The Youth Pill: Scientists at the Brink of an Anti-Aging Revolution

  • David Stipp
Current: 2010. 320 pp. $26.95 9781617230004 | ISBN: 978-1-6172-3000-4

We are poised on the verge of being able to control ageing, according to two books. In The Youth Pill and Long for This World, science writers David Stipp and Jonathan Weiner each explain the latest findings in longevity research and in the commercial development of drugs to modulate or prevent ageing. Both books highlight the shift from treating diseases of the elderly towards the comprehensive control of ageing itself. Weiner weaves a more writerly narrative; Stipp examines the scientific advances in more detail.

The ageing process is clearly plastic. Human lifespans have more than doubled in the developed world since 1800, thanks to improved public health, hygiene and medicine. Today, centenarians comprise the fastest growing age group. The successful control of ageing in laboratory animals has kindled expectations for interventions and drugs that might prolong human lives.

Centenarians now constitute the fastest-growing age group owing to advances in health care. Credit: REUTERS/CORBIS

But there is a dark side to living for a long time, as Stipp touches on in The Youth Pill. Dementia increases exponentially after the age of 65 and affects about 50% of those aged 100 and older. The US Alzheimer's Association predicts that dementia cases will triple by 2050 to affect 13.5 million people aged 65 and over in the United States alone. Pensions, social and medical support are underfunded: there are only around 7,000 geriatricians for the 35 million US citizens aged over 65. Escalating health-care costs for the elderly threaten to swamp national budgets. Robert Butler's The Longevity Revolution (PublicAffairs, 2008) considers these issues more closely.

Stipp and Weiner both document several widely cited lab studies of animal ageing models, with Stipp digging deeper into the research. Genetic manipulations of metabolic pathways have increased the lifespans of mice by 50%, and made that of nematodes ten times longer. Dietary restriction also slows ageing, and can extend the lifespans of lab rats by up to 40%. Decades of research on dietary restriction has led to testable hypotheses on links between the oxidative effects of metabolism, tissue damage and various diseases. But ageing studies in primates have been inconclusive. The dietary effects on ageing are best described in Greg Critser's Eternity Soup (Harmony, 2010; see also Nature 464, 491–492; 2010), named after the recipe for long life conceived in Renaissance Italy by Luigi Cornaro — a story that both Stipp and Weiner also relate.

Efforts are under way to mimic dietary restriction in humans using a 'youth pill'. These include the development of drugs that block the metabolic pathways of sirtuin enzymes and mTOR protein signalling. Both pathways are involved in many ageing processes, normal and diseased. Resveratrol — a polyphenol from red grape skins that targets sirtuins — prolongs the lifespans and increases the motor coordination of mice made obese by a high-calorie diet. These findings have triggered a burst of commercial development.

The pharmaceutical industry is interested in the profitability of anti-ageing remedies and is willing to invest big sums; GlaxoSmithKline paid more than US$720 million to acquire the specialist sirtuin firm Sirtris in 2008, for example. Both Stipp and Weiner rightly warn that, as for any drug, longevity boosters must follow a long and tortuous path of tests to gain approval. Stipp points out that even though many biotech start-ups have tried, few have developed effective age-modulating drugs. Even after approval, drugs that target multiple systems may reveal new side-effects in ageing groups who have diverse conditions.

Faith that such drugs will eventually pass all the hurdles may be premature given the many complexities that underlie the animal studies. Environmental variation may overlap with drug effects. Neither book discusses the Interventions Testing Program of the US National Institute of Aging, which trials anti-ageing drugs at three separate sites using the same mouse stock. The increase of lifespan in mice fed with rapamycin, a drug that affects mTOR signalling, differed up to two-fold between these sites. Local factors also affect lifespan in other animal studies. For example, researchers studying mutant dwarf mice in the 1970s observed their short, six-month lifespans and accelerated ageing. Improved husbandry, including the elimination of infections once endemic in rodent colonies, now enables dwarf mice to live ten times longer than normal mice, with slowed ageing.

The dwarf mutation and some others that alter metabolism also affect immune responses and wound healing, as do caloric restriction and resveratrol. This raises the question of whether longevity drugs that weaken immune defences would work in our dirty, germy world. Who would want extra decades if it meant living in a bubble? The unusual genetics of inbred lab rodents, selected over decades for rapid growth and large litters, may also skew results, as Stipp notes briefly. Wild-caught mice are smaller and reach maturity later. The effects of diet restriction on lifespan in wild mice were modest relative to most lab-bred rodent studies. For these and other reasons, the extension of rodent findings to humans is fraught with uncertainty.

Although recognizing some biogerontology pioneers, Stipp and Weiner give the impression that the field has only gained respect recently, with the identification of gene mutations that extend lifespans in model organisms. The advent of recombinant genetics accelerated progress in ageing research in the 1980s, but this phase built on several decades of biochemical, cellular and physiological studies. This has parallels with the field of developmental biology: the century of classical embryology that defined the cell lineages in differentiation enabled the recent understanding of genes that regulate development. However, neither book addresses the deep links between development and ageing. It is the genetic regulation of differentiation that determines which cells and molecules are replaced in adults; for example, the elastin in our arteries ages progressively because it is not replaced.

Long for this World: The Strange Science of Immortality

  • Jonathan Weiner
Ecco: 2010. 320 pp. $27.99 9780060765361 | ISBN: 978-0-0607-6536-1

If humans could retain the mortality rates of young adults, our survival curves would resemble radioactive decay, with median lifespans of more than 500 years. The general exponential increase of mortality is driven by numerous morbidities, but particularly by arterial disease and cancer. The utopian goal of arresting ageing is propounded by British gerontologist Aubrey de Grey, who plans to engineer negligible senescence through a multi-pronged attack on each molecular and cellular cause of ageing. Weiner's book is almost a paean to de Grey; he is treated with greater balance by Stipp.

The conclusion that we are on the threshold of controlling ageing is premature.

De Grey's goal of negligible senescence extends my use of this terminology in 1990 to describe rockfish, turtles and other long-lived species that showed no decline in reproduction, no age-related pathology and no mortality acceleration (updated in C. E. Finch Gerontol. 55, 307–313; 2009). Another such species is the naked mole-rat, which lives for up to 30 years while maintaining reproduction but without incurring tumours or other age-related disease. Nonetheless, its cells exhibit considerable oxidative damage. Such examples challenge the evolutionary theory that senescence is inevitable or a simple sequel to oxidative stress.

In both Stipp and Weiner's accounts I had hoped for more on the comparative and evolutionary approaches to ageing, which promise to identify systems of genes that regulate many such processes, by analogy with developmental gene regulation. Also missing is a discussion of how global climate change will affect future life expectancy. Both books include a few misleading statements: brain shrinkage during normal ageing after the age of 50 is “like a bowl of Jell-O left out in the hot sun”, writes Stipp; Weiner holds that fibroblasts get “old and tired”. In fact, extreme brain shrinkage after 50 occurs mainly from Alzheimer's disease, and senescent fibroblasts can live for years if growth media are refreshed.

The conclusion of both these useful summaries of longevity research — that we are on the threshold of controlling ageing — is premature. We have much to learn about the ageing process, and developing drugs to combat it is an increasingly complex challenge. We cannot simply extrapolate into the future from the remarkable lengthening of lifespans during the past two centuries.