Death is inevitable - but is it predictable? Some researchers think it might be.

They say that experiments with fruit flies have revealed a new and distinct phase of life that heralds the approach of death. It’s a stage of life they call the death spiral - and they think humans might experience it too.

In the early 1990s researchers identified a third phase of life

Until about 25 years ago biologists assumed there were just two fundamental phases of life: childhood and adulthood. This is a division we can all recognise. Childhood is characterised by rapid growth and development, a stage before we are sexually mature. During the phase, the likelihood of dying is constantly low.

Adulthood begins when we reach sexual maturity. The chance of death is low when we begin our adult lives - this is when we are in our prime and most likely to have children. But as time marches on, our bodies begin to age and degrade. With every passing year the likelihood of our death increases - slowly at first, but then faster and faster as we get older and older.

In the early 1990s researchers realised there was more to life than this. They identified a third phase of life that the very oldest members of our society pass through: “late life”.

What distinguished late life from the rest of adulthood is its unique pattern of mortality. The year-on-year rise in death rates that are a feature of adulthood don’t apply in late life. Whereas a 60-year-old has a much higher chance of imminent death than a 50-year-old, a 90-year-old has roughly the same chance of dying as a 100-year-old.

“The mortality rates level off and you see these plateaus,” says Laurence Mueller at the University of California in Irvine.

When the researchers took a close look at the data they realised something entirely different was going on

Exactly why these mortality plateaus occur is debated to this day - there is still no single accepted explanation. To throw some light on the problem, Mueller and his colleague, Michael Rose, began to look for signs that other biological features aside from mortality rates level off during late life. “We wondered whether reproduction or female fecundity [fertility] followed the same pattern,” he says.

They began to study the problem in the population biologist’s lab animal of choice - Drosophila fruit flies.

“We took 2,828 females, and placed each one individually in a vial with two males,” says Mueller. “Every day we moved each female to a new vial and counted how many eggs they had left. And we continued to do this until they had all died.”

The flies typically have a lifespan of several weeks. “This was a massive experiment,” says Mueller. He admits it was also a tedious one: moving so many tiny flies on a daily basis - and counting their even tinier eggs - gets tiresome quickly. Rose’s graduate student, Casandra Rauser, and dozens of undergraduates took on the task.

And, after all of that effort, the results initially seemed disappointing. Fertility rates didn’t obviously level off when the flies entered the ‘late life’ phase.

It was a universal feature of life, a new fourth phase

In fact, when the researchers took a close look at the data they realised something entirely different was going on.

“I noticed that if I separated out the females that were close to death, and compared them to other females of the same age that I knew from the dataset still had several more weeks to live, there was a difference in the fecundity,” says Mueller.

Put simply, a fly’s fertility rate - the number of eggs she laid per day - plummeted in the two weeks before she died.

Even more remarkably, this reduction in fertility held true no matter how old the fly in question was at death. If an elderly 60-day-old fly was approaching death its fertility rate plummeted - but so did the fertility rate of a 15-day-old fly that happened to be heading for an early grave.

it’s possible, to a limited degree, to predict whether a fly will die on a particular day

It was a universal feature of life, a new fourth phase that was distinct from either childhood, adulthood or late life. Mueller and Rose called it the “death spiral”.

That was in 2007; in the intervening years they have been searching for more evidence of this death spiral. In 2012, for instance, they found that male fruit flies go through a similar fertility decline in the days leading up to death. The repetitive collecting of data this time was taken on by graduate student Parvin Shahrestani.

We were predicting about 80% of the deaths correctly

“As a male gets older his ability to fertilise females gets worse and worse,” says Mueller. “But when males are about to die - whether young, middle-aged or old - their ability to reproduce is much lower than males of the same age who will live several weeks more.”

Most recently, in 2016, Mueller and Rose took data from a series of experiments exploring fruit fly longevity and fertility that had been run by researchers working independently in four different laboratories. Again, the combined dataset revealed the presence of the death spiral, says Mueller.

Female flies, regardless of their age, experience a dramatic drop in their fertility rates in the two weeks prior to death.

The two researchers and their colleagues even found that it’s possible, to a limited degree, to predict whether a fly will die on a particular day just by looking at how fertile it was on the previous three days - and ignoring other data including the fly’s age. “We were predicting about 80% of the deaths correctly,” says Mueller.

Rose and Mueller aren’t alone in drawing this link between fertility and death. James Curtsinger at the University of Minnesota has been running his own experiments into ageing and death in fruit flies - most recently discussed in a 2016 paper - and his work has also revealed a decline in fertility in the run up to death, in broad agreement with Mueller and Rose’s findings.

I’m working on a new biological concept I call retirement

Significantly, Curtsinger also found that this drop in fertility with impending death doesn’t depend on age: relatively young flies and old flies both follow a similar pattern.

Curtsinger’s work differs from Mueller and Rose’s in some important respects, though. For one thing he doesn’t think these observations are evidence of a distinct and universal fourth phase of life - he’s not convinced that humans or other species that are biologically different from fruit flies will experience the same fertility decline. He also thinks the term “death spiral” is vague and ambiguous. He has devised his own terminology that he thinks biologists may find more useful.

“When I was in my 20s my research focused on sex ratios, during my 40s I began working on the science of ageing - now I’m 65 I’m working on a new biological concept I call retirement,” he says.

It’s an observation that might require biologists to rethink their theories of ageing

“Retirement” is easy to spot in female fruit flies and consequently a much more valuable tool for researchers, says Curtsinger. It begins on the day that a mature female fails to lay a single egg.

To understand the significance of this “zero egg day” it helps to know a little about female fruit flies. “A fly is 2.5mm in length, and a fruit fly egg is 0.5mm in length,” says Curtsinger. “A female will lay about 1,200 eggs in her lifetime - that’s about half a metre of eggs if you line them up.”

Why exactly does this strong link between fertility and death exist?

In other words, female fruit flies are egg-laying machines. It’s almost the only thing on their mind. If a fly goes for an entire day without laying one egg - even if she then resumes laying eggs the next day - it’s a pretty good indication that something is wrong.

Curtsinger draws a comparison with a car that’s running dangerously low on fuel. It may begin to sputter a few miles before the engine finally cuts out, but that first sputter still tells the driver that the situation has become critical.

Curtsinger’s work also reveals something else that Mueller and Rose’s analyses have not.

At the very end of the retirement phase, when fertility rates are low and death is imminent, he realised that his flies experienced mortality plateaus just like those associated with the “late life” stage. “That’s a brand new observation,” he says. “Mortality plateaus aren't just a feature of old age, they can happen at middle age or at young ages too.”

There is evidence that people destined to die from natural causes will experience a death spiral

The consensus view at the moment is that mortality plateaus are connected with age - but Curtsinger thinks his new work shows they - like death itself - may really be more about fertility. It’s an observation that might require biologists to rethink their theories of ageing.

There is one thing that still puzzles Curtsinger, though. Why exactly does this strong link between fertility and death exist? “We don’t have an explanation,” he says.

However, James Carey at the University of California in Davis thinks it probably just reflects the well-understood idea that reproduction comes at a cost to parents - particularly to mothers. Women can experience poorer dental health, for instance, as a consequence of having many children.

And more than a decade ago, Carey and his colleagues showed that by modifying the reproductive systems of mice they could also alter lifespans. They put aged female mice under the knife, replacing their exhausted ovaries with equivalent organs from much younger females - the elderly mice lived longer than expected after the surgery.

The people who had died were generally those who had performed more poorly on the tests

“There were some signs that the mice that received the new ovaries had healthier hearts with fewer heart problems than mice that didn't get new ovaries,” he says.

Curtsinger may not be convinced that humans go through his “retirement” stage before death, but Mueller thinks there is evidence that people destined to die from natural causes will experience a death spiral. “There was a nice study that might be relevant to that idea involving a retirement home in Denmark,” he says.

Researchers put a group of nonagenarian volunteers through a battery of tests to assess their strength, coordination and mental acuity. A few years later they checked back with the retirement home to see which of their volunteers had died and which were still alive.

“The people who had died were generally those who had performed more poorly on the tests,” says Mueller. “There was a decline in physiological capabilities near death.”

Shortening the death spiral so you’re as healthy as everyone else until just before you die

What interests him the most is the idea that the work with fruit flies might reveal strategies to stave off the death cycle, so it begins a few days before death rather than a few weeks.

The hope is that such work might provide new clues to prevent humans going through a potentially long and slow deterioration before death. “That would be a really interesting pay off,” he says. “Shortening the death spiral so you’re as healthy as everyone else until just before you die.”

So while it’s true that Mueller and Rose think they have found a fourth phase of life, their long-term hope is for humans to spend as little time experiencing it as possible.

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