Deficiency of circadian protein CLOCK reduces lifespan and increases age-related cataract development in mice

Abstract

Circadian clock is implicated in the regulation of aging. The transcription factor CLOCK, a core component of the circadian system, operates in complex with another circadian clock protein BMAL1. Recently it was demonstrated that BMAL1 deficiency results in premature aging in mice. Here we investigate the aging of mice deficient for CLOCK protein. Deficiency of the CLOCK protein significantly affects longevity: the average lifespan of Clock-/- mice is reduced by 15% compared with wild type mice, while maximum lifespan is reduced by more than 20%. CLOCK deficiency also results in the development of two age-specific pathologies in these mice, cataracts and dermatitis, at a much higher rate than in wild type mice. In contrast to BMAL1 deficient animals, Clock-/- mice do not develop a premature aging phenotype and do not develop the multiple age-associated pathologies characteristic of BMAL1 deficiency. Thus, although CLOCK and BMAL1 form a transcriptional complex, the physiological result of their deficiency is different. Our results suggest that CLOCK plays an important role in aging, specifically; CLOCK activity is critical for the regulation of normal physiology and aging of the lens and skin.

Figure 1.. CLOCK deficiency does not affect body weight of mice.

Age-dependent changes in body weight of wild type and Clock^−/− mice. (a) Males, (b) females.

Figure 2.. Effect of CLOCK on mouse lifespan. Kaplan-Meyer survival curves of wild type and Clock^−/− mice of both genders

(a) Survival data for death only from natural causes, (b) combined data for mice which died from natural causes and mice sacrificed due to severe dermatitis. For both graphs, the genotypes differ significantly (p<0.01).

Figure 3.. Relative weights of major organs from 24-months old wild type and Clock^−/− mice.

Relative weights were calculated as the organ weight divided by body weight, and the average value for wild-type mice for each organ was set to 100.

Figure 4.. Deficiency of CLOCK results in increased rate of cataract development.

Chronological incidence of cataracts in wild type and Clock^−/− mice. Abscissas show the mouse ages at which data for each time point were collected. Ordinates show the fraction of eyes with cataracts. (a) Males, (b) females. For both graphs, the genotypes differ significantly (p<0.01).

Figure 5.. Deficiency of CLOCK results in an increased rate of dermatitis.

Chronological incidence of dermatitis in wild type and Clock^−/− mice. Abscissas show the mouse ages at which data for each time point were collected. Ordinates show the fraction of mice with detected dermatitis. (a) Males, (b) females. For both graphs, the genotypes differ significantly (p<0.01).

Figure 6.. Model for the involvement of the circadian clock and circadian clock proteins in the control of aging.

(a) The circadian clock synchronizes multiple metabolic processes in the organism and regulates the expression and activity of circadian clock proteins, which have unique physiological functions. Disruption of circadian clock functions will affect both activity and expression of circadian clock proteins and can contribute to aging; (b) BMAL1 can regulate aging through different pathways: through the circadian clock, through functional interactions with CLOCK, through interaction with NPAS2, and through circadian clock and CLOCK/NPAS2-independent mechanisms (indicated by X).