As Shakespeare put it, we all have our entrances and our exits on this grand stage we call life, and now researchers have identified the specific point in middle-age when our brain cells show the first signs of starting down a downward slope.

That age, based on brain scans and tests covering 19,300 individuals, is on average around 44 years. It's here that degeneration starts to be noticeable, before hitting its most rapid rate at age 67. By the time we reach 90, the speed of brain aging levels off.

According to the team behind the new study, led by researchers from Stony Brook University in the US, the findings could be helpful in figuring out ways to promote better brain health during the later stages of life.

"Understanding exactly when and how brain aging accelerates gives us strategic timepoints for intervention," says Stony Brook University neuroscientist Lilianne Mujica-Parodi.

"We've identified a critical mid-life window where the brain begins to experience declining access to energy but before irreversible damage occurs, essentially the 'bend' before the 'break'."

The team was also able to identify a potential main driver of this decay: neuronal insulin resistance. The results suggest that as our brains age, insulin has a reduced effect on neurons, meaning less glucose is taken up as energy – which then starts to break brain signaling.

This idea that metabolism affects brain aging was supported by a genetic analysis conducted by the researchers. Activity related to the glucose-absorbing protein GLUT4 and the fat-transporting protein APOE matched signs of brain wear and tear.

It follows that somehow replacing or repairing energy sources for neurons could help slow down brain aging – and potentially give us another treatment option for neurodegenerative diseases (APOE has also been strongly associated with Alzheimer's in the past).

"During mid-life, neurons are metabolically stressed due to insufficient fuel; they're struggling, but they're still viable," says Mujica-Parodi.

"Therefore, providing an alternative fuel during this critical window can help restore function. However, by later ages, neurons' prolonged starvation may have triggered a cascade of other physiological effects that make intervention less effective."

The researchers tested the hypothesis with a group of 101 individuals who were given ketone supplements, which seem to promote insulin sensitivity in brain cells and suppress metabolic damage.

Brain degradation stabilised after the ketone supplements were taken, with the biggest benefits appearing for those in middle-age (40 to 59 in this case). That suggests a treatment of this type could work, but timing will be crucial.

"This represents a paradigm shift in how we think about brain aging prevention," says neuroscientist Botond Antal, from Stony Brook University.

"Rather than waiting for cognitive symptoms, which may not appear until substantial damage has occurred, we can potentially identify people at risk through neurometabolic markers and intervene during this critical window."

The research has been published in PNAS.