Aging and the biological clock
Van Leeuwenhoek Lecture on BioScience.
Aging exerts a profound effect on physiology and behavior. One important impact of aging is on sleep and wakefulness. Aged humans and other mammals show decreases in the quality and duration of sleep. as well as an inability to adjust promptly to alterations in the sleep cycle brought about by rotating shiftwork, transmeridian flight and even daylight savings time.
Age-related changes in the physiology of the circadian system governing sleep and wakefulness are being studied through the use of mammalian models, primarily mice. The central clock of the otherwise distributed chronobiologic system is the Suprachiasmatic Nucleus (SCN), a dense collection of approximately 10.000 neurons, bilaterally represented, at the base of the hypothalamus. The SCN expresses an intrinsic circadian rhythm in multi-unit electrical activity both in vivo, as revealed by deep brain recording, and in vitro in brain slice. The SCN plays a critical but not exclusive role in controlling the timing, duration and, most likely,, the quality of sleep. Research conducted over the last decade is beginning to reveal the system, circuit and neuron-specific changes that occur during aging.
At the level of the SCN, aging reduces the amplitude of the circadian rhythm of multi-unit electrical activity. In young animals, electrical recordings from brain slices containing the SCN exhibit high levels of neuronal impulses during the time interval that corresponds to nighttime. The reduction in circadian amplitude in aged mice is due largely to the increase in neuronal firing during the night, rather than a decrease in peak firing during the daytime. There appear to be multiple causes for the increase in nocturnal impulse activity. Some of the age-related changes involve alterations in specific K+ currents.
The SCN is part of a highly distributed timing system with many mammalian tissues and organs demonstrating self-sustained circadian oscillations in molecular cycling (the so-called "peripheral clocks"). These oscillations can be recorded optically in isolated tissues with single-cell resolution using luciferase reporters linked to the promoters of one of several "clock genes". Most peripheral clocks rely on the SCN, and its intimate relationship with the retina, for appropriate phasing and synchronization to environmental cycles. As with the SCN, the circadian timing system as a whole does not escape the effects of aging. Studies in mice and rats reveal that many peripheral clocks exhibit age-related changes in their phase with respect to the SCN rhythm. In addition, aging dramatically slows the time-course of resynchronization of many peripheral oscillators. These age-related changes in system-behavior are likely caused by the attenuation of the SCN rhythm, now less capable of effectively synchronizing the many peripheral clocks. However, there may also be age-related changes in peripheral tissues.
While many details await elucidation, a very satisfying picture is emerging of how aging impacts circadian timing at multiple levels of organization. Collectively the studies suggest that the aged timing system is less agile and less capable of accommodating to changes in routine. Indeed, interesting questions are raised about the need for enhanced "temporal structure"in the environment to compensate, in aged adults, for a weakening of internal temporal order. In a world with a growing aging population these are important questions to address.