Health Consequences of Circadian Disruption in Humans and Animal Models - Progress in Molecular Biology and Translational Science - page 290

fitness is reduced if organisms are housed under LD cycles that differ from
the inherent period of the organism. While the relatively long gestation and
lifespan of mammals limits the number of comparable studies conducted,
some evidence indicates that circadian misalignment imposes a biological
cost that can decrease lifespan and accelerate the aging processes. 73

4.1.1 Environmental models
Halberg and Cadotte first demonstrated that mortality was increased in mice
provided weekly LD cycle inversions. 74 Similar results were obtained in a
line of Syrian hamsters predisposed to develop cardiomyopathy: weekly
inversions of the LD cycle led to a 11% decrease in median lifespan. 75 It
was postulated that this result reflected the effect of circadian disruption
rather than increased light exposure as constant light can produce therapeu-
tic effects in cardiomyopathic hamsters. 76 Weekly 6 h shifts of the LD cycle
can also have profound effects on lifespan, with aged mice displaying a
higher mortality without increases in fecal corticosterone. 77 Simulated
changes in season can also affect lifespan, with mouse lemurs held under
accelerated seasonal cycles displaying a 30% reduction in average lifespan. 78
Similarly, rapid and repeated changes in day length decreased the lifespan
of flies. 79

4.1.2 Genetic models
Recent studies have provided evidence that molecular deficits in circadian
clock function decrease survival and accelerate aging, despite earlier sugges-
tions that health was not adversely affected. 61,62,80 A 38% decrease in median
lifespan with pervasive organ dysfunction occurs when heterozygote tau
mutant hamsters are housed under static 24 h LD cycles to which they
entrain in a species-atypical manner. 81 Interestingly, homozygote tau
mutant hamsters, which fail to entrain entirely, did not display a significantly
increased mortality (9% decrease in median lifespan), prompting the sugges-
tion that misalignment (like that which occurs in jetlag and shift work) may
incur worse physiological costs than lack of entrainment (as in non-24 h
sleep/wake disorder). In addition, it is now appreciated that bmal1 mice

display an increased mortality and accelerated development of age-related
pathologies starting at about 26 weeks of age. 82,83 Similarly, an accelerated
rate of aging and a 13% decrease in average lifespan has been reported for
clock mutant mice. 84,85

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It is unclear whether pathology would emerge if

bmal1 and clock mutant mice were permitted to live arrhythmic under

constant conditions, but this question is of interest given previous work on

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