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Circadian rhythms are endogenous biological cycles that regulate physiology and behavior for optimal adaptive function and survival; they are synchronized to precisely 24 hours by daily light exposure. Disruption of the daily light-dark (LD) cycle by exposure to artificial light at night (ALAN) dysregulates core clock genes and biological function. Exposure to ALAN has been associated with increased health risks in humans, and elderly individuals are at elevated risk for poor outcome from disease and often experience elevated exposure to ALAN due to increased care requirements. The role of disrupted circadian rhythms in healthy, aged animals remains unspecified; thus, we hypothesized that disrupted circadian rhythms via chronic exposure to dim ALAN (dLAN) impair immune response and survival in aged mice. Twenty-month-old C57BL/6 male and female mice were exposed to 24 weeks of LD conditions or dLAN (5 lux); then, cell-mediated immune response was assessed using a delayed-type hypersensitivity test. Aged female mice exposed to dLAN displayed dysregulated hypersensitivity and inflammation as a measure of cell-mediated immune response and decreased lifespan compared to females housed in dark nights. Nighttime lighting did not affect cell-mediated immune response or lifespan in males but dysregulated body mass and increased adrenal mass after immune challenge after chronic exposure to dLAN. Together, these data indicate that chronic exposure to dLAN affects lifespan in aged females and suggest that females are more susceptible to the detrimental consequences of disrupted circadian rhythms.

Disruption of circadian rhythms has detrimental host consequences. Indeed, both clinical and foundational science demonstrate a clear relationship between disruption of circadian rhythms and cancer initiation and progression. Because timing of food intake can act as a zeitgeber (i.e., entrainment signal) for the circadian clock, and most individuals in the developed world have access to food at all times of the day in a “24/7” society, we sought to determine the effects of timing of food intake on mammary tumor growth. We hypothesized that restricting access to food to during the inactive phase would accelerate tumor growth. Adult female Balb/C mice received a unilateral orthotopic injection of murine mammary carcinoma 4T1 cells into the ninth inguinal mammary gland. Beginning on the day of tumor injection and continuing until the end of the experiment, mice were food restricted to their active phase (ZT12 (lights off)- ZT0 (lights on), inactive phase (ZT0 - ZT12), or had ad libitum access to food. Mice that were food restricted to their inactive phase displayed a significant increase in body mass on days 7 and 14 of tumor growth relative to active phase or ad libitum fed mice. Additionally, mice fed during their inactive phase demonstrated a 20% reduction in food consumption relative to mice fed during their active phase and a 17% reduction in food consumption relative to ab libitum fed mice. Tumor volume was not significantly different between groups. However, food restricting mice to their inactive phase increased mammary tumor growth efficiency (i.e., mg of tumor mass per gram of food intake) relative to mice fed during the active phase and approached significance (p=0.06) relative to ad libitum fed mice. To determine a potential explanation for the increased tumor growth efficiency, we examined rhythms of activity and body temperature. Mice fed during the inactive phase displayed significantly disrupted daily activity and body temperature rhythms relative to both other feeding regimens. Together, these data demonstrate that improperly timed food intake can have detrimental consequences on mammary tumor growth likely via disrupted circadian rhythms.

Breast cancer survivors receiving chemotherapy often report increased anxiety and depression. However, the mechanism underlying chemotherapy-induced changes in affect remains unknown. We hypothesized that chemotherapy increases cytokine production, in turn altering exploratory and depressive-like behavior. To test this hypothesis, female Balb/C mice received two injections, separated by two weeks, of vehicle (0.9% saline) or a chemotherapeutic cocktail [9 mg/kg doxorubicin (A) and 90 mg/kg cyclophosphamide (C)]. Peripheral and central cytokine concentrations were increased one and seven days, respectively, after AC. Because of the beneficial effects of social enrichment on several diseases with inflammatory components, we examined whether social enrichment could attenuate the increase in peripheral and central cytokine production following chemotherapy administration. Socially isolated mice receiving AC therapy demonstrated increased depressive-like and exploratory behaviors with a concurrent increase in hippocampal IL-6. Whereas, group housing attenuated AC-induced IL-6 and depressive-like behavior. Next, we sought to determine whether central oxytocin may contribute to the protective effects of social housing after AC administration. Intracerebroventricular administration of oxytocin to socially isolated mice recapitulated the protective effects of social enrichment; specifically, oxytocin ameliorated the AC-induced effects on IL-6 and depressive-like behavior. Furthermore, administration of an oxytocin antagonist to group housed mice recapitulated the responses of socially isolated mice; specifically, AC increased depressive-like behavior and central IL-6. These data suggest a possible neuroprotective role for oxytocin following chemotherapy, via modulation of IL-6. This study adds to the growing literature detailing the negative behavioral effects of chemotherapy and provides further evidence that social enrichment may be beneficial to health.

Circadian rhythms are endogenous biological cycles that synchronize physiology and behaviour to promote optimal function. These ~24-hr internal rhythms are set to precisely 24 hr daily by exposure to the sun. However, the prevalence of night-time lighting has the potential to dysregulate these biological functions. Hospital patients may be particularly vulnerable to the consequences of light at night because of their compromised physiological state. A mouse model of stroke (middle cerebral artery occlusion; MCAO) was used to test the hypothesis that exposure to dim light at night impairs responses to a major insult. Stroke lesion size was substantially larger among animals housed in dLAN after reperfusion than animals maintained in dark nights. Mice housed in dLAN for three days after the stroke displayed increased post-stroke anxiety-like behaviour. Overall, dLAN amplified pro-inflammatory pathways in the CNS, which may have exacerbated neuronal damage. Our results suggest that exposure to LAN is detrimental to stroke recovery.

Artificial light at night (LAN) is a pervasive phenomenon in today's society, and the detrimental consequences of LAN exposure are becoming apparent. LAN is associated with the increased incidence of metabolic disorders, cancers, mood alterations, and immune dysfunction in mammals. Consequently, we examined the effects of dim LAN (DLAN) on wound healing. Female C57BL/6 mice were housed for 3 weeks in DLAN or LD conditions prior to wounding. Following wounding, mice were maintained in either their previous light conditions or switched to the opposite lighting conditions for 3 weeks. DLAN prior to wounding impaired healing; specifically, mice in DLAN/DLAN had significantly larger wounds on day 8. Additionally, mice in DLAN/LD had significantly larger wounds on days 5, 7, 8, and 9, and increased average time to closure. These data demonstrate a potential harmful effect of DLAN on wound healing that should be considered and may represent a target for therapeutic intervention.

The advent and wide-spread adoption of electric lighting over the past century has profoundly affected the circadian organization of physiology and behavior for many individuals in industrialized nations; electric lighting in homes, work environments, and public areas have extended daytime activities into the evening, thus, increasing night-time exposure to light. Although initially assumed to be innocuous, chronic exposure to light at night (LAN) is now associated with increased incidence of cancer, metabolic disorders, and affective problems in humans. However, little is known about potential acute effects of LAN. To determine whether acute exposure to low-level LAN alters brain function, adult male, and female mice were housed in either light days and dark nights (LD; 14 h of 150 lux:10 h of 0 lux) or light days and low level light at night (LAN; 14 h of 150 lux:10 h of 5 lux). Mice exposed to LAN on three consecutive nights increased depressive-like responses compared to mice housed in dark nights. In addition, female mice exposed to LAN increased central tendency in the open field. LAN was associated with reduced hippocampal vascular endothelial growth factor-A (VEGF-A) in both male and female mice, as well as increased VEGFR1 and interleukin-1β mRNA expression in females, and reduced brain derived neurotrophic factor mRNA in males. Further, LAN significantly altered circadian rhythms (activity and temperature) and circadian gene expression in female and male mice, respectively. Altogether, this study demonstrates that acute exposure to LAN alters brain physiology and can be detrimental to well-being in otherwise healthy individuals.

Changes to photoperiod (day length) occur in anticipation of seasonal environmental changes, altering physiology and behavior to maximize fitness. In order for photoperiod to be useful as a predictive factor of temperature or food availability, day and night must be distinct. The increasing prevalence of exposure to artificial light at night (ALAN) in both field and laboratory settings disrupts photoperiodic time measurement and may block development of appropriate seasonal adaptations. Here, we review the effects of ALAN as a disruptor of photoperiodic time measurement and season-specific adaptations, including reproduction, metabolism, immune function, and thermoregulation.

Although much has been learned about circadian clocks and rhythms over the past few decades, translation of this foundational science underlying the temporal regulation of physiology and behavior to clinical applications has been slow. Indeed, acceptance of the modern study of circadian rhythms has been blunted because the phenomenology of cyclic changes had to counteract the 20th century dogma of homeostasis in the biological sciences and medicine. We are providing this review of clinical data to highlight the emerging awareness of circadian variation in efficacy of medications for physicians, clinicians, and pharmacists. We are suggesting that gold-standard double-blind clinical studies should be conducted to determine the best time of day for optimal effectiveness of medications; also, we suggest that time of day should be tracked and reported as an important biological variable in ongoing clinical studies hereafter. Furthermore, we emphasize that time of day is, and should be considered, a key biological variable in research design similar to sex. In common with biomedical research data that have been historically strongly skewed toward the male sex, most pharmaceutical data have been skewed toward morning dosing without strong evidence that this is the optimal time of efficacy.

For many individuals in industrialized nations, the widespread adoption of electric lighting has dramatically affected the circadian organization of physiology and behavior. Although initially assumed to be innocuous, exposure to artificial light at night (ALAN) is associated with several disorders, including increased incidence of cancer, metabolic disorders, and mood disorders. Within this review, we present a brief overview of the molecular circadian clock system and the importance of maintaining fidelity to bright days and dark nights. We describe the interrelation between core clock genes and the cell cycle, as well as the contribution of clock genes to oncogenesis. Next, we review the clinical implications of disrupted circadian rhythms on cancer, followed by a section on the foundational science literature on the effects of light at night and cancer. Finally, we provide some strategies for mitigation of disrupted circadian rhythms to improve health.

With the exception of high latitudes, life has evolved under bright days and dark nights. Most organisms have developed endogenously driven circadian rhythms that are synchronized to this daily light/dark cycle. In recent years, humans have shifted away from the naturally occurring solar light cycle in favor of artificial and sometimes irregular light schedules produced by electric lighting. Exposure to unnatural light cycles is increasingly associated with obesity and metabolic syndrome; however, the means by which environmental lighting alters metabolism are poorly understood. Thus, we exposed mice to dim light at night and investigated changes in the circadian system and metabolism. Here we report that exposure to ecologically relevant levels of dim (5 lux) light at night altered core circadian clock rhythms in the hypothalamus at both the gene and protein level. Circadian rhythms in clock expression persisted during light at night; however, the amplitude of Per1 and Per2 rhythms was attenuated in the hypothalamus. Circadian oscillations were also altered in peripheral tissues critical for metabolic regulation. Exposure to dimly illuminated, as compared to dark, nights decreased the rhythmic expression in all but one of the core circadian clock genes assessed in the liver. Additionally, mice exposed to dim light at night attenuated Rev-Erb expression in the liver and adipose tissue. Changes in the circadian clock were associated with temporal alterations in feeding behavior and increased weight gain. These results are significant because they provide evidence that mild changes in environmental lighting can alter circadian and metabolic function. Detailed analysis of temporal changes induced by nighttime light exposure may provide insight into the onset and progression of obesity and metabolic syndrome, as well as other disorders involving sleep and circadian rhythm disruption.

Most organisms display circadian rhythms that coordinate complex physiological and behavioral processes to optimize energy acquisition, storage, and expenditure. Disruptions to the circadian system with environmental manipulations such as nighttime light exposure alter metabolic energy homeostasis. Exercise is known to strengthen circadian rhythms and to prevent weight gain. Therefore, we hypothesized providing mice a running wheel for voluntary exercise would buffer against the effects of light at night (LAN) on weight gain. Mice were maintained in either dark (LD) or dim (dLAN) nights and provided either a running wheel or a locked wheel. Mice exposed to dim, rather than dark, nights increased weight gain. Access to a functional running wheel prevented body mass gain in mice exposed to dLAN. Voluntary exercise appeared to limit weight gain independently of rescuing changes to the circadian system caused by dLAN; increases in daytime food intake induced by dLAN were not diminished by increased voluntary exercise. Furthermore, although all of the LD mice displayed a 24 h rhythm in wheel running, nearly half (4 out of 9) of the dLAN mice did not display a dominant 24 h rhythm in wheel running. These results indicate that voluntary exercise can prevent weight gain induced by dLAN without rescuing circadian rhythm disruptions.