New protein found that controls longevity — in roundworms
14 May 2010
The lifespan of the roundworm C. elegans is
controlled by the level of a single protein, according to a study by
researchers at Thomas Jefferson University.
Worms born without this protein, called arrestin, lived about
one-third longer than normal, while worms that had triple the amount
of arrestin lived one-third less.
The research also showed that arrestin interacts with several
other proteins within cells to regulate longevity. The human version
of one of these proteins is PTEN, a well-known tumour suppressor.
The study is published in the online edition of the Journal of
Because most proteins in worms have human counterparts, these
findings may have relevance to human biology and the understanding
of cancer development, said Jeffrey L Benovic PhD, professor and
chair of the Department of Biochemistry and Molecular Biology .
“The links we have found in worms suggest the same kind of
interactions occur in mammals although human biology is certainly
more complicated. We have much work to do to sort out these
pathways, but that is our goal,” said Dr Benovic.
Researchers use the roundworm as a model because it offers a
simple system to study the function of genes and proteins that are
relevant to human biology. The worm, for example, has one arrestin
gene, whereas humans have four. Worms only have 302 neurons compared
to the 100 billion or so in the human brain. In addition, their
short lifespan of two to three weeks allows for timely observation
of effects on longevity.
Dr Benovic and the study’s first author, Aimee Palmitessa, PhD, a
postdoctoral research fellow, studied signaling pathways activated
by G protein-coupled receptors. These receptors bind to all kinds of
hormones, sensory stimuli (such as light, odorants and tastants),
neurotransmitters, etc, which then activate a cascade of signals
inside the cell. They regulate many physiological processes and are
the target for about half of the drugs currently on the market.
“When it comes to receptors, worms are actually more complex,”
said Dr Benovic. “Humans have about 800 different kinds of G
protein-coupled receptors while the worm has about 1,800. It relies
upon these receptors to respond to sensory stimuli as well as
various neurotransmitters and hormones.”
Arrestins were initially found to turn off the activation of G
protein-coupled receptors inside cells. “Their name comes from the
fact that they arrest the activity of receptors, so the worm offers
a good way to study how its single arrestin protein interacts with
protein receptors,” says Dr Benovic. Two of the four arrestins that
humans have are devoted to regulating receptors that respond to
visual stimuli while the other two regulate most other receptors.
In this study, Dr Palmitessa deleted the single arrestin gene in
worms to see what would happen, and found, to her surprise, that
these worms lived significantly longer. She also found that
over-expressing arrestin in worms shortened their lifespan. “A
little less arrestin is good — at least for worms,” Dr Benovic
This isn’t the first discovery made regarding longevity in worms.
Researchers have already found that activity of the insulin-like
growth factor-1 (IGF-1) receptor can influence longevity in worms —
a finding that has also been replicated in fruit flies, mice, and
humans. Like arrestin, a little less IGF-1 receptor activity is
good, Dr Benovic explained. Further research has shown that caloric
restriction can also reduce IGF-1 receptor activation and,
conversely, over-expression of the IGF-1 receptor is found in some
In this study, Dr Benovic and Dr Palmitessa dug a little deeper
and found that in the worms, arrestin interacted with two other
proteins that play a critical role in its ability to regulate
longevity. One of those proteins is the tumour suppressor PTEN;
mutations in PTEN are involved in a number of different cancers.
Dr Benovic said the connection between human arrestin and PTEN is
not clear. “We don’t know at this point if human arrestins regulate
PTEN function or if anything happens to arrestin levels during the
development of cancer,” he said. “Do increasing levels turn off more
PTEN, thus promoting cancer, or do levels decrease and allow PTEN to
be more active?
“If it turns out to be the first scenario — that increasing
amounts of arrestin turn off the tumour suppressor activity of PTEN,
then it may be possible to selectively inhibit that process,” he
says. “We have some interesting work ahead.”