Scientists Say Aging May Result From Brain's Hormonal Signals

Could it be that aging, like puberty and menopause, is a programmed
life-cycle event set off by hormonal signals from the brain?

A new study suggests that in the laboratory roundworm, and maybe people
too, youthfulness is maintained by hormonal signals from the brain. When
the neurons that transmit the signal suffer damage from the wear and tear
of normal metabolism, the youthfulness signal fails, and the body's tissues
all lapse into senescence at about the same time.

The theory that aging is a programmed, hormonal event has been proposed
before, but the new study, by Dr. Gary Ruvkun and colleagues at Harvard
Medical School, seems to present the most detailed support of it so far.

They focused on a gene that is well known for the curious fact that
roundworms seem to be a lot better off without it, at least in the
protected conditions of the laboratory. When biologists disable the gene,
worms live up to three times as long as usual, the equivalent of a person's
living to age 240.

The gene's role is to specify a kind of protein known as a receptor;
embedded in the membrane of cells, the receptor waits to be activated by
the worm's equivalent of insulin and then transmits the hormone's message
to the cell's metabolic machinery.

The worms live longer when the receptor is dysfunctional because when cells
are deaf to insulin signaling they burn less glucose and make fewer free
radicals, a cell-damaging byproduct of glucose metabolism.

Confirming the link between free radicals and life span, a research team at
the University of Manchester in England and elsewhere reported last month
that they could make worms live more than 40 percent longer by dosing them
with a drug that mops up free radicals. The drug mimics and enhances the
action of natural enzymes that dispose of free radicals.

Though worms and people differ, they share many fundamental processes, and
the link between glucose metabolism, free radicals and aging may be one of
them. Caloric restriction — a healthy and normal diet but with 30 percent
fewer calories than usual — is the one intervention that reliably extends
the life span of laboratory rats and mice.

Presumably burning fewer calories reduces free radicals and extends life
span. It is not yet known if caloric restriction would increase people's
life span but preliminary trials with monkeys look promising.

But by what perverse calculus has evolution arranged for worms, mice and
maybe people to die sooner if they metabolize energy faster?

In fact, the logic of the situation is probably the other way around:
evolution has created a mechanism for stretching out life span if the
prospects for reproduction are bleak. Across a wide range of organisms,
natural selection has probably favored genes that allow an animal to ride
out periods of famine and to postpone reproduction until times get better.

The question addressed by Dr. Ruvkun was that of whether some types of cell
might be more important than others in mediating the evident link between
the insulin receptor gene and life span.

With his colleagues — Dr. Catherine A. Wolkow, Dr. Koutarou D. Kimura and
Dr. Ming-Sum Lee — he took a long-lived strain of worms with a defective
receptor gene and restored the gene's function in different tissues one by
one.

This clever genetic trick was done by inserting functional copies of the
receptor gene into all a worm's cells. The gene was linked to another piece
of DNA, one that serves as an on- switch for the gene. Since different
tissues have different on-switches, the working copy of the receptor gene
was in each experiment active only in tissues for which it had the matching
on-switch.

Because strains of worm with the defective receptor gene live far longer
than usual, the effect of correcting the gene is to restore a normal,
briefer life span. Dr. Ruvkun found that only when the gene was activated
in the nerve cells of the worm's brain did life span revert to normal.

"If aging were just a matter of skin and muscles wearing out, why would
dogs age seven times faster than us?" Dr. Ruvkun said. "It's more likely
that this is a programmed event." Dr. Ruvkun says he believes that rather
than the body's just falling apart from wear and tear, as some theories of
aging assume, there must be some central trigger of senescence, and that
the activation of the trigger explains why everything in the body seems to
age at about the same time.

He believes that his worm experiment has pinpointed the location of the
central trigger, he said. The worm's nerve cells must produce some
youth-promoting factor while the worm is young, but when the nerve cells
become damaged by their own metabolism and free radicals, production of the
youth factor wanes and the body begins to decay.

When the receptor gene's function was restored in other tissues, like nerve
or muscle, the cells' metabolic response to insulin was restored but there
was no change in their life spans, confirming that the gene's effect on
life span is mediated via the brain cells. Dr. Ruvkun's findings are
reported in last week's issue of Science.

Dr. Leonard Guarente, a biologist who studies aging at the Massachusetts
Institute of Technology, described Dr. Ruvkun's work as "an elegant
demonstration that really nails down in a convincing way the primary
importance of neurons in regulating life span."

Working on a different aspect of the metabolism and aging knot, Dr.
Guarente recently showed how metabolism was directly linked to the cell's
machinery for keeping its genes under control.

Dr. Caleb Finch, an authority on aging at the University of California,
said he had argued for 30 years that the brain contained pacemakers for
aging and that Dr. Ruvkun's finding provided "an exciting and profound
working hypothesis."

Understanding the link between metabolism and aging would be significant
but would not complete the story. "Most evolutionary and molecular
biologists are uncomfortable with the thought that just one or two genes
control aging," said Dr. Judith Campisi, who studies aging at the Lawrence
Berkeley Laboratory. The worms given longer life by their inactivated
receptor genes "still age and die," she said.

"We haven't abrogated aging," she added. All we have done is postpone it."

In what passes for its brain, the little roundworm has 302 nerve cells of
118 different types. Dr. Ruvkun has assembled several of the different
on-switches used by these types and intends to find exactly which nerve
cell holds the trigger for determining the worm's life span.

By NICHOLAS WADE
Copyright 2000 The New York Times Company
http://www.nytimes.com/2000/10/10/science/10AGIN.html

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