(Corrects typo in paragraph 5)
By Sharon Begley
NEW YORK Aug 28 Scientists have good news for
all the older adults who occasionally forget why they walked
into a room - and panic that they are getting Alzheimer's
Not only is age-related memory loss a syndrome in its own
right and completely unrelated to that dread disease, but unlike
Alzheimer's it may be reversible or even preventable,
researchers led by a Nobel laureate said in a study published on
Using human brains that had been donated to science as well
as the brains of lab mice, the study for the first time
pinpointed the molecular defects that cause cognitive aging.
In an unusual ray of hope for a field that has had almost
nothing to offer older adults whose memory is failing, the
study's authors conclude that drugs, foods or even behaviors
might be identified that affect those molecular mechanisms,
helping to restore memory.
Any such interventions would represent a significant advance
over the paltry offerings science has come up with so far to
prevent memory decline, such as advice to keep cognitively
active and healthy - which helps some people, but not all, and
has only a flimsy scientific foundation. By identifying the
"where did I park the car?" molecule, the discovery could also
kick-start the mostly moribund efforts to develop drugs to slow
or roll back the memory lapses that accompany normal aging.
"This is a lovely set of studies," said Molly Wagster of the
National Institute on Aging, an expert on normal age-related
memory decline who was not involved in the new study. "They
provide clues to the underlying mechanism of age-related memory
decline and will, hopefully, move us down the road toward
About 40 percent of Americans age 85 and older say they
experience some memory loss, a 2009 survey by the Pew Research
Center found, as did 27 percent of those 75 to 84 and 20 percent
of those ages 65 to 74.
The researchers began with eight brains from the New York
Brain Bank at Columbia University donated by people aged 33 to
88 who were free of brain disease when they died. They extracted
two structures in the hippocampus, a vital cog in the brain's
memory machinery: the dentate gyrus, a boomerang-shaped region
whose function declines with age but is not affected by
Alzheimer's, and the entorhinal cortex, which is largely
unaffected by aging but is where Alzheimer's first takes hold,
The scientists then measured which genes had been active in
each structure, and found one suspicious difference: 17 genes in
the dentate gyrus became more active, or less, as the age of the
The most significant change was that the gene for a protein
called RbAp48 had essentially retired: The gene's activity
tailed off dramatically the older a brain got. As a result, old
brains had about half the RbAp48 of young brains, the scientists
report online in the journal Science Translational Medicine.
The scientists then sampled 10 more healthy human brains,
ranging from 41 to 89 years at the time of death. Once again,
the amount of RbAp48 protein declined with age in the dentate
gyrus. They next confirmed that RbAp48 protein was also less
abundant in the dentate gyrus of old mice compared to young
For the final step, the scientists had to nail down whether
the missing protein caused age-related memory loss. They
genetically engineered mice whose RbAp48 genes were disabled.
Result: The young mice had memories as poor as animals four
times their age (the mouse equivalent of late middle age), and
they had terrible trouble navigating a water maze or
differentiating objects they had seen before from novel ones.
Crucially, the scientists also did the reverse experiment,
engineering mice so their brains had extra doses of RbAp48. The
mice's memories returned to the flower of youth.
"With RbAp48, we were able to reverse age-related memory
loss in the mice," said Columbia's Dr Eric Kandel, who shared
the 2000 Nobel Prize in medicine for discoveries of the
molecular basis of memory and led the research. "Unlike in
Alzheimer's, there is no significant cell death in age-related
memory loss, which gives us hope it can be prevented or
Exactly how RbAp48 does that is not clear. The protein acts
as a sort of genetic master key: By causing chromosomes to
loosen their hold on the molecular spool they are wound around
like thread, it allows genes to be turned on. Among the
activated genes, Kandel explained, are those involved in forming
The emerging picture is that levels of RbAp48 decline with
age, allowing chromosomes to maintain a death grip on their
spools. Memory genes remain dormant, and you can't remember that
you promised your spouse you would make dinner.
The researchers plan to see what social and dietary factors
might boost RbAp48 in mice, said Kandel, who will be 84 in
November. Pharmaceuticals, nutraceuticals, physical and
cognitive exercise are all candidates, said Columbia's Dr Scott
Small, co-senior author of the study.
Testing such interventions in mice should be more useful to
humans than tests of drugs for Alzheimer's, he said. RbAp48 "is
different," Small said. "Alzheimer's does not occur naturally in
the mouse. Here, we've caused age-related memory loss in the
mouse, and we've shown it to be relevant to human aging."
(Reporting by Sharon Begley; Editing by Julie Steenhuysen and