The Role of Race, Sex, and Age in Circadian Disruption and Metabolic Disorders

Abstract

Circadian rhythms are 24-hour internal biological cycles that play an important role in metabolism, and their disruption has been implicated in the development of diseases such as diabetes mellitus type 2, obesity, coronary artery disease, hypertension, and metabolic syndrome. This phenomenon is illustrated by increased rates of risk factors for cardiovascular disease in night shift workers. Race, sex, and age are factors that play a role in circadian rhythms and metabolic disorders. The focus of this review article is to assess the link between circadian rhythm physiology and metabolic disorders from a race, sex, and age perspective. Black Americans were noted to have shorter free-running circadian periods, or tau, increased cortisol levels, and poorer sleep habits compared to white Americans, possibly contributing to increased rates of obesity, hypertension, and hyperlipidemia. Women were also noted to have shorter tau, increased levels of proinflammatory gut bacteria, and reduced sleep quality compared to men, possibly leading to higher rates of obesity, metabolic syndrome, hypertension (in postmenopausal women), and nonalcoholic fatty liver disease. Older people were noted to have decreased expression of anti-inflammatory clock genes compared to younger people, possibly leading to increased rates of obesity, diabetes, hyperlipidemia, and hypertension. Groups that are at a higher risk for metabolic disorders such as black Americans, women, and the elderly may have internal time keeping systems that place them at a higher risk for developing abnormal hormonal and/or inflammatory pathways. Circadian rhythms are 24-hour internal biological cycles that play an important role in metabolism, and their disruption has been implicated in the development of diseases such as diabetes mellitus type 2, obesity, coronary artery disease, hypertension, and metabolic syndrome. This phenomenon is illustrated by increased rates of risk factors for cardiovascular disease in night shift workers. Race, sex, and age are factors that play a role in circadian rhythms and metabolic disorders. The focus of this review article is to assess the link between circadian rhythm physiology and metabolic disorders from a race, sex, and age perspective. Black Americans were noted to have shorter free-running circadian periods, or tau, increased cortisol levels, and poorer sleep habits compared to white Americans, possibly contributing to increased rates of obesity, hypertension, and hyperlipidemia. Women were also noted to have shorter tau, increased levels of proinflammatory gut bacteria, and reduced sleep quality compared to men, possibly leading to higher rates of obesity, metabolic syndrome, hypertension (in postmenopausal women), and nonalcoholic fatty liver disease. Older people were noted to have decreased expression of anti-inflammatory clock genes compared to younger people, possibly leading to increased rates of obesity, diabetes, hyperlipidemia, and hypertension. Groups that are at a higher risk for metabolic disorders such as black Americans, women, and the elderly may have internal time keeping systems that place them at a higher risk for developing abnormal hormonal and/or inflammatory pathways. Circadian rhythms are an integral part of healthy biological functioning. They affect sleep-wake cycles, hormone release, body temperature, and metabolism.1Egan K.J. Knutson K.L. 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Fogg L.F. et al.Racial differences in the human endogenous circadian period.PLoS One. 2009; 4e6014Crossref Scopus (78) Google Scholar In humans, experiments with blind people have measured average tau to be a little over 24 hours.5Sack R.L. Lewy A.J. Blood M.L. et al.Circadian rhythm abnormalities in totally blind people: incidence and clinical significance.J Clin Endocrinol Metab. 1992; 75: 127-134Crossref PubMed Scopus (0) Google Scholar The suprachiasmatic nucleus (SCN) of the hypothalamus regulates the biological clock.6Asher G. Sassone-Corsi P. Time for food: the intimate interplay between nutrition, metabolism, and the circadian clock.Cell. 2015; 161: 84-92Abstract Full Text Full Text PDF PubMed Scopus (494) Google Scholar It operates autonomously on a schedule close to 24 hours (tau) but also senses zeitgebers from light intake via ocular photoreceptors, nutrient ingestion, and temperature.7Freedman M.S. 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Glucocorticoid hormones inhibit food-induced phase-shifting of peripheral circadian oscillators.EMBO J. 2001; 20: 7128-7136Crossref PubMed Scopus (385) Google Scholar In clinical medicine, abnormal circadian rhythms have been implicated in the development of obesity, diabetes mellitus type 2, coronary artery disease, thrombosis, inflammatory disorders, and metabolic syndrome.13Maury E. Ramsey K.M. Bass J. Circadian rhythms and metabolic syndrome: from experimental genetics to human disease.Circ Res. 2010; 106: 447-462Crossref PubMed Scopus (346) Google Scholar Metabolic syndrome refers to the multiple metabolic derangements linked to obesity and insulin resistance with a high risk of diabetes mellitus and cardiovascular disease.14Laaksonen D.E. Metabolic syndrome and development of diabetes mellitus: application and validation of recently suggested definitions of the metabolic syndrome in a prospective cohort study.Am J Epidemiol. 2002; 156: 1070-1077Crossref PubMed Scopus (766) Google Scholar Circadian disruption is thought to be linked to weight gain and obesity by improper timing of meals. It is possible that eating during habitual sleep time limits opportunities for energy expenditure.15Noh J. The effect of circadian and sleep disruptions on obesity risk.J Obes Metab Syndr. 2018; 27: 78-83Crossref PubMed Google Scholar In regard to diabetes, experimental data have shown that circadian disruption impairs pancreatic beta cell function and insulin sensitivity, and this combined effect of reduced insulin levels and penetrance results in abnormal glucose tolerance and an increased risk for progression to diabetes.16Mason I.C. Qian J. Adler G.K. et al.Impact of circadian disruption on glucose metabolism: implications for type 2 diabetes.Diabetologia. 2020; 63: 462-472Crossref PubMed Scopus (75) Google Scholar Disruption of regular circadian cycles can also increase the risk of developing cardiometabolic disorders, as is evidenced by increased rates of risk factors for cardiovascular disease in shift workers (Figure 1B).17Reutrakul S. Knutson K.L. Consequences of circadian disruption on cardiometabolic health.Sleep Med Clin. 2015; 10: 455-468Abstract Full Text Full Text PDF PubMed Scopus (85) Google Scholar Studies show that the prevalence of metabolic disorders varies depending on race, sex, or age.1Egan K.J. Knutson K.L. Pereira A.C. et al.The role of race and ethnicity in sleep, circadian rhythms and cardiovascular health.Sleep Med Rev. 2017; 33: 70-78Crossref PubMed Scopus (49) Google Scholar,18Kautzky-Willer A. Harreiter J. Pacini G. Sex and gender differences in risk, pathophysiology and complications of type 2 diabetes mellitus.Endocr Rev. 2016; 37: 278-316Crossref PubMed Scopus (777) Google Scholar,19Sohail S. Yu L. Bennett D.A. et al.Irregular 24-hour activity rhythms and the metabolic syndrome in older adults.Chronobiol Int. 2015; 32: 802-813Crossref PubMed Scopus (50) Google Scholar Black Americans and Hispanics are at an increased risk for developing hypertension, hyperlipidemia, and obesity compared to white Americans.20Mozaffarian D. Benjamin E.J. Go A.S. et al.Heart disease and stroke statistics—2015 update: a report from the American Heart Association.Circulation. 2015; 131: e29-e322Crossref PubMed Scopus (5637) Google Scholar, 21Wang Y. 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Sullivan J.C. Sex differences in hypertension: where we have been and where we are going.Am J Hypertens. 2018; 31: 1247-1254Crossref PubMed Scopus (92) Google Scholar Older people are at a higher risk for developing obesity, diabetes, hyperlipidemia, and hypertension than younger people.19Sohail S. Yu L. Bennett D.A. et al.Irregular 24-hour activity rhythms and the metabolic syndrome in older adults.Chronobiol Int. 2015; 32: 802-813Crossref PubMed Scopus (50) Google Scholar While these studies note that certain ethnicities, genders, or age groups are more prone to developing certain diseases, they rarely comment on possible differences in circadian rhythm physiology, let alone linking these differences to metabolic disease. This review article will explore potential mechanisms by which race, sex, or age variations in circadian rhythms and response to disruption may influence susceptibility to metabolic disorders. Race, sex, and age are intertwined and sometimes produce mixed patterns in metabolism.26Moore J.X. Chaudhary N. Akinyemiju T. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, national health and nutrition examination survey, 1988-2012.Prev Chronic Dis. 2017; 14: E24Crossref PubMed Scopus (451) Google Scholar,27Hood S. Amir S. The aging clock: circadian rhythms and later life.J Clin Invest. 2017; 127: 437-446Crossref PubMed Scopus (208) Google Scholar For example, the prevalence of metabolic syndrome is higher in black women than that in white women, but the opposite pattern is seen in men.26Moore J.X. Chaudhary N. Akinyemiju T. Metabolic syndrome prevalence by race/ethnicity and sex in the United States, national health and nutrition examination survey, 1988-2012.Prev Chronic Dis. 2017; 14: E24Crossref PubMed Scopus (451) Google Scholar Advanced age also has different effects on circadian rhythms in men vs women, with core body temperature fluctuating less in older men vs younger men but unchanged in women of different ages.27Hood S. Amir S. The aging clock: circadian rhythms and later life.J Clin Invest. 2017; 127: 437-446Crossref PubMed Scopus (208) Google Scholar Men go to bed later than women before 40 years old, but earlier after this age.28Fischer D. Lombardi D.A. Marucci-Wellman H. et al.Chronotypes in the US – influence of age and sex.PLoS One. 2017; 12e0178782Crossref Scopus (202) Google Scholar This complex interplay makes studying the effects of race, sex, and age on circadian rhythms and metabolic disorders all the more nuanced. Before discussing the effects of race, it is important to note that race is a complex topic that is inevitably linked to confounding factors and bias. Broad racial categories such as “black”, “white”, “Asian”, or “Hispanic” tend to be monolithic and oftentimes are poorly defined with respect to geographical location and/or socioeconomic factors. For a more comprehensive analysis, both within-group and between-group differences should be analyzed to better appreciate the effect of race on circadian and metabolic disruption. For example, a study of race may actually be a study of underlying socioeconomic and historical differences among groups of people, and frequently if those variables are controlled, the effect of race is no longer statistically significant.1Egan K.J. Knutson K.L. Pereira A.C. et al.The role of race and ethnicity in sleep, circadian rhythms and cardiovascular health.Sleep Med Rev. 2017; 33: 70-78Crossref PubMed Scopus (49) Google Scholar One previous study of over 10,000 people of West African descent found that African Americans were twice as likely to develop hypertension as West Africans. Rates of obesity and salt intake varied consistently with the prevalence of disease, with higher rates of both factors noted in African Americans. This suggests that environmental rather than genetic factors drive differences.29Cooper R. Rotimi C. Ataman S. et al.The prevalence of hypertension in seven populations of West African origin.Am J Public Health. 1997; 87: 160-168Crossref PubMed Scopus (552) Google Scholar There are studies that show African Americans and Hispanic Americans are at a higher risk of developing risk factors for cardiovascular disease such as hypertension, hyperlipidemia, and obesity.20Mozaffarian D. Benjamin E.J. Go A.S. et al.Heart disease and stroke statistics—2015 update: a report from the American Heart Association.Circulation. 2015; 131: e29-e322Crossref PubMed Scopus (5637) Google Scholar, 21Wang Y. Beydoun M.A. The obesity epidemic in the United States--gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis.Epidemiol Rev. 2007; 29: 6-28Crossref PubMed Scopus (2077) Google Scholar, 22National Center for Health Statistics (US)Health United States, 2013: with special feature on prescription drugs. National Center for Health Statistics (US), Hyattsville2014Google Scholar A 2009 US National Health and Nutrition Examination Survey showed that Hispanic American males had the highest prevalence of low-density lipoprotein-cholesterol, followed by black Americans and then by white Americans.20Mozaffarian D. Benjamin E.J. Go A.S. et al.Heart disease and stroke statistics—2015 update: a report from the American Heart Association.Circulation. 2015; 131: e29-e322Crossref PubMed Scopus (5637) Google Scholar A 2001 Behavioral Risk Factor Surveillance Study showed that obesity, defined as body mass index (BMI) ≥30, was the highest in Black Americans (34.8%) and Native Americans (34.3%), while lowest in Asian Americans (4.8%).21Wang Y. Beydoun M.A. The obesity epidemic in the United States--gender, age, socioeconomic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis.Epidemiol Rev. 2007; 29: 6-28Crossref PubMed Scopus (2077) Google Scholar Nonwhite American groups are also at an increased risk for mortality from cardiovascular disease. One study showed that African Americans had the highest age-adjusted cardiovascular disease mortality in the United States in 2010, followed by white Americans, Hispanic Americans, and then East Asian Americans.22National Center for Health Statistics (US)Health United States, 2013: with special feature on prescription drugs. National Center for Health Statistics (US), Hyattsville2014Google Scholar The degree to which such disparity is attributed to differences in circadian rhythms is less well documented with few studies that evaluate this hypothesis. A healthy circadian rhythm includes an evening blood pressure (BP) drop or “dip” of around 10% or more.30Sherwood A. Hill L.K. Blumenthal J.A. et al.The effects of ambulatory blood pressure monitoring on sleep quality in men and women with hypertension: dipper vs. nondipper and race differences.Am J Hypertens. 2019; 32: 54-60Crossref PubMed Scopus (13) Google Scholar However, there is a correlation between patients who have “nondipping” circadian BP (<10% fall in average BP from day to evening) and cardiovascular morbidity.30Sherwood A. Hill L.K. Blumenthal J.A. et al.The effects of ambulatory blood pressure monitoring on sleep quality in men and women with hypertension: dipper vs. nondipper and race differences.Am J Hypertens. 2019; 32: 54-60Crossref PubMed Scopus (13) Google Scholar In a study by Sherwood et al,30Sherwood A. Hill L.K. Blumenthal J.A. et al.The effects of ambulatory blood pressure monitoring on sleep quality in men and women with hypertension: dipper vs. nondipper and race differences.Am J Hypertens. 2019; 32: 54-60Crossref PubMed Scopus (13) Google Scholar sleep quality was worse in “nondipping” patients than that in patients with standard circadian BP drop, and African Americans were found to have decreased sleep efficiency. Another study on BP “dipping” by Hyman et al31Hyman D.J. Ogbonnaya K. Taylor A.A. et al.Ethnic differences in nocturnal blood pressure decline in treated hypertensives.Am J Hypertens. 2000; 13: 884-891Crossref PubMed Scopus (42) Google Scholar showed that black Americans and Hispanic Americans are less likely to be “nondippers” than white Americans. Lack of this natural decrease in nocturnal BP has been associated with a worse prognosis from hypertension including more severe end-organ damage.32Fagher B. Valind S. Thulin T. End-organ damage in treated severe hypertension: close relation to nocturnal blood pressure.J Hum Hypertens. 1995; 9: 605-610PubMed Google Scholar In addition to the “dipping” phenomenon, differences in the timing of heart attacks in people of distinctive ethnic backgrounds further support the link between circadian rhythms and metabolic disorder. López et al33López F. Lee K.W. Marín F. et al.Are there ethnic differences in the circadian variation in onset of acute myocardial infarction?.Int J Cardiol. 2005; 100: 151-154Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar studied 340 acute myocardial infarction patients and found that British Caucasians and Indo-Asians were more likely to have heart attacks between midnight and noon, whereas the converse pattern was true for Mediterranean Caucasians. This study suggests that there are possible differences in circadian rhythms among 3 separate ethnic groups leading to the timing of acute myocardial infarction. One possible mechanism by which race differences in circadian rhythms affect metabolism might be observed in the adaptation differences to night shift work. Eastman et al compared the circadian rhythms of African Americans to that of European Americans. Of the 23 African Americans and 22 European Americans studied, European Americans, on average, had a statistically significant longer free-running circadian period, or tau, than African Americans by over 0.2 hours (24.31 hours vs 24.06 hours, respectively).34Eastman C.I. Tomaka V.A. Crowley S.J. Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work.Sci Rep. 2016; 6: 36716Crossref PubMed Scopus (31) Google Scholar A significant correlation was found between longer tau at baseline and more extensive phase delays upon circadian disruption; more phase delays mean being able to fall asleep and wake up later, which is adaptive for night shift work. When these subjects underwent a 9-hour phase delay of the light-dark, sleep-wake, and meal schedule, which mimics flying west or sleeping during the day following night shifts, European Americans were found to have more phase delays than African Americans (3.6 hours vs 2.4 hours, respectively).34Eastman C.I. Tomaka V.A. Crowley S.J. Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work.Sci Rep. 2016; 6: 36716Crossref PubMed Scopus (31) Google Scholar African Americans were conversely found to have shorter tau and consequently more minor phase delays.34Eastman C.I. Tomaka V.A. Crowley S.J. Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work.Sci Rep. 2016; 6: 36716Crossref PubMed Scopus (31) Google Scholar This translates to, on average, longer jet lags upon westward travel and more difficulty adapting to night shift work (Figure 2). It is hypothesized that these variations in tau arose from differences in migration patterns out of East Africa tens of thousands of years ago. Those who migrated to Europe had to adapt to a seasonally changing photoperiod, whereas those who migrated to West Africa found themselves around the equator where the photoperiod is more constant throughout the year.34Eastman C.I. Tomaka V.A. Crowley S.J. Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work.Sci Rep. 2016; 6: 36716Crossref PubMed Scopus (31) Google Scholar It is possible that a longer circadian period developed in Europeans as an adaptation to changing photoperiods because it could help hunters at the time track dawn.35Eastman C.I. Tomaka V.A. Crowley S.J. 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A review study showed that shift work and poor sleep were correlated with increased incidence and severity of inflammatory bowel disease.44Canakis A. Qazi T. Sleep and fatigue in IBD: an unrecognized but important extra-intestinal manifestation.Curr Gastroenterol Rep. 2020; 22: 8Crossref PubMed Scopus (12) Google Scholar Circadian dysregulation plays a central role in the increased risk of metabolic disorders in shift workers.45Brum M.C.B. Filho F.F.D. Schnorr C.C. et al.Shift work and its association with metabolic disorders.Diabetol Metab Syndr. 2015; 7: 45Crossref PubMed Scopus (102) Google Scholar There is evidence that disrupted sleep can decrease leptin and increase ghrelin levels, effectively promoting hunger.46Taheri S. Lin L. 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Circadian rhythms of European and African-Americans after a large delay of sleep as in jet lag and night work.Sci Rep. 2016; 6: 36716Crossref PubMed Scopus (31) Google Scholar The circadian rhythm also affects the hypothalamic-pituitary-adrenal axis, which impacts hormone levels. Cortisol is a hormone under the control of the circadian rhythm, with levels rising at night and peaking within the first hour after awakening.47Elverson C.A. Wilson M.E. Cortisol: circadian rhythm and response to a stressor.Newborn Infant Nurs Rev. 2005; 5: 159-169Crossref Scopus (23) Google Scholar Cortisol is directly related to the stress response, and prolonged high cortisol levels lead to Cushing syndrome, a disease process associated with a constellation of symptoms including weight gain, diabetes, hypertension, muscle weakness, and poor bone health.48Thau L, Gandhi J, Sharma S. Physiology, Cortisol. In: StatPearls [Internet]. 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