Longevity

As we learn more about the diseases that affect us, we also get better at controlling them. But will we ever manage to overcome the most inevitable of afflictions – old age?

By Britt Wray, 4th February 2018

The list of diseases humankind has managed to defeat is impressive – polio, typhoid, measles, tetanus, yellow fever, smallpox, diphtheria and chicken pox have been almost completely eliminated in many parts of the world. Vaccines and powerful drugs have allowed our species to fight back against the bacteria, parasites and viruses that threaten to kill us.

But throughout history, humans have suffered from a condition that they have never been able to escape – ageing. As we get older, our cells stop working as well and can break down, leading to conditions like cancer, heart disease, arthritis and Alzheimer’s disease. Together, ageing-related diseases are responsible for 100,000 deaths per day and billions are spent around the world trying to slow their steady march on our bodies.

Some researchers, however, believe we may be thinking about these conditions in the wrong way. They say we should start treating ageing itself as a disease – one that can be prevented and treated. In a recent episode of the BBC Tomorrow’s World podcast, my fellow presenter Ellie Cosgrave and I spoke to some of those who are investigating ways to slow and even halt the ageing process.

Can age-related disease be stopped? (Credit: Getty Images)

Their hopes are founded on recent discoveries that suggest biological ageing may be entirely preventable and treatable. From a biological perspective, the body ages at different rates according to genetic and environmental factors. Tiny errors build up in our DNA and our cells begin developing faults that can accumulate into tissue damage. The extent of these changes over time can mean the difference between a healthy old age or one spent housebound and afflicted by chronic diseases.

The hopes are founded on recent discoveries that suggest biological ageing may be entirely preventable and treatable  

The scientists who hope to do this sit on the fringes of the mainstream medical landscape. But there are now a number of research centres around the world that have made identifying ways of preventing biological ageing a priority. Studies in animals have shown that it is indeed possible to dramatically extend the lifespan of certain species, giving hope that it could also be possible in humans.

Aubrey De Grey has bold ambitions to tackle ageing (Credit: Sens Foundation/Wikipedia)

One common diabetes drug, metformin, was able to extend the lifespan of rodents. In the early 1990s, Cynthia Kenyon, now vice president of ageing research at Calico Labs, the Google-backed anti-ageing research company, demonstrated that roundworms could live six weeks instead of their natural three just by changing a single letter of their genetic code.

In our Tomorrow’s World podcast episode about ageing, one of the leading figures in human longevity research, Aubrey De Grey, tells us how similar increases in lifespan could be achieved in humans. De Grey is the chief science officer at the Strategies for Engineered Negligible Senescence (Sens) Research Foundation, a California-based regenerative medicine research foundation focused on extending the healthy human lifespan. He explains their goal is to develop a suite of therapies for middle-aged and older people that will leave them physically and mentally equivalent to someone under the age of 30. “Of course, without wiping their memories,” he adds.

LISTEN: Aubrey de Grey discusses his aim to create a suite of regenerative therapies

De Grey says they want “to fix the things we don’t like about the changes that happen between the age of 30 and the age of 70”. There are seven biological factors De Grey argues are predominantly responsible for cellular damage that accompanies ageing and underlies ageing-related diseases.

We want to fix the things we don’t like about the changes that happen between the age of 30 and the age of 70 ­– Aubrey De Grey  

These include when cells in a tissue are not renewed quickly enough; when cells replicate uncontrollably as occurs in cancer; when cells don’t die when they should, which is another problem in cancer; damage to the DNA of the tiny power plants found in cells, known as mitochondria; the accumulation of waste products inside the cell; waste products that build up outside cells; and the stiffening of the lattice structure outside of cells, called the extra-cellular matrix, which allows tissues to stretch and bend.

De Grey and his team at the Sens Research Foundation say they have identified ways for each of these problems to be combated with therapies they’re developing.

“The fix for the first (problem) of having too few cells is stem cell therapy,” says De Grey. This provides tissue with a fresh supply of young cells to replace those that die during ageing. Other issues, such as when cells don’t die when they are supposed to, may require more complex solutions.

Could humans be treated for ageing like any other disease? (Credit: Getty Images)

In principle, we could use gene targeting to introduce suicide genes – genes which the cells will express that will make proteins that will simply kill the cell,” says De Grey. The trick here, however, will be engineering the genes in such a way that they will only express the lethal protein if the cell’s growth patterns are doing more bad than good.

De Grey doesn’t think that it will be possible stop ageing altogether with these types of approaches, but they may give patients an extra 30 years or so of life. He envisages a future where “rejuvenation technologies” can be administered to old people in order to revert their cells to what they were like when they were in their youth, buying them extra time. The idea is that someone who is treated at the age of 60 will be biologically reverted to 30. But because the therapies are not permanent fixes, their cells will end up becoming 60 years old again in another 30 years time.

By then De Grey hopes the therapies could be reapplied as “version 2.0” to revert the same individuals once again to become younger in their cells. As a result, that person’s cells wouldn’t become 60 again until they’re about 150 years old.  

But, there needs to be some caution when dealing with claims like this. There is no experimental evidence to show that our bodies would respond to this sort of “software update”. Much like computers, with too many updates our bodies could grind to a halt.

We culturally accept ageing as unavoidable and so attempts to halt the damage it causes are often dismissed as quack science ­  

But De Grey believes this kind of thinking, something he calls “the pro-ageing trance”, is holding back the advance of anti-ageing technologies. The problem, he says, is that we culturally accept ageing as unavoidable and so attempts to halt the damage it causes are often dismissed as quack science.

And he is not alone in believing ageing-related diseases can be solved. George Church, a geneticist at Harvard Medical School, told us that while some of his colleagues argue many age-related diseases are so complex that they simply can’t be treated, he finds such thinking to be incorrect.

“If you can control both the environment and the genetics, you can get people that live youthful healthy lives for exceptionally much longer than others,” says Church. “In industrialised nations, most of the diseases are due to age-related diseases and I think those too can be handled.”

Could blood transfusions from the young slow ageing? (Credit: Getty Images)

Among the prominent approaches to increasing longevity is a gruesome-sounding procedure that is commonly known as “vampire therapy”. Dementia patients who were given transfusions of blood plasma from younger donors aged between 18 and 30 years old showed signs of improvement in a recent trial. Patient’s with early-onset Alzheimer’s disease regained the ability to bathe or dress themselves, or to do other tasks such as housework.

While this trial is still ongoing, one US start-up called Ambrosia is already offering older customers the chance to receive transfusions of blood from donors aged between 16 and 25 years old for $8,000 (£5,985) per treatment. The company says that these transfusions can boost the performance of older people’s lethargic cells, and also claims to have improved the condition of an early-onset Alzheimer’s patient as well as have turned the hair of a 60-something-year-old patient darker. Their research, however, has yet to be published in any peer-reviewed journals and has been criticised for not accounting for the placebo effect.

But there are some studies in animals that suggest there may be a biological basis for the effects these treatments are having. In 2013, a study by researchers at the Harvard Stem Cell Institute showed the muscle strength of mice could be improved by a growth factor found in young blood called GDF11, though the findings could not be replicated. BBC Future has previously explored some of the other approaches in animals that could lead to a longer life. Meanwhile, others say the key to longevity is as simple as cutting the amount of calories you consume in a day

LISTEN: Could it be possible to be biologically 60 when you’re chronologically 150?

But what about actually “curing” death? There have long been proposals to do this by cryogenically freezing a person’s brain or body immediately after death so they can be revived at a later date when technology has advanced sufficiently. A number of companies even offer the opportunity for wealthy clients to preserve their bodies in this way, such the Alcor Life Extension Foundation. However, to date, none of their clients have ever been resurrected from their icy storage units.

Others, such as Ray Kurzweil, theorist of the Singularity and lead engineer at Google have espoused “mind uploading” as a way to achieve (at least digital) immortality.

It’s easy to conflate these outlandish ideas, which seem more based in science fiction than reality, with the lab-based work De Grey and others in longevity research are doing. But regardless of how it is achieved, extending human lifespans by decades or even hundreds of years will present us with some difficult social realities. As BBC Future has explored before, there could be major societal impacts if we all start living longer. There are some that fear greater longevity could lead to swelling populations and raise doubts that our planet could support such numbers.

De Grey himself says he is often asked about whether the technologies he is working on could be abused by wealthy tyrants to give them extended lifespans, while others ask whether we will simply be bored by lives that can be continuously extended.

He has little time for such questions and believes that other technologies – such as artificial meat, desalination, solar energy and other renewables – will increase the carrying capacity of the planet, allowing more people to live longer lives. But this rationale suffers from a dependence on uncertain techno-fixes that may not alleviate suffering in an equally distributed manner.

Yet, if concerns like these had paralysed the early pioneers of vaccination and antibiotics, it is unlikely many of us today could expect to live much beyond the age of 40-years-old. Advances in medicine over the last two centuries have taught us that we have the power to defeat the diseases that afflict us. Perhaps if we apply ourselves, then we can beat ageing too.

The secret to a long and healthy life?

Is it possible to end ageing?

The secret to a long and healthy life? Eat less

FOOD

Why do women live longer than men?

Permanently cutting the daily calories you consume may turn out to have a profound effect on your future life, according to some tantalising scientific studies.

By Alex Riley

1st June 2017

In a restaurant setting sometime in the not-too distant future, a man and a woman are on their first date. After the initial nerves subside, all is going well.

The man is 33, he says, has been single for most of those years, and, although he doesn’t mention it, knows he is looking to settle down and have a family. The woman replies that she is 52, has been married, divorced, and has children in their early 20s. He had no idea – she looked his age, or younger.

This is a dream of Julie Mattison from the National Institute on Ageing (NIA) in the United States. She envisions a time when chronological age ticks by with every year, but biological age can be set to a different timer, where elderly doesn’t mean what it does now.

It sounds far-fetched, but our society has already made great strides towards that goal, thanks to advances in medicine and improvements in healthy living. In 2014, for instance, the United States Health Interview Survey reported that 16% of people aged between 50 and 64 were impaired every day with chronic illness. Three decades earlier that number was 23%. In other words, as well as benefiting from longer lifespans, we are also experiencing longer “healthspans” – and the latter is proving to be even more malleable. To paraphrase and update a speech from John F Kennedy given at the first White House Conference on Ageing in 1961, life can indeed be added to years, rather than just years added to life.

Healthspan is proving to be even more malleable than lifespan  

So, what do we need to do to enhance the length and quality of our lives even more? Researchers worldwide are pursuing various ideas, but for Mattison and colleagues, the answer is a simple change in diet. They believe that the key to a better old age may be to reduce the amount of food on our plates, via an approach called “calorie restriction”. This diet goes further than cutting back on fatty foods from time-to-time; it’s about making gradual and careful reductions in portion size permanently. Since the early 1930s, a 30% reduction in the amount of food consumed per day has been linked to longer, more active lives in worms, flies, rats, mice, and monkeys. Across the animal kingdom, in other words, calorie restriction has proven the best remedy for the ravages of life. And it’s possible that humans have just as much to gain.

High calorie foods can be hard to avoid today (Credit: Getty Images)

The idea that what a person eats influences their health no doubt predates any historical accounts that remain today. But, as is often the case for any scientific discipline, the first detailed accounts come from Ancient Greece. Hippocrates, one of the first physicians to claim diseases were natural and not supernatural, observed that many ailments were associated with gluttony; obese Greeks tended to die younger than slim Greeks, that was clear and written down on papyrus.

Spreading from this epicentre of science, these ideas were adopted and adapted over the centuries. And at the end of the 15th Century, Alvise Cornaro, an infirm aristocrat from a small village near Venice in Italy, turned the prevailing wisdom on its head, and on himself.

If indulgence was harmful, would dietary asceticism be helpful? To find out, Cornaro, aged 40, ate only 350g (12oz) of food per day, roughly 1000 calories according to recent estimates. He ate bread, panatela or broth, and eggs. For meat he chose veal, goat, beef, partridge, thrush, and any poultry that was available. He bought fish caught from the local rivers.

Restricted in amount but not variety, Cornaro claimed to have achieved “perfect health” up until his death more than 40 years later. Although he changed his birthdate as he aged, claiming that he had reached his 98th year, it is thought that he was around 84 when he died – still an impressive feat in the 16th Century, a time when 50 or 60 years old was considered elderly. In 1591, his grandson published his posthumous three-volume tome entitled “Discourses on the Sober Life,” pushing dietary restriction into the mainstream, and redefining ageing itself.

With an additional boost of health into the evening of life, the elderly, in full possession of their mental capacities, would be able to put decades of amassed knowledge to good use, Carnaro claimed. With his diet, beauty became the aged, not the youthful.

Longevity trials

Cornaro was an interesting man but his findings are not to be taken as fact by any branch of science. Even if he was true to his word and did not suffer ill health for nearly half a century, which seems unlikely, he was a case study of one – not representative of humans as a whole.

But since a foundational study in 1935 in white rats, a dietary restriction of between 30-50% has been shown to extend lifespan, delaying death from age-related disorders and disease. Of course, what works for a rat or any other laboratory organism might not work for a human.

It may sound obvious, but what you choose to put in your trolley can have a profound effect on the length and quality of your life (Credit: Getty Images)

Long-term trials, following humans from early adulthood to death, are a rarity. “I don’t see a human study of longevity as something that would be a fundable research programme,” says Mattison. “Even if you start humans at 40 or 50 years old, you’re still looking at potentially 40 or 50 more years [of study].” Plus, she adds, ensuring that extraneous factors – exercise, smoking, medical treatments, mental wellbeing – don’t influence the trial’s end results is near impossible for our socially and culturally complex species.

That’s why, in the late 1980s, two independent long-term trials – one at NIA and the other at the University of Wisconsin – were set up to study calorie restriction and ageing in Rhesus monkeys. Not only do we share 93% of our DNA with these primates, we age in the same way too.

Slowly, after middle age (around 15 years in Rhesus monkeys) the back starts to hunch, the skin and muscles start to sag, and, where it still grows, hair goes from gingery brown to grey. The similarities go deeper. In these primates, the occurrence of cancer, diabetes, and heart disease increases in frequency and severity with age. “They’re an excellent model to study ageing,” says Rozalyn Anderson, a gerontologist from the University of Wisconsin. 

Sherman is the oldest Rhesus monkey ever recorded, nearly 20 years older than the average lifespan for his species in captivity  

And they’re easy to control. Fed with specially made biscuits, the diets of the 76 monkeys at the University of Wisconsin and the 121 at NIA are tailored to their age, weight, and natural appetite. All monkeys receive the full complement of nutrients and minerals that their bodies crave. It’s just that half of the monkeys, the calorie restricted (or CR) group, eat 30% less.

They are far from malnourished or starving. Take Sherman, a 43-year-old monkey from NIA. Mattison says that since being placed on the CR diet in 1987, aged 16, Sherman hasn’t shown any overt signs of hunger that are well characterized in his species.

Rhesus monkeys given a stricter, low calorie diet lived longer (Credit: Getty Images)

Sherman is the oldest Rhesus monkey ever recorded, nearly 20 years older than the average lifespan for his species in captivity. As younger monkeys were developing diseases and dying, he seemed to be immune to ageing. Even into his 30s he would have been considered an old monkey, but he didn’t look or act like one. 

The same is true, to varying extents, for the rest of his experimental troop at NIA. “We have a lower incidence of diabetes, and lower incidence of cancer in the CR groups,” says Mattison. In 2009, the University of Wisconsin trial published similarly spectacular results.

Not only did their CR monkeys look remarkably younger – with more hair, less sag, and brown instead of grey – than monkeys that were fed a standard diet, they were healthier on the inside too, free from pathology. Cancers, such as the common intestinal adenocarcinoma, were reduced by over 50%. The risk of heart disease was similarly halved. And while 11 of the ad libitum (“at one’s pleasure,” in Latin) monkeys developed diabetes and five exhibited signs that they were pre-diabetic, the blood glucose regulation seemed healthy in all CR monkeys. For them, diabetes wasn’t a thing.   

Overall, only 13% of the monkeys in the CR group had died of age-related causes in 20 years. In the ad libitum group, 37% had died, nearly three times as many. In an update study from the University of Wisconsin in 2014, this percentage remained stable.

The results show that ageing itself is a reasonable target for clinical intervention and medical treatment – Rozalyn Anderson  

“We have demonstrated that ageing can be manipulated in primates,” says Anderson. “It kind of gets glossed over because it’s obvious, but conceptually that’s hugely important; it means that ageing itself is a reasonable target for clinical intervention and medical treatment.”

If ageing can be delayed, in other words, all of the diseases associated with it will follow suit. “Going after each disease one at a time isn’t going to significantly extend lifespan for people because they’ll die of something else,” says Anderson. “If you cured all cancers, you wouldn’t offset death due to cardiovascular disease, or dementia, or diabetes-associated disorders. Whereas if you go after ageing you can offset the lot in one go.”

Calorie restriction involves a permanent reduction in a diet (Credit: Getty Images)

Eating less certainly seemed to help the monkeys, but calorie restriction is much tougher for people out in the real world. For one, our access to regular, high-calorie meals is now easier than ever; with companies like Deliveroo and UberEats, there is no longer a need to walk to the restaurant anymore. And two, gaining weight simply comes more naturally to some people.

“There’s a huge genetic component to all of this and its much harder work for some people than it is for others to stay trim,” says Anderson. “We all know someone who can eat an entire cake and nothing happens, they look the exact same. And then someone else walks past a table with a cake on it and they have to go up a pant size.”

Ideally, the amount and types of food we eat should be tailored to who we are – our genetic predisposition to gaining weight, how we metabolise sugars, how we store fat, and other physiological fluxes that are beyond the scope of scientific instruction at the moment, and perhaps forever.

But a predisposition to obesity can be used as a guide to life choices rather than an inevitability. “I personally have a genetic history of obesity running through my family, and I practice a flexible form of caloric restriction,” says Susan Roberts a dietary scientist at Tufts University in Boston. “I keep my BMI at 22, and [have calculated] that that requires eating 80% of what I would eat if my BMI was at 30 like every other member of my family.” Roberts stresses that it isn’t hard – she follows her own weight management programme using a tool called iDiet to help her eat less but avoid feeling hungry or deprived of enjoyment. If this wasn’t possible, she adds, she wouldn’t practise calorie restriction.

Not only has Roberts seen the problems of obesity first-hand in her family, she knows the benefits of CR better than most. For over 10 years she has been a leading scientist in the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy trial, also known as Calerie. Over two years, 218 healthy men and women aged between 21 and 50 years were split into two groups.  In one, people were allowed to eat as they normally would (ad libitum), while the other ate 25% less (CR). Both had health checks every six months.

Unlike in the Rhesus monkey trials, tests over two years can’t determine whether CR reduces or delays age-related diseases. There simply isn’t enough time for their development. But the Calerie trials tested for the next best thing: the early biological signs of heart disease, cancer, and diabetes.

Published in 2015, the results after two years were very positive. In the blood of calorie-restricted people, the ratio of “good” cholesterol to “bad” cholesterol had increased, molecules associated with tumour formation – called tumour necrosis factors (TNFs) – were reduced by around 25%, and levels of insulin resistance, a sure sign of diabetes, fell by nearly 40% compared to people who ate their normal diets. Overall, the blood’s pressure was lower.

Significant health benefits may be garnered in an already healthy body, but further trials are needed  

Admittedly, some benefits may come from weight-loss. Earlier trials from Calerie had included people that were obese as well as those with a healthy body mass index (BMI) of 25 or below, and slimming down would have certainly improved the welfare of the heavier participants. “One thing that’s been very clear for a long time is that being overweight or obese is bad for you,” says Roberts. Diseases and disorders previously thought to be age-associated diseases are now popping up in the obese population, she adds.

But the latest results suggested that significant health benefits can be garnered in an already healthy body – a person who isn’t underweight or obese. That is, someone whose BMI lies between 18.5 and 25.

Despite these results, evidence from further trials will be needed before someone with an already healthy BMI should be advised to reduce their calorie intake. (And anyone wanting to change their diet would be advised to consult a medical professional beforehand.)

Elderly life need not be one of disease and illness (Credit: Getty Images)

In the meantime, the scientists will be hoping that their rhesus macaques may help us to understand exactly why calories restriction may have these effects. With nearly 30 years of data on lives and deaths, and blood and tissue samples, from nearly 200 monkeys, the work at NIA and the University of Wisconsin aim to shine a light into the black box of calorie restriction, illuminating just how it delays ageing.

With less food, is the metabolism forced to be more efficient with what it has? Is there a common molecular switch regulating ageing that is turned on (or off) with fewer calories? Or is there an as of yet unknown mechanism underpinning our lives and deaths? The importance of monkeys like Sherman far outspans their lives.

Calorie restriction may be one of the most promising avenues for improving health and how long it lasts in our lives

Answers to such questions might be long in coming. “If I cloned 10 of myself and we all worked furiously, I don’t think we’d have it solved,” says Anderson. “The biology is inordinately complicated.” It’s a worthwhile undertaking – understand how CR works and other treatments could then be used to target that specific part of our biology. Ageing could be treated directly, that is, without the need of calorie restriction. “And I think that’s really the golden ticket,” says Anderson.

Although lacking a neat explanation, calorie restriction is one of the most promising avenues for improving health and how long it lasts in our lives. “There was nothing in what we saw that made us think caloric restriction doesn’t work in people,” says Roberts, from the Calerie trial. And, unlike drug-based treatments, it doesn’t come with a long list of possible side effects. “Our people were not hungrier, their mood was fine, their sexual function was fine. We looked pretty hard for bad things and didn’t find them,” says Roberts.

One expected issue was a slight decrease in bone density that is often tied to gradual weight loss, says Roberts. But as a precaution, volunteers were provided with small calcium supplements throughout the trial.

Even with such promising findings, “this [the Calerie trial] is the first study of its kind, and I don’t think that any of us would feel confident in saying, ‘okay, we’re going to recommend this to everyone in the world,’” says Roberts. “But it’s a really exciting prospect. I think that delaying the progression of chronic diseases is something that everyone can get behind and get excited about, because nobody wants to live life with one of those.”

Alex Riley is a writer based in Berlin, Germany. 

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