Immortality - no thanks

We are looking over the precipice that is a revolution in lifespan modification. Following recent observations the wildest suggestions from pundits are predicting lifespans of 500 years or more, even making death optional.

It is universally agreed that over the last 150 years access to sanitation, waste removal, electricity, refrigerators, vaccinations and our constant improvements in healthcare have been responsible for increases in average population life expectancy. Factors such as exercise, diet and smoking cessation coupled with education and mental health have been identified (in the last 25 years) as modifiable lifestyle factors to not only further extend our lifespan but also counter the inevitable effects of ageing on health. In addition, we are beginning to benefit from progress in the understanding and creation of drugs to alleviate the effects of ‘the deadly quintet’ of comorbidities of ageing (cancer, cardiac disease, respiratory disease, dementia and diabetes). In a series of brief articles we provide a snapshot of current developments in the science of ageing to mark the conclusion of the clinical phase of the MID-Frail study, which is looking at ways of modifying disease in old age, and the first phase of the Frailomic initiative, investigating inherent markers for the development of frailty. Both initiatives are funded by multimillion Euro grants from the European FP7 Framework and managed by Niche Science & Technology Ltd.

Ignoring the centuries long search by alchemists for a fountain-of-youth, we have become accustomed to the pharmaceutical companies creating solutions to the causes of all our fevers and other morbidities. Currently, future thinkers, clairvoyants and fortune-tellers are putting faith in science providing effective elixirs to hold back the ravages of time on our bodies in the next few decades. However, we have thus far failed to uncover any firm mechanisms and/or candidates they can exploit. We have seen some candidates given serious consideration over the last 20 years but testing anti-aging therapies in humans is difficult. Clinical trials to evaluate effects on human health or life spans require decades of study and investment. Consequently, researchers have been looking for biomarkers of aging, biological indicators confirm whether or not a particular intervention is working as they hope. 

Even if we are successful there wil still be problems. For example little progress is being made in the field of dementia and many people seemed pre-programmed to become frail as they age. Sadly, parts of the body stop working properly, making it difficult to enjoy the time you’ve got. Despite considerable advances, conditions like Alzheimer’s, cancer, diabetes, heart disease and arthritis are making the final years of life more of an exercise in suffering than a period of satisfied reflection on a life well spent. Estimates suggest that time spent needing daily care in later life has doubled over the past two decades. Many of our elderly are relegated to nursing homes, isolation and loneliness; more life doesn’t necessarily mean a better life. Will an extended lifespan be a benefit or a curse if the last 10, 20 or 100 years are going to be unpleasant and lonely? And there are tremendous associated costs of care. Governments are responding to concerns over the cost of ageing by limiting access to retirement schemes. Designed to provide relief to the elderly and introduced at the end of the 19th century, pensions have failed to respond to the changing demography reflected in our ageing population with schemes becoming financially unsustainable. Who will pay for extended retirements and when should retirement start?

Scientists refer to the number of years a person is healthy as the health span, but measuring that is tricky. A person is considered healthy if the body is generally functioning as it should, with no signs of disease but we know that as we age and our cells break down, chemical reactions that clear away waste happen slower or less frequently, and there are fewer stem cells around to replace malfunctioning tissues. At what point does this become pathological? The Frailomic initiative is looking at whether we can identify inherent markers to identify any predisposition for frailty with the hope we can clarify whether getting sick with age is anything but inevitable. Unfortunately, at the moment opportunities to categories what represents health in the very, very old are rare; fewer than 0.002% of the population reach 100 years old. This is what makes MID-Frail and Frailomic so special, they are signposts for future research.

Animal studies have shown that drastically reducing the calories in their diet not only extends lifespan, but also health span. A few major biological pathways — chains of chemical reactions within the body — that likely play a key role in aging have been identified. Some, such as one that makes a hormone called insulin-like growth factor 1 (IGF-1), correspond to growth; studies have indicated that reducing its activity in older but healthy animals delays the signs of aging. Others, such as an immune signaling protein called Interleukin 1, are tied to inflammation, the immune system’s destructive reaction to something it perceives as a threat; dialing down the pathways that signal inflammation in the body seems to keep animals from aging. Analysis of the genetic makeup of long-lived humans, called super-agers, have also provided some clues to the underlying mechanisms and where to start looking. The evidence suggests that the pundits are on the right track — change is coming.

Though the scientific community has more or less agreed on the types of pathways that play a key role in aging and related diseases, it is far from reaching a consensus on how best to alter them. Of the 50 or so candidates currently being considered drugs like metformin, long available for treatment of type 2 diabetes and rapamycin, originally developed to suppress the immune system following organ transplant, are providing a blueprint as to how we could test new agents. We also know that certain experimental cancer drugs already undergoing clinical trials, such as navitoclax and obatoclax, have been shown to have some senolytic properties, however it is important to remember that human aging encompasses progressive major changes in multiple organ systems involving a broad range of changes in poorly understood biological processes and unspecific targets. Looking into the far future, genetic manipulation using tools like CRISPR may also be an option to increase health span. But the prospect is so distant — and so ethically fraught — that researchers can’t seriously consider it in the current environment.

The search for life-extending treatments has faced a reputation problem. For centuries, products running the gamut from skin creams to herbal supplements to health-giving radiation have claimed to have ‘anti-ageing’ properties. In all cases the claims have been made with little or no supporting evidence. Often they have been found to have caused harm. Consequently, people associate the anti-ageing field with the selling of snake oil. What’s more, people in general are reluctant to talk about getting old and dying. New treatments are going to need public acceptance and appropriate recognition of safety and efficacy by regulatory agencies. This in itself represents a challenge. For example, the US Food and Drug Association only approves treatments for acceptable medical conditions. It would represent a challenge to identify when they should be used and how to measure whether or not these interventions are effective. Clinical trials that might evaluate effects on life expectancy span would most probably require huge numbers of subjects, decades to run studies and considerable investment. Without extensive long-term clinical trials, it’s impossible to anticipate how the decades-long use of an anti-aging drug will affect other aspects of long-term health. There will almost inevitably be some side effects, and the public will have to wade through discussions of whether or not it’s worth it.

A drug company that solves this problem is likely to benefit significantly. It seems unlikely that people would not feel the need to delay ageing and prolong life. It would seem unlikely that the pharmaceutical industry would want to change its current reimbursement and profit based models and so in the current drug-pricing environment one might predict that extending your life will be expensive - paying for the investment in development. This can only serve to have socioeconomic consequences. Whatever your starting wealth, paying for longevity (which we already do indirectly) will reverse much of the social progress we have seen in the last 50 years – will we return to a ‘work-to-live’ society? And as humans live longer, new diseases of the very, very old could emerge. We have already witnessed this in some sense, rates of heart disease and strokes have dropped over the last 50 years whereas Alzheimer’s has become more and more commonplace. What will happen when extended lifespans provide more time for physical problems to unfurl and accumulate? Our genomes likely have more surprises waiting for us. The real question, of course, is whether individuals are ready to live significantly longer, dying in worlds radically different from those into which they were born. Given humans’ perpetual desire to live forever, it seems unlikely that many would throw away such an opportunity. What we would actually do with it — and whether living forever will make us happy is another matter altogether.