Up All Night
Authors: Davenport R. John 
Published: August 2003

Fear of aging keeps some people awake at night, and growing old doesn't help matters. As we age, the internal clock that coordinates our physiology with the 24-hour day falters. New research provides the first glimpse at molecular changes that underlie the mistiming. The results suggest that aging disrupts the connection between the brain's central clock and timekeepers elsewhere in the body.

Sleep problems, which commonly trouble the elderly, aren't just an annoyance. Lack of sleep can impair memory, disrupt metabolism, and perhaps even hasten death. In addition, disjointed internal clocks prompt many Alzheimer's patients to do things at inappropriate times, "like making breakfast at 3:00 in the morning," says molecular biologist Christopher Driver of the National Ageing Research Institute in Melbourne, Australia. Scientists have identified a network of clock proteins whose concentrations wax and wane over the course of the day. The proteins tick away in the brain's central clock, known as the suprachiasmatic nucleus (SCN), and in tissues throughout the body. But how aging alters their oscillations has mystified scientists.

To investigate this issue, Yamazaki and colleagues scrutinized rats that carry an artificial DNA segment consisting of a gene that encodes a light-producing enzyme linked to a control region from a clock gene called
Period
. This system allows the researchers to gauge
Period
's output by measuring the amount of light beaming from the animals' tissues. The team extracted various tissues from young and withering rats and grew them in culture. Over the course of a week,
Period
turned on and off normally in most tissues from young and old animals, including the SCN.

Further experiments showed that the SCN's cycle was shorter in older animals than in controls and that it matched up with aged rats' daily cycle of activity and rest. Aging also altered
Period
waves in other tissues, but in different ways. For instance, the kidney and the pineal gland--a brain structure that releases the hormone melatonin and is inhibited by light--exhibited
Period
oscillations that were out of synch with the SCN. And the gene's output didn't ebb and flow at all in the lung and the retrochiasmatic area: a brain region that receives information about external light intensity from the eye. The researchers conclude that aging doesn't impede
Period
waves in the central clock, but it might disrupt the clock's capability to synchronize tissues throughout the body.

Other researchers agree. "There seems to be a failure of the connections between the clocks with age," says Driver, although he adds that scientists don't understand how the clocks link up or how they control behavior. This is one of the few papers to analyze age-related molecular changes in circadian clocks, according to Driver. "The genius of this particular publication is that they keep a tissue alive and look at the rise and fall of a particular protein just by visualizing it," he says, making it a robust method for monitoring circadian cycling. Tracking other components of circadian clocks and deciphering how they break down in elderly animals could awaken researchers to the cause of old-age sleeplessness.

--R. John Davenport

S. Yamazaki, M. Straume, H. Tei, Y. Sakaki, M. Menaker, G. D. Block, Effects of aging on central and peripheral mammalian clocks.
Proc. Natl. Acad. Sci. U.S.A.
, 29 July 2002 [e-pub ahead of print].
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