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 [1].

Everyone agrees that easier access to sanitation, garbage collection, electricity, refrigerators, immunisations, and steady improvements in healthcare have all led to longer life expectancy over the last 150 years. Over the last 25 years, lifestyle choices like exercise, food, and quitting smoking, along with education and mental health, have been found to not only make us live longer but also fight the health problems that come with getting older. On top of that, we are starting to see improvement in understanding and making drugs that can help with "the deadly quintet" of age-related illnesses: cancer, heart disease, lung 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 [2], a major new international research study examining the effectiveness of combining optimised medical management with exercise and dietary programmes to maintain function and quality of life in people aged over 70 years who have Type 2 diabetes, and the first phase of the Frailomic initiative [3], 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 fact that alchemists have been looking for a spring of youth for hundreds of years, we are used to drug companies finding cures for all our illnesses and fevers. Right now, people who think about the future, are clairvoyants, or fortune-tellers believe that science will eventually find effective elixirs to protect our bodies from the damage of time in the next few decades. On the other hand, we haven't found any solid methods or candidates that they can use yet. Over the last 20 years, some candidates have been given a lot of thought, but it's hard to try anti-aging treatments on people. It takes decades of research and money to set up clinical trials to see how drugs affect people's health or length of life. As a result, scientists have been looking for biomarkers of ageing, or biological signs that show if a certain strategy is working as planned.

Everything will not be fine even if we succeed. For instance, not much progress is being made in the study of dementia, and it seemed like a lot of people were born weak and would stay that way as they age. Sadly, some body parts stop working right, which makes it hard to enjoy the time you have left. Even though a lot of progress has been made, diseases like Alzheimer's, cancer, diabetes, heart disease, and arthritis are making the last few years of life more of a test of endurance than a time to reflect on a life well lived. Estimates suggest that time spent needing daily care in later life has doubled over the past two decades [4]. 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, currently 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 the MID-Frail and Frailomic projects 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 signalling protein called Interleukin 1, are tied to inflammation, the immune system’s destructive reaction to something it perceives as a threat; dialling 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.

The scientific community has mostly agreed on the types of pathways that are important in ageing and diseases linked to it, but they haven't agreed on how to best change them. There are about 50 candidates being studied right now. Drugs like metformin, which has been used for a long time to treat type 2 diabetes, and rapamycin, which was first created to weaken the immune system after an organ transplant, show us how to test new drugs. Some experimental cancer drugs, like navitoclax and obatoclax, which are already in clinical trials, have been shown to have some senolytic properties. However, it is important to keep in mind that ageing involves big changes happening over time in many organ systems, affecting a lot of biological processes and targets that aren't well understood. 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 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 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 it’s worth it.

If a drug company can solve this situation, they will probably make a lot of money. It seems odd that people wouldn't want to slow down ageing and live longer. It doesn't seem likely that the pharmaceutical industry would want to change the way it handles compensation and profit. Based on how drugs are priced now, you might guess that extending your life will cost a lot, to cover the costs of developing new drugs. In the long run, this can only hurt the economy and society. No matter how much money you have now, paying for longevity (which we already do in a roundabout way) will undo a lot of the social gains made in the last 50 years. Will we go back to a "work-to-live" society? And because people are living longer, very old diseases may come back. In some ways, we can already see this happening. Over the last 50 years, the rates of heart disease and stroke have gone down, but Alzheimer's has become more widespread. What will happen when people live longer and have more time for health problems to develop and get worse? There may be more shocks in store for us in our genomes. Of course, the real question is whether people are ready to live a lot longer and die in worlds that are very different from the ones they were born into. Since people always want to live forever, it doesn't seem likely that many would miss this chance. What we would do with it and whether (or not) living forever would make us happy are two different things.

References

1. Friend T. Silicon Valley’s Quest to Live Forever. The New Yorker March 27, 2017.
2. www.midfrail-study.org
3. www.frailomic.org
4. Time spent frail in old age 'doubles'. 16 August 2017.