Sci. Aging Knowl. Environ., 18 June 2003
Vol. 2003, Issue 24, p. nw87
[DOI: 10.1126/sageke.2003.24.nw87]


Good Timing

Defects in two proteins leave the body's clock vulnerable to age-related breakdown

Caroline Seydel;2003/24/nw87

Key Words: periodcryptochrome

Many people would relish the opportunity to slow one type of biological clock, but if they were wise, they'd want to keep a different kind running. As we age, the internal system that synchronizes our bodies with Earth's daily cycle breaks down, causing sleep problems for the elderly. New research in mice reveals that disabling certain timekeeping proteins hastens the clock's demise. The results indicate that only some proteins are essential for the daily rhythm, and they raise the possibility that age-related disorders stem from an unsteady clock.

Many characteristics oscillate on a 24-hour cycle, including blood pressure, body temperature, and hormone concentrations. Light sensors in the retina reset the clock every morning, and proteins in a brain region called the suprachiasmatic nucleus (SCN) collaborate to maintain its rhythm--but scientists don't know exactly how the clock governs other physiological systems. Declining SCN activity accompanies normal aging and Alzheimer's disease (see "Up All Night"). Proper clock function requires a web of interacting proteins, including mPER1, mPER2, mCRY1, and mCRY2.

To analyze the relations among these proteins, molecular biochemist Urs Albrecht of the University of Fribourg, Switzerland, and his colleagues examined mice that lacked mPER1 and either mCRY1 or mCRY2. For 2 weeks, the mice experienced 12 hours of light followed by 12 hours of darkness to calibrate their clocks. Then the lights went out. In constant darkness, mice without mPER1 and mCRY1 behaved normally. Mice without mPER1 and mCRY2 appeared fine at first, running at night and resting during the day despite the lack of visual cues. However, their rhythm eventually crumbled, and by 1 year of age most behaved erratically in perpetual darkness, running and resting randomly at all hours. These results demonstrate that certain combinations of clock components are more important than others, which gives researchers new information about the timekeeping system, says neurobiologist Gene Block of the University of Virginia in Charlottesville: "This is a move forward in looking at the structure of the clock."

The researchers also found that the loss of mPER1 and mCRY2 reduces activity of the Avp gene, which helps regulate blood pressure, and of the Per2 gene. Previous work had shown that mice lacking mPER2 develop more tumors than normal. Such findings are consistent with the notion that a faltering clock promotes aging and its associated blights, Albrecht says. Under this hypothesis, a malfunctioning clock is not just a result of the body's deterioration; it contributes to that demise.

That idea is "intriguing," says Block, but he cautions that the experiments don't distinguish between that interpretation and the more conventional scenario, in which aging weakens the clock. In any case, the new work suggests that defects in clock components can trigger physiological alterations that might be linked to aging. Albrecht says that his group is conducting experiments that investigate the potential connection between the timekeeping mechanism and hallmarks of aging, such as Alzheimer's-associated brain plaques, cardiovascular disease, and diabetes. If the idea pans out, manipulating the clock could help our bodies take a licking and keep on ticking.

--Caroline Seydel

June 18, 2003
  1. H. Oster, S. Baeriswyl, G. T. J. van der Horst, U. Albrecht, Loss of circadian rhythmicity in aging mPer1-/-mCry2-/- mutant mice. Genes Dev. 17, 1366-1379 (2003). [Abstract/Free Full Text]
Citation: C. Seydel, Good Timing. Sci. SAGE KE 2003, nw87 (18 June 2003);2003/24/nw87

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