Here’s a brain teaser: Surprising study shows reduced neuronal activity extends life
Here’s a brain
teaser: Surprising study shows reduced neuronal activity extends life
Say this about the kinds of molecular mayhem that
we know underlie aging: Mechanisms like whether the ends of chromosomes fray
(bad) and whether genes’ on-off status breaks down (really bad) at least sound
like plausible ways to impair vital organs, from skin to brains and hearts, and
produce the whole sorry mess known as aging.
On
Wednesday, scientists reported a driver of aging that, in contrast, even the
lead researcher diplomatically calls “counterintuitive”: neuronal activity.
Aging, of course, affects the brain. But the brain seems to affect aging, too,
they found: In creatures from worms to mice to people, high levels of neuronal
firing spell a shorter life span. Lower levels — naturally, or due to drugs
that dampen neurons’ activity — increase longevity.
The discovery was so surprising that it’s
taken two years to be published (in Nature) because of how much additional data
the outside scientists reviewing the study requested. Geneticist Bruce Yankner
of Harvard Medical School, who led the research, understood their skepticism.
“If you say you have a cat in your backyard, people believe you,” he said. “If
you say you have a zebra, they want more evidence.”
So
evidence is what he and his colleagues kept generating, in humans and mice and
the roundworm C. elegans that has long been biology’s
go-to animal for studies of aging, finally persuading the skeptics.
“I
think this is a significant new finding,” said molecular biologist Nektarios
Tavernarakis of the University of Crete, an expert in aging who reviewed the
paper for Nature. “It’s definitely a surprising twist in the saga of aging, but
it’s too early to talk about manipulating the human lifespan based on this. In
my opinion, things are going to be more complicated.”
On
the other hand, earlier studies have hinted
that excessive neuronal activity is a factor in dementia, and some
Alzheimer’s experts recommend yoga and
meditation (both of which can quiet the brain) as possible ways to slow the progression of
that life-shortening disease. Now, with the additional evidence linking
neuronal activity to life span, the idea that neuron-quieting drugs might one
day extend life span seems somewhat less far-fetched.
The
Harvard scientists’ first clue that neuronal activity — electrical signals that
zip along nerve cells — might have something to do with life span came from
human brains donated for research. In the frontal cortex, the site of
higher-order thinking, a gene called REST was more active in brains of people
who lived to 85 or beyond than in the frontal cortex of brains whose owners
died in their 60s or 70s. (Evidence of gene activity lingers in dead brains for
months if they’re properly frozen.) All the brains were cognitively normal.
REST
didn’t come out of the blue. In 2014, Yankner and his colleagues showed that this gene protects aging
brains from dementia.
“REST
is involved in neuronal excitation, and is normally active during fetal brain
development,” Yankner said. “It usually gets turned off after that. But as the
brain ages it seems to turn back on again” — in some people more than others.
REST, which Yankner calls “a master gene regulator” that quiets neuronal
activity, “is turned up in people who live longer, ” he said.
That
seems counterintuitive. “You’d expect more neuronal activity to be associated
with living longer,” Yankner said. But the lower activity in the world’s
Methuselahs is not so low as to impair thinking — only quiet enough that their
brains expend no more energy on a problem than, say, people decades younger do.
On average, imaging studies show, older people have more intense and widespread
brain activity when they puzzle over a mental problem, whereas young and even
middle-aged brains are more neurally efficient. It’s like the difference
between the no-wasted-movement of a champion runner and the flailing arms and
legs of a weekend jogger.
The
association between human brains’ low levels of neuronal activity due to high
levels of REST, on the one hand, and greater longevity, on the other, might be
a simple coincidence, rather than cause and effect. To figure out if neural
activity somehow influences longevity, the scientists inhibited that activity
in C. elegans, including by boosting activity in the worm version of the
neuron-quieting REST gene.
With
their neurons shushed, the worms live around one-third longer — four weeks
rather than the standard three. The Harvard scientists ran similar experiments
in mice, and found the same thing. “The animals could still function — we
didn’t put their brains into hibernation,” Yankner said. “But by suppressing
neural activity you can affect the aging process.”
Together,
the mice and worm experiments are strong evidence that mellower neurons
increase life span. “I think they established that neuronal activity is a
determinant of longevity,” Tavernarakis said.
Exactly
how quieter neurons extend life span isn’t clear. One clue: Lowering neuronal
activity is known to activate genes that protect brains (and bodies) from
stress. The same resilience genes are also activated by caloric restriction,
which similarly extends life span in worms and mice.
That
makes “REST and other molecules that control neural excitability … possible
targets for interventions aimed at battling the decline and maladies of old
age,” Tavernarakis wrote in an essay in Nature.
Yankner
and his colleagues didn’t exactly sit around doing nothing in the two years
since they submitted their study to Nature. They have been studying compounds
that might increase the activity of the REST gene, as a way of quieting neuronal
activity and extending healthy life spans in people. But it’s way too early to
know if any of these potential drugs is even safe, let alone effective.
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