Aging Markers Based On Behavior And Circadian Rhythms

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We are also attempting to document age-related changes in behavior and circadian rhythms of adult zebrafish. These studies on zebrafish aging markers have been pursued in collaboration with Irina Zhdanova at the Boston University School of Medicine.

It has been reported that zebrafish is a diurnal vertebrate with a clear circadian pattern of daytime activity and nighttime rest (Cahill, 1996; Cahill, 2002; Dekens et al., 2003; Delaunay et al., 2000; Hurd et al., 1998; Kazimi and Cahill, 1999). Zhdanova has been studying the sleep-like state in zebrafish, using a high-throughput image-analysis system (Zhdanova et al., 2001). Previous studies have shown that the sleep-like state in zebrafish has fundamental similarities with sleep in mammals, including characteristic postures, elevated arousal threshold to sensory stimulation and a compensatory rest rebound following rest deprivation (Zhdanova et al., 2001). ''Sleep'' in zebrafish can be induced by conventional hypnotics, diazepam and sodium pentobarbital, and the circadian hormone melatonin (Zhdanova et al., 2001). While the age-related decline in human sleep is a well-known phenomenon, it is not yet established whether this is true in lower vertebrates.

In order to determine whether sleep alteration could be a sensitive behavioral marker of aging, we have assessed the effects of zebrafish age on the sleep-like state. Using image analysis of locomotor activity, we documented the overall duration and continuity of sleep-like behavior (defined as period of immobility of 3 min or more, with increased arousal threshold) and changes in arousal threshold during this behavioral state in young and aged zebrafish adults. Our results on the intrinsic circadian rhythm of activity in larval and adult zebrafish maintained under constant conditions have also shown that the endogenous circadian period becomes more variable in adults, compared with larval fish. This might result from the weakening of the circadian oscillator with age or reduction in nighttime melatonin secretion.

By conducting a continuous 10-day analysis of zebrafish locomotor activity under constant conditions, we have compared the amplitude and period of the circadian rhythm in fish of 12 and 36 months of age and determined whether these circadian parameters might serve as a useful marker of aging. Preliminary results comparing locomotor activity in young (12-month-old) and old (36-month-old) zebrafish suggest that aging may be associated with an increased stochastic variability in locomotion. If these results are confirmed in a larger sample, extreme changes in locomotor activity might potentially represent an interesting biological marker of aging in zebrafish.

We have also assessed the circadian rhythm of melatonin production (levels in the pineal gland) and excretion (levels in the surrounding water). There are two major reasons to use melatonin levels as a prospective biological marker in zebrafish aging studies. In humans, melatonin secretion is known to be highest in children of 3-5 years of age, and to decline with age. Similar age dependency of melatonin levels was documented in other species as well. In our preliminary results, adult zebrafish also have significantly lower melatonin production, compared to zebrafish larvae. We are assessing whether melatonin levels further decline in aged fish, by comparing melatonin production in young and old zebrafish. In addition, the assessment of the circadian rhythm of melatonin production is widely considered to be the most sensitive way to document individual phases of the circadian rhythm and its changes. In zebrafish, a temporal pattern of melatonin secretion can be determined by measuring melatonin levels in different tissues, including the pineal gland or brain. Importantly, the relatively high amounts of melatonin excreted into the medium (surrounding water) allow the melatonin rhythm to be repetitively sampled without disturbing the animal. We have successfully used both methods in our studies of zebrafish circadian physiology. Thus, we can longitudinally measure melatonin excretion in individual fish from young to old age (6-months to 42-months old), in order to establish whether the decline in the circadian amplitude and/or the degree of entrainment to environmental cues can serve as useful biomarkers of aging in zebrafish.

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