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Exposure to Light at Night Accelerates Aging and Spontaneous Carcinogenesis in Mice
Posted on: May 30, 2013

The alternation of the day and night seems is a most important regulator of a wide variety of physiological rhythms in living organisms. Exposure to the bright light during the night suppresses the night peak of melatonin – the "hormone of the night." Melatonin is a principal hormone of the pineal gland – the small neuroendocrine gland connected with the brain that mediates information on light from the retina of the eyes to the organism. Light exposure at night has been found to be related to a number of serious behavior as well as health problems, including cancer.

Significant increase in the risk of breast and colorectal cancers was found among women who frequently did not sleep during the period of the night, about 1:30 a.m., when melatonin levels are typically at their highest.

"Melatonin hypothesis" suggests that reduced pineal melatonin production might increase human breast cancer risk, because lower melatonin output would lead to an increase in the level of female sex hormones and would stimulate proliferation of breast tissue. Global co-distribution of light at night and cancers of breast, prostate and some others was demonstrated in humans.

Constant illumination probably exerts its detrimental effects on health, tumorigenesis as well as survival via disturbances of the female reproductive cycle. The mechanisms involved can be assumed to include the pineal hormone melatonin as well, which, as chemical signal of darkness and controlled by the central circadian clock in N.suprachiasmatici, may play a very central part, since it is suppressed by constant exposure to light and participates in the neuroendocrine control of the female reproductive system. Latest data from experiments in model organisms, gene expression studies and clinical trials imply that dysfunctions of the circadian clock contribute to aging and age-associated pathologies, thereby suggesting a functional link between the circadian clock and age-associated decline of brain functions. Potential molecular mechanisms underlying this link include the circadian control of physiological processes such as brain metabolism, reactive oxygen species homeostasis, hormone secretion, autophagy and stem cell proliferation. On the basis of "limited evidence in humans for the carcinogenicity of shift-work that involves night work" and "sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)," the International Agency for Research on Cancer (IARC) Working Group concluded that "shift-work that involves circadian disruption is probably carcinogenic to humans". In rodents, light at night leads to disruption of the ovulatory cycles followed by hyperplastic processes and tumor development in mammary gland, ovarian and uterine. The tumor-promoting effect of exposure to the constant illumination regimen was shown on chemical carcinogenesis of mammary gland, liver and nervous system in rats and spontaneous endometrial carcinogenesis in rats.

In mammals, exposure to bright constant illumination alters the central circadian pacemaker activity of the suprachiasmatic nucleus in the hypothalamus. Constant light exposure or pinealectomy blocks the circadian melatonin signal emanating from the mammalian pineal gland during every 24 h dark period. When introduced during the dark phase, bright light inhibits melatonin production. Artificial increase of the length of light phase of the day (by 2-4 h) was typically followed by the increase in the duration of estrous cycle and in some cases to its disturbances. If the light will be switched on for 24 h per day, the majority of female mice and rats in a short period revealed the persistent estrus syndrome. In physiological circumstances, this syndrome naturally develops at some age (in rats, as usual between 15th and 18th months) and precedes to the anestrus, being the physiological equivalent of climacteric syndrome and climacteric in women.

The ovary of persistent-estrus rats contains follicular cysts, hyperplasia of theca-tissue, whereas the corpora lutea are absent. Instead cyclic production of gonadotropins, prolactin, estrogens and progesterone characteristic for normal reproductive period of life, their acyclic production is followed by hyperplastic processes in mammary gland, ovaries and uterus.

Scientists have found that the exposure to the LL (constant illumination; 24 h a day, 2,500 lx, LL) regimen leads to the increase in the threshold of sensitivity of the hypothalamus to the feedback inhibition by estrogens in female rats. This mechanism is a key mechanism in the aging of reproductive system in female rats as well as in women.

The disturbances in the estrous function developed much more early in 129/Sv mice in the LL group than that in the LD [12 h light (70 lx):12hr dark; LD, control group] group. Scientists also have observed excess of the body weight in the old female 129/Sv mice maintained at LL regimen as compared with the control LD mice. The obesity, decrease of tolerance to glucose and of the sensitivity to insulin have been observed in rats with persistent estrus. Metabolic syndrome characterized by obesity, hypertriglyceridemia and hypercholesterinemia is observed to decrease the level of high density lipoproteins, blood fibrinolytic activity, arterial hypertension, tolerance to glucose and insulin resistance more frequently.

The metabolic syndrome is a risk factor not only for cardiovascular diseases but for cancer too. The inhibition of pineal function due to exposure to continuous light probably facilitates the metabolic syndrome development. The exposure to the LL regimen promoted spontaneous mammary carcinogenesis in female LIO rats and in transgenic HER-2/neu FVB/N mice, mammary carcinogenesis induced by 7,12-dimethylbenz(a)anthracene or N-nitrosomethylurea in female rats and colon carcinogenesis induced by 1,2-dimethylhydrazine in rats. The exposure to the LL regimen accelerated spontaneous uterine carcinogenesis in BDII rats.

It was first shown in these experiments that the constant light illumination promotes the spontaneous development of uterine tumors in 129/Sv mice. The mechanisms of the protective effect of melatonin on carcinogenesis include the variety of possibilities discussed in several comprehensive reviews and include antioxidant and antiproliferative effects, the increase in apoptosis and inhibitory effect on telomerase activity in tumor cells both in vivo and in vitro, antiestrogenic effect, the decrease IGF-1 and insulin levels, etc.

In conclusion, the results of the study demonstrate that exposure to light at night may have an important role in development of not only mammary tumors, but also a wide spectrum of tumors at different localization.

Keywords: 129/Sv mice, lifespan, light at night, tumorigenesis.

Source: Popovich IG, Anisimov VN et al. Exposure to light at night accelerates aging and spontaneous uterine carcinogenesis in female 129/Sv mice.; Cell Cycle. 2013 May 6;12(11). [Epub ahead of print]
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