Has the time come to take on time itself?

Abstract

Staying healthier for longer has benefits for society as well as individuals. Colin Farrelly examines the efforts of science to delay ageing

Has the time come to get more serious about the effort to slow human ageing? The advocates of the longevity dividend believe it has.¹ On 12 September 2006 the not-for-profit citizen advocacy organisation Alliance for Aging Research held a Capitol Hill symposium entitled “Going for the longevity dividend: scientific goals for the world’s aging populations.” This campaign calls on Congress to invest $3bn (£1.5bn; €2bn) annually into understanding the biology of ageing. That would amount to about 1% of the current Medicare budget.

In an era where media headlines are dominated by the war on terror and global warming, and much of the world’s population live in conditions of poverty and disease, it might seem insensitive and unfair to suggest that we should divert more scarce public funding into tackling ageing. But such a knee jerk reaction can be overcome once you consider the science and ethics behind the proposal.

Science of ageing

So is there any reason to believe that real, tangible benefits could be reaped through slowing down ageing? The scientists working in these areas certainly believe there is. Just two or three decades ago, research on ageing was a backwater.² But cellular, molecular, and genetic studies using in vitro models and short lived invertebrates have resulted in an impressive pace of discovery.³ Success in increasing longevity in laboratory organisms has shown that ageing is not an immutable process.

For example, many studies have found that the lifespan of organisms such as worms, flies, and mice can be extended by restricting food intake. Dietary restriction delays and slows the progression of various diseases associated with age, including neoplasia, and maintains many physiological processes in a youthful state on to very advanced ages.⁴

Energy restriction would be a burdensome means to promote health. Nevertheless its effect on our susceptibility to age related disease is important because it gives us hope that we may better understand the causal biological mechanisms underlying ageing and thus, ultimately, develop safe and effective ways of modulating the ageing process to extend the healthy human life span.

The transmembrane protein Klotho, for example, may affect ageing in mammals. Kurosu and colleagues showed that overexpression of the Klotho gene in mice extends life span.⁵ Other research has supported the role of free radicals in ageing.⁶ The formation of reactive oxygen species that can damage cellular constituents is prevented by catalase.⁷ Schriner and colleagues found that overexpression of human catalase in the mitochondria of mice extends the median and maximal life span by about 20%.⁶ And Baur and colleagues showed that resveratrol, an antioxidant found in wine, can shift the physiology of middle aged mice on a high energy diet towards that of mice on a standard diet and greatly increase their survival.⁸

This research suggests that new approaches to treating obesity related disorders and the diseases of ageing could be viable. Understanding of the ageing process is a crucial component of such innovations and must have a prominent role in new strategies for extending the health of a population that is highly susceptible to the diseases of ageing. Cancer, for example, largely affects elderly people. Most tumours arise in the last quarter of life, with the incidence increasing exponentially with time.⁹ The efficiency of the pathway controllingthe tumour suppressor protein p53 also declines with age, predicting the increased rates of mutation (caused by a fall in DNA repair) and fixation of mutations (caused by a decline in p53 mediated apoptosis) in older people, especially in response to stress.⁹

And finally, researchers have been able to increase the life expectancy of mice by 20% by lowering their body temperature by 0.3-0.5°C.¹⁰ The lower body temperature was achieved by inserting an uncoupling protein 2 gene into the brain cells of a mouse’s hypothalamus, near to the region that senses and controls body temperature. The gene then tricked the mouse’s internal thermostat into thinking it was heating up and thus the body was cooled.

Improving on nature

Studies like these should dislodge any presuppositions that our current biological design is optimal. The evolution of humans is an amazing story but one that may require (further) human intervention to help alleviate or postpone some of the intrinsic fallibilities we have inherited from our evolutionary legacies.

Of course, potential interventions to counter ageing have a long way to go before they can be tested in humans. Current strategies to administer antioxidant chemicals such as vitamins A, E, and C as a supplement to counter free radical damage or prolong survival have questionable effectiveness.^{11 12} But there is a credible scientific basis for believing that we could slow ageing in the foreseeable future. Research in basic biogerontology may lead to a pill that slows ageing and, as a pleasant side effect, delays all age related diseases.⁷ And the amount of public funding we invest into such research will determine the likelihood and timescale of success for ageing interventions.

Why stop ageing?

Perhaps the greatest obstacle facing the advocates of the longevity dividend is convincing the general public that the aspiration to slow ageing is a laudable goal that deserves a larger share of the public funds available for scientific research. Proponents of research into slowing ageing have gone to great lengths to emphasise how, given the current demographics, even modest success would reap large and diverse socioeconomic benefits across generations.

If we succeed in slowing ageing by seven years, the age specific risk of death, frailty, and disability will be reduced by about half at every age. People who reach the age of 50 in the future would have the health profile and disease risk of today’s 43 year old; those aged 60 would resemble current 53 year olds, and so on. Equally important, once achieved, this seven year delay would yield equal health and longevity benefits for all subsequent generations, in much the same way that children born in most nations today benefit from the discovery and development of immunisation.¹

The predicted growth in the number of people aged over 65 shows the importance of slowing ageing (figure). The rapid rise in older people over the next few decades will be accompanied by an increase in the number of people with disease and chronic illness.

Number of people aged over 65 and 85 in US, 1900-2050 (data for 2010-50 are projected)¹³

Almost half (45.1%) of the current population over 75 years of age have their activity limited by chronic conditions.¹⁴ Older people are less resistant to injury, whether from physiological events (for example, surviving a heart attack) or environmental trauma (for example, bone fracture), and they are less resistant to infection.¹⁵

Furthermore, ageing is a major risk factor for developing complex diseases like cancer. According to the National Cancer Institute, the lifetime risk of being diagnosed with cancer is currently 45.7% for males and 38.1% for females in the US. But these risks drastically change as we get older. The risk of being diagnosed with cancer in the next 20 years for men who are cancer-free is 1.1% at age 20, 21.4% at age 50, and 34.5% at age 60.¹⁶ These statistics are important given that in 2007, cancers cost the US an estimated $219bn, including $130bn for lost productivity and $89bn in direct medical costs.¹⁷ With a rapidly expanding aged population these costs are set to also rapidly increase.

Given the current predicament we face, we cannot ignore the call to tackle ageing more aggressively. To those who ask: “Can we really afford to invest more in such research?” we can reply: “Can we really afford not to tackle ageing?” That is the really important question. And the answer is clearly no. By extending the life span when higher levels of physical and mental capacity are expressed, people would remain in the workforce longer, personal income and savings would increase, age entitlement programmes would face less pressure from shifting demographics, and national economies would flourish.¹

The ultimate goal of retarding ageing is the same goal that cancer therapies strive for—namely, to extend healthy living. This can be achieved by curing disease but it can also be achieved by increasing the duration of disease-free life. There is no reason why we cannot pursue both strategies—aggressively tackling individual diseases and ageing. Given the high stakes involved, policy makers must be both imaginative and ambitious. So considering where the science actually is, the magnitude of the benefits of even modest success, and the certainty and severity of the costs of inaction, the longevity dividend campaign deserves a prominent place on the policy agenda.

Cite this as: BMJ 2008;337:a414