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Pagliai G, Sofi F, Dinu M, et al. CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians – The MUGELLO Study. Sci Rep. 2019;9(1):1472.
Prospective, observational cohort of an ongoing epidemiological study
To find associations between genotypes of the CLOCK gene and quality of aging
All participants (n=356; 237 women, 99 men) were between the ages of 86 and 106 years, living in or near the Mugello region in Tuscany, Italy. All were participating in the MUGELLO study, an ongoing epidemiological study investigating many parameters of aging to gauge associations with quality of life.
Study Outcome Measures
All participants underwent genotyping for 3 polymorphisms of the CLOCK gene (rs1801260, rs11932595, rs4580704). Data was collected by home/nursing home visits where blood was drawn and objective parameters (ie, blood pressure, weight, waist circumference, height) were assessed and BMI calculated. Objective measures of cognitive function included the Mini-Mental Status Exam and Clock Drawing Test. Basic activities of daily living were also assessed. Laboratory measurements included a cholesterol panel and fasting glucose.
Questionnaires were used to evaluate sleep, mood, and diet. Sleep was tracked through a questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and a SenseWear Armband calorimeter was used for objective sleep pattern assessment (worn for 1 week of study). A short form of the Geriatric Depression Scale (GDS) was used to detect possible depression. The Mediterranean Diet Score (MDS) was used to gauge adherence to the Mediterranean diet.
There was an association between CLOCK gene polymorphisms and weight, glycemia, low-density lipoprotein (LDL) cholesterol, and triglycerides in this elderly population. In addition, there were significant associations of individual polymorphisms (and various haplotypes) with cognitive decline, depressive state, and quality of diet.
The authors postulate that all the parameters measured—cholesterol levels, weight gain, cognitive function, and dietary choices—are partly regulated by circadian rhythm. They hypothesize that polymorphisms in the CLOCK gene may be at least partly responsible for differences in the quality of life and health conditions of nonagenarians.
This is the first study to look at polymorphisms in the CLOCK gene relative to quality of aging in an elderly population. To date, variations in clock gene expression due to shift work, sleep deprivation, light at night exposure, aging itself, and genetic variations of the CLOCK gene have been associated with obesity, type 2 diabetes, mood disorders, cardiovascular diseases, psychiatric disorders, and various cancers.1-4
The term “clock genes” is used to describe “genes involved in maintaining the internal coordination of multiple oscillators within and between various organs systems, in order to increase physical fitness of an organism and provide the most efficient response to the periodical environmental events such as the day/night cycle.”5 Such oscillators are found throughout nature, including in bacteria, fungi, plants, insects, and mammals.6 In addition to presence across kingdoms, clock genes are found within cells in nearly all tissues of the body, including all glandular tissues, fat stores, bone marrow, tendons/ligaments, skin, and immune cells.
Disruptions to normal circadian rhythms, which are common in this population, may be linked to conditions that are associated with specific underlying CLOCK gene polymorphisms.
Clock genes are the central players in a complex system of endogenous time-keeping that, while entrained by light from the environment, act independently of light to oscillate bodily functions within a 24-hour biorhythm. The gene locus in the current study being reviewed is the CLOCK gene, which stands for the Circadian Locomotor Output Cycle Kaput gene, and it was one of the first clock genes discovered. It encodes the corresponding CLOCK protein, which is part of a transcription factor complex controlling 2 other clock gene types—Period genes (PER1, PER2, PER3) and the Cryptochrome genes (CRY1, CRY2). As an upstream controller, the CLOCK gene/protein has greater influence on circadian regulation than its downstream products, whose transcription is essentially under its control.7
The current study under review found that differences in weight, cholesterol levels, mood, cognition, and quality of life in participants over 90 years old were associated with polymorphisms in the CLOCK gene. It is well known that aging often leads to changes in circadian rhythm, typically an earlier time of day to fall asleep, greater sleep disturbance, and shortened sleep time, all of which are influenced by clock genes.8 However, how much circadian disruption contributes to diseases and conditions of aging is not well-studied. Pagliai and colleagues confirmed that there is a genetic variation in circadian rhythm that is under the control of the CLOCK gene, and that this is associated with various conditions of aging. For example, they confirmed that single nucleotide polymorphism (SNP) rs1801260 is associated with better sleep patterns and less risk of being overweight. (This was specifically associated with haplotypes AAG and GGC.) That better sleep correlates to better weight control is in keeping with evidence linking poor sleep and weight gain.9
The relationship between clock genes and blood glucose is an area of ongoing study, with a growing appreciation for the 24-hour entrainment of clock gene expression from not only light/dark cycles, but also from feeding/fasting cycles.10 In addition, most human clock genes are expressed in pancreatic islet cells, where they take part in glucose regulation by regulating a background of rhythmic insulin secretion.11 In this study, the GGC haplotype for all 3 polymorphisms was associated with a lower risk of hyperglycemia, while other SNPs in rs1801260 and rs11932595 were related to higher levels of fasting glucose. The authors postulated that “the effects of the CLOCK gene on glucose metabolism in the peripheral organs may be a mechanism involved in the development of hyperglycemia.” This corroborates evidence for the involvement of clock genes in the underlying pathophysiology in type 2 diabetes.12,13
They also confirmed that polymorphisms in clock genes, and specifically the CLOCK gene, is associated with dyslipidemia. This is not surprising. Inherent rhythmicity of circulating lipids has been known for some time, and recently there is evidence that it is under the control of clock genes.14 In keeping, this study showed that higher triglycerides and LDL cholesterol were associated with an SNP in rs4580704 and that the haplotype AAG was associated with high triglycerides and higher total cholesterol. Ultimately, variations in clock genes may, at least partly, account for the apparent familial disposition in cholesterol levels.
Lastly, there were associations between CLOCK gene polymorphisms and cognitive function as well as depressive state. The authors propose that, in the case of depression and cognitive function, it is not only clock genes’ regulation of circadian rhythm but clock gene involvement in the hypothalamic-pituitary-adrenal stress response.14 For example, in this study, those who were homozygous (GG) for SNP rs1801260 had worse scores on the geriatric depression scale. This same cohort, however, had better scores on clock drawing, implying better hand-eye skills and abstract thinking. The authors propose that better clock drawing as well as a tendency toward depressive states in those with this variation of the CLOCK gene may be due to a heightened cellular sensitivity to endogenous glucocorticoids from acute stressors.
In this study, the quality of aging, as measured by various objective and subjective parameters, was associated with CLOCK gene variations in an elderly population. This implies that clock genes not only regulate the 24-hour rhythm but are involved in peripheral cellular responses to changes in that rhythm as well.
Regardless of underlying SNPs or haplotypes of clock genes in our patients, the continuing work to elucidate how these genes keep us in sync with a 24-hour planetary biorhythm should remind us all to pan back when assessing a person’s health. No matter why a given patient is being seen, it will be difficult if not impossible to completely correct underlying pathophysiology without normalization of their circadian rhythm, which is always anchored by a proper sleep cycle.
- Valladares M, Obregón AM, Chaput J-P. Association between genetic variants of the clock gene and obesity and sleep duration. J Physiol Biochem. 2015;71(4):855-860.
- Schuch JB, Genro JP, Bastos CR, Ghisleni G, Tovo-Rodrigues L. The role of CLOCK gene in psychiatric disorders: evidence from human and animal research. Am J Med Genet Part B Neuropsychiatr Genet. 2018;177(2):181-198.
- Garbazza C, Benedetti F. Genetic factors affecting seasonality, mood, and the circadian clock. Front Endocrinol (Lausanne). 2018;9:481.
- Kelleher FC, Rao A, Maguire A. Circadian molecular clocks and cancer. Cancer Lett. 2014;342(1):9-18.
- Pagliai G, Sofi F, Dinu M, et al. CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians – The MUGELLO Study. Sci Rep. 2019;9(1):1472.
- Saini R, Jaskolski M, Davis SJ. Circadian oscillator proteins across the kingdoms of life: structural aspects. BMC Biol. 2019;17(1):13.
- CLOCK clock circadian regulator [Homo sapiens (human)]. https://www.ncbi.nlm.nih.gov/gene/9575. Updated April 15, 2019. Accessed April 27, 2019.
- Gibson EM, Williams WP, Kriegsfeld LJ. Aging in the circadian system: considerations for health, disease prevention and longevity. Exp Gerontol. 2009;44(1-2):51-56.
- Beccuti G, Pannain S. Sleep and obesity. Curr Opin Clin Nutr Metab Care. 2011;14(4):402-412.
- Javeed N, Matveyenko A V. Circadian etiology of type 2 diabetes mellitus. Physiology. 2018;33(2):138-150.
- Pulimeno P, Mannic T, Sage D, et al. Autonomous and self-sustained circadian oscillators displayed in human islet cells. Diabetologia. 2013;56(3):497-507.
- Prasai MJ, George JT, Scott EM. Molecular clocks, type 2 diabetes and cardiovascular disease. Diabetes Vasc Dis Res. 2008;5(2):89-95.
- Karthikeyan R, Spence DW, Brown GM, Pandi-Perumal SR. Are type 2 diabetes mellitus and depression part of a common clock genes network? J Circadian Rhythms. 2018;16:4.
- Dallmann R, Viola AU, Tarokh L, Cajochen C, Brown SA. The human circadian metabolome. Proc Natl Acad Sci U S A. 2012;109(7):2625-2629.