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This article is part of the 2018 NMJ Oncology Special Issue. Download the full issue.
Relation
Pagliai G, Sofi F, Dinu M, et al. CLOCK gene polymorphisms and quality of aging in a cohort of nonagenarians - The MUGELLO study.Scientific Rep. 2019;9(1):1472.
Draft
Prospective observational cohort of an ongoing epidemiological study
Objective
To find associations between genotypes of the CLOCK gene and the quality of aging
Participant
All participants (n=356; 237 women, 99 men) were between 86 and 106 years old and lived in or near the Mugello region of Tuscany, Italy. All took part in the MUGELLO study, an ongoing epidemiological study that examines many parameters of aging to measure associations with quality of life.
Study outcome measures
All participants underwent genotyping for 3 polymorphisms of the CLOCK gene (rs1801260, rs11932595, rs4580704). Data were collected through home/nursing home visits during which blood was drawn and objective parameters (ie, blood pressure, weight, waist circumference, height) were assessed and BMI was calculated. Objective measures of cognitive function included the Mini-Mental Status Exam and the Clock Drawing Test. Basic activities of daily living were also assessed. Laboratory measurements included a cholesterol panel and fasting glucose.
Questionnaires were used to assess sleep, mood and diet. Sleep was tracked by a questionnaire, the Pittsburgh Sleep Quality Index (PSQI), and a SenseWear wristband calorimeter was used to objectively assess sleep patterns (worn for 1 week of the study). A short form of the Geriatric Depression Scale (GDS) was used to identify possible depression. The Mediterranean Diet Score (MDS) was used to measure adherence to the Mediterranean diet.
Key insights
In this older population, there was an association between CLOCK gene polymorphisms and weight, glycemia, low-density lipoprotein (LDL) cholesterol, and triglycerides. In addition, there were significant associations of individual polymorphisms (and different haplotypes) with cognitive decline, depressive state, and diet quality.
The authors postulate that all measured parameters – cholesterol levels, weight gain, cognitive function and dietary habits – are partially regulated by circadian rhythms. They hypothesize that polymorphisms in the CLOCK gene may be at least partially responsible for differences in the quality of life and health status of nonagenarians.
Practice implications
This is the first study to examine polymorphisms in the CLOCK gene in relation to the quality of aging in an older population. To date, variations in clock gene expression due to shift work, sleep deprivation, light at night, aging itself, and genetic variations in the CLOCK gene have been linked to obesity, type 2 diabetes, mood disorders, cardiovascular disease, 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 different organ systems to increase an organism's physical fitness and the most efficient response to periodic environmental events such as the day/night cycle.”5Such oscillators occur throughout nature, including in bacteria, fungi, plants, insects and mammals.6In addition to being present in all kingdoms, clock genes are found in cells in almost all tissues of the body, including all glandular tissues, fat stores, bone marrow, tendons/ligaments, skin, and immune cells.
Disturbances in normal circadian rhythms, common in this population, may be associated with conditions associated with specific underlying polymorphisms of the CLOCK gene.
Clock genes are the central players in a complex system of endogenous timekeeping that, although entrained by light from the environment, act independently of light to oscillate body functions within a 24-hour biorhythm. The 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 that controls two other clock gene types - period genes (PER1, PER2, PER3) and the cryptochrome genes (CRY1, CRY2). As an upstream controller, the CLOCK gene/protein has a greater impact 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 were associated with polymorphisms in the CLOCK gene in participants over 90 years of age. It is known that aging often leads to changes in circadian rhythms, typically an earlier time of day to fall asleep, greater sleep disturbances, and reduced sleep time, all of which are influenced by clock genes.8However, how much circadian disruption contributes to disease and aging is not well understood. Pagliai and colleagues confirmed that there is genetic variation in circadian rhythms under the control of the CLOCK gene and that this is associated with various aging conditions. For example, they confirmed that the single nucleotide polymorphism (SNP) rs1801260 is associated with better sleep patterns and a lower risk of obesity. (This has been specifically linked to the AAG and GGC haplotypes.) That better sleep correlates with better weight control is consistent with evidence linking poor sleep and weight gain.9
The relationship between clock genes and blood glucose is an area of ongoing study, with the 24-hour entrainment of clock gene expression not only to light/dark cycles but also to feeding/fasting cycles increasingly appreciated.10Furthermore, most human clock genes are expressed in pancreatic islet cells, where they participate in glucose regulation by regulating a background of rhythmic insulin secretion.11In this study, the GGC haplotype was associated with a lower risk of hyperglycemia for all 3 polymorphisms, while other SNPs in rs1801260 and rs11932595 were associated with higher fasting glucose levels. The authors postulated that “the effects of the CLOCK gene on glucose metabolism in peripheral organs may be a mechanism involved in the development of hyperglycemia.” This confirms the 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 particularly in the CLOCK gene are associated with dyslipidemia. This is not surprising. The 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.14Consistent with this, this study showed that higher triglycerides and LDL cholesterol were associated with a SNP in rs4580704 and that haplotype AAG was associated with high triglycerides and higher total cholesterol. Ultimately, variations in clock genes may be at least partially responsible for the apparent familial disposition of cholesterol levels.
Finally, there were associations between CLOCK gene polymorphisms and cognitive function and depressive state. The authors suggest that in the case of depression and cognitive function, it is not only about the regulation of circadian rhythms by clock genes, but also about the involvement of clock genes in the hypothalamic-pituitary-adrenal stress response.14For example, in this study, those who were homozygous (GG) for SNP rs1801260 had worse scores on the geriatric depression scale. However, the same cohort had better clock drawing scores, suggesting better hand-eye skills and abstract thinking. The authors suggest that better clock drawing as well as a tendency to depressive states in individuals with this variation in the CLOCK gene may be due to increased cellular sensitivity to endogenous glucocorticoids from acute stressors.
In this study, the quality of aging, measured by various objective and subjective parameters, was associated with variations in the CLOCK gene in an older population. This implies that clock genes not only regulate the 24-hour rhythm but are also involved in peripheral cell responses to changes in this rhythm.
Regardless of the underlying SNPs or haplotypes of clock genes in our patients, the ongoing work to elucidate how these genes keep us in sync with a planetary 24-hour biorhythm should remind us all to look back when assessing a person's health. Regardless of why a particular patient is being studied, it will be difficult, if not impossible, to fully correct the underlying pathophysiology without normalizing their circadian rhythm, which is always anchored by a proper sleep cycle.