aging to provide leadership in ageing research and training.

  Research on ageing expanded significantly as it was realised that life expectancy was increasing, and thus the number of elderly. The Gerontological Society of America was founded in 1946 and the field has grown very fast. There are now many scientific journals devoted to the topic, such as Gerontology and Age and Ageing. But compared with certain fields of medical research, this topic is still relatively neglected. In the words of Professor Tom Kirkwood:

  I think doctors struggle with ageing as their training is to diagnose and treat diseases—they want to cure someone. For them ageing is a medical failure. There is a little progress with age-related diseases. It may be possible to cure Alzheimer’s but this is very difficult and prevention is more promising. There has not been enough research on very old people, which is what we are doing in Newcastle. Not a single person in our study over 85 has zero age-related disease, most have four or five.

  6. Evolving

  ‘Getting older is no problem. You just have to live long enough’

  — Groucho Marx

  Research into the nature of ageing has helped us to understand its mechanisms first in terms of evolution, and then cell behaviour. We are essentially a society of cells and all our functions are determined by the activities of our cells. Evolution plays a key role, since it has selected cells to behave in a way that gives organisms reproductive success—a fundamental feature of Darwinian evolution. Evolution is not interested in health but only in reproductive success. Almost all the features of an organism, including of course humans, have been selected on this basis. The fertilised egg gives rise by division to all the cells that make up our body, as well as those of all other animals. Genes are turned on and off during the development of the embryo and this determines when and where particular proteins are made in cells and so also their behaviour. The details of this process have been selected for during evolution to give rise to adults that will reproduce.

  Has ageing also been selected, and is it adaptive in that it helps reproduction? There have been suggestions that ageing was selected in order to reduce the number of adults so they did not compete with each other and so reduce reproduction in the group, but there is evidence to show that this is wrong.

  It is essential to distinguish changes with time as an organism develops, and later grows, from the process of ageing. Ageing is not similar to the other biological changes that we go through with time as we develop in the embryo, and then grow older and mature after birth. An embryo gets older from the time it is fertilised, and the most obvious change with age after birth is growth itself, which is part of our genetically controlled developmental programme. We continue to grow for some 16 years. Puberty begins around 11 years and is the period of transition from childhood to adolescence, marked by the development of secondary sexual characteristics, accelerated growth, behavioural changes, and eventual attainment of reproductive capacity. Puberty changes occur as a consequence of the activation of a complex system that leads to an increase in frequency and amplitude of the hormones which stimulate the growth of sexual organs. This system is active in the early infancy periods, but becomes relatively quiescent during childhood, and puberty is marked by its reactivation leading to sexual maturity.

  A remarkable case of failure to grow is Brooke Greenberg, a girl from Maryland who at 17 years old remained physically and cognitively similar to a toddler, despite her increasing age. She was about 30 inches tall, weighed about 16 pounds and had an estimated mental age of 9 months to 1 year. Brooke’s doctors termed her condition Syndrome X.

  Another major change with age is that each of us will have two successive sets of teeth. The baby teeth begin to erupt at the age of around six months. Usually by 2 years old most of a child’s baby teeth will be in place. Some children get their teeth early, others later. Then typically by the age of 12, all of a child’s baby teeth will have fallen out and been sequentially replaced by a second set of teeth.

  All these changes with age are quite different from ageing with its negative effects, and have been selected in evolution as part of our development programme to help with reproduction. So why do we have the negative effects of ageing? Was ageing selected and programmed into our development?

  The blame must fall heavily on evolution. To repeat, evolution is only interested in reproduction and not in health once we have reproduced. Ageing, as we shall see, is due to the accumulation of damage in our cells with time. Ageing is not part of our developmental programme and there are no normal genes that promote ageing, though as we shall see there are changes in genes which can cause premature ageing. On the contrary, evolution has sensibly selected cell activities that prevent the damage in cells due to ageing, but which are usually only active until reproduction is greatly reduced. No animals die of old age, but they die because of predators and illnesses, including those which are age-related. The effect of evolution can be seen by comparing two-year-old mice with baby elephants at the same age. The mice are already old. Evolution has selected mechanisms to prevent the elephant ageing before it has offspring, and for some elephants old age is only evident from worn-out tusks. Evolution has generated great diversity in lifespan. For example, rats live for 7 years, and squirrels for 12.

  As mentioned earlier, August Weismann, the great German theorist and experimental biologist of the nineteenth century, was one of the first biologists to use evolutionary arguments to explain ageing. His initial idea was that there exists a specific death-mechanism designed by natural selection to eliminate the old, and therefore worn-out, members of a population. The purpose of this programmed death of the old is to clean up the living space and to free up resources for younger generations: ‘… there is no reason to expect life to be prolonged beyond the reproductive period; so the end of this period is usually more or less coincident with death.’ Weismann probably came to this idea while reading the following notes of one of Darwin’s contemporaries and a co-discoverer of natural selection, Alfred Russel Wallace, which he later cited in his essay ‘The Duration of Life’:

  …when one or more individuals have provided a sufficient number of successors they themselves, as consumers of nourishment in a constantly increasing degree, are an injury to those successors. Natural selection therefore weeds them out, and in many cases favours such races as die almost immediately after they have left successors.

  But the theory is wrong, as almost all animals in the wild die before they get old. Death in the natural environment is not caused by ageing but is due to many other factors, particularly predators. Some animals like elephants do age in the wild, but such cases are rare. Wild mice die in the field at about 10 months, while in the laboratory they can live for several years. A number of animals have lifespans longer than might have been expected—for example flying birds live three times longer than land-living animals. Robins can live for 14 years but the albatross 50 years. This is because flying enabled them to escape predators and find new food sites, so early reproduction was no longer necessary. Why some reptiles like crocodiles and turtles have long lives is not clear.

  The illnesses associated with ageing have a significant negative impact on human mortality. Weissman later rejected his theory, and then wisely proposed that ageing was the result of resources being given to the germ line rather than the body. If deleterious ageing occurred in germ cells, eggs or sperm, the species would die out—how right he was.

 
; Theories concerning the ageing process emerged which are not based on it being adaptive, and thus not due to pressures of natural selection. The first was the ‘mutation accumulation’ theory, first proposed by the great scientist Peter Medawar in 1952, and referred to earlier, which proposes that mutations in the DNA of genes which lead to detrimental age-related changes in cells could accumulate over successive generations, if their serious negative effects were only expressed well after the age of peak reproductive success. These mutations are chance events. Life tables for humans show that the lowest likelihood of death in human females comes at about the age of 14, which in primitive societies would likely be an age of peak reproduction. Evolution has ensured that the peak of reproduction is when animals are young. Women lose their eggs at a more or less constant rate until they are 35, when the rate increases twofold.

  Deleterious mutations expressed later in life are relatively neutral to selection because their bearers have already reproduced, and so have transmitted their genes to the next generation. As few individuals would actually reach those ages, such mutations would escape negative selective pressure—evolution would neglect them. The theory also predicts that if there are fewer external hazards for an animal, ageing will be slowed down, as is the case for animals like the albatross. According to this theory, ageing is a non-adaptive trait because natural selection is negligent of events that occur in a few long-lived animals that provide little additional contribution to offspring numbers.

  Genes can be beneficial in early life, and then damaging later on. In other words, genes showing favourable effects on fitness at young ages, and deleterious ones at old age, could explain the ageing process. Such genes will be maintained in the population due to their positive effect on reproduction at young ages despite their negative effects at older post-reproductive ages, and those effects in later life will look exactly like the ageing process.