The association between serum alpha klotho and circadian syndrome: data from NHANES 2007–2016

doi:10.21203/rs.3.rs-5275449/v1

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The association between serum alpha klotho and circadian syndrome: data from NHANES 2007–2016

https://doi.org/10.21203/rs.3.rs-5275449/v1

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Background Circadian syndrome (CircS) is characterized by disrupted circadian rhythm. α-klotho, an anti-aging protein, has garnered particular attention recently. The study aimed to assess the associations of serum alpha klotho and CircS.

Methods Data from National Health and Nutrition Examination Survey (NHANES) 2005-2016 were analyzed. CircS further encompasses sleep disorders and depression, in addition to the components of the metabolic syndrome (MetS). Multivariate logistic regression, subgroup analysis and restricted cubic spline plot were used to analyze the associations.

Results We found a negative relationship between circulating α-klotho and the risk of CircS. Using multivariate logistic regression models, we assessed the association between α-klotho and CircS while adjusting for potential confounders. Compared to the first quartile of klotho, the second quartile group showed 16% decrease in CirS risk (OR=0.84, 95%CI = 0.74-0.96, P = 0.012), and the third quartile group exhibited 21% decrease in CirS risk (OR=0.79, 95%CI = 0.69-0.91, p<0.001) after adjusting all demographic and lifestyle variables. Subgroup analyses revealed significant interactions between α-klotho and alcohol consumption (p=0.008). Additionally, we observed inverse association between α-klotho and odds ratio of CirS in a restricted cubic spline plot.

Conclusion In this large cross-sectional study, our results suggest that higher serum α-klotho levels are significantly associated with a reduced likelihood of circadian syndrome in U.S. adults. Further studies are needed to confirm these findings and elucidate the underlying mechanisms..

klotho

aging

circadian rhythm

circadian syndrome

NHANES

Circadian syndrome, which is characterized by disrupted circadian rhythm, can lead to a range of health issues.
This study investigated the correlation between serum α-klotho and the prevalence of circadian syndrome among US adults.
Mechanistic studies are required to investigate the effects of α-klotho on circadian syndrome.

MetS is a clinical syndrome characterized by a cluster of metabolic abnormalities, including central obesity, hypertension, dyslipidemia, and hyperglycemia [1]. Recent studies indicate that the prevalence of MetS is rising globally, driven by both genetic and environmental factors [2]. Circadian rhythms are the internal biological clocks that regulate daily cycles of sleep, wakefulness, and various physiological functions [3]. Disruptions to these rhythms, often termed circadian syndrome, can lead to a range of health issues, including insomnia, fatigue, daytime sleepiness, mood disorders, and an increased risk of cardiovascular diseases [4, 5]. A recent study showed that CircS was believed to provide a better prediction of cardiovascular diseases than MetS [6]. Unlike MetS, the concept of CircS further encompasses sleep disorders and depression [7].

α-klotho, a longevity-associated protein, has emerged as a promising candidate for investigating the underlying mechanisms of circadian syndrome. Originally identified as a regulator of aging and metabolism [8], recent studies have highlighted its involvement in various biological processes, including neuroprotection, bone metabolism, and reproductive function [9]. A study examining data from the National Health and Nutrition Examination Survey (NHANES) in the United States found that individuals who slept more than 7.5 hours per night had significantly lower levels of α-klotho compared to those who slept less than 5.5 hours. This suggests that longer sleep duration may be associated with decreased α-klotho levels [10], suggesting a potential link between α-klotho and sleep disorders. Another study from NHANES highlighted that serum α-klotho was positively associated with an increased risk of major depression. Moreover, studies have shown that α-klotho can influence the expression of clock genes within the suprachiasmatic nucleus (SCN), a critical region for maintaining circadian rhythms [11]. Furthermore, α-klotho levels have been observed to fluctuate in a circadian pattern, indicating a potential role in regulating the body's internal clock [12].

Currently, the specific relationship between α-klotho and CirS has not been extensively investigated. Given the growing evidence for klotho's role in regulating circadian rhythms and the significant health implications of CirS, it is important to examine the potential association between these two factors. In this study, we aimed to utilize data from the National Health and Nutrition Examination Survey (NHANES) to provide valuable insights into the potential association between α-klotho and CirS.

Data source and participants

The NHANES serves as a comprehensive data repository, providing insights into the health and nutritional status of the U.S. population. This unique resource collects data through a multifaceted approach that includes interviews, physical examinations, and biospecimen collection [13]. In this study, we analyzed data from five continuous 2-year cycles of NHANES between 2007 and 2016, encompassing a total of 50,558 individuals. Participants who were missing data on serum α-klotho concentrations were excluded from the study. Additionally, individuals with missing values for components used to define CircS or incomplete data on covariates were also excluded. Ultimately, 5,520 participants were included in our analysis. The flowchart of participants selection is presented in Fig. 1. Ethical approval for the NHANES study was obtained from the National Center for Health Statistics (NCHS) Research Ethics Review Board, and informed consent was obtained from all participants. The study methods were designed in accordance with the Declaration of Helsinki.

Figure 1. Flow diagram of the enrollment of study participants. Abbreviations: NHANES, National Health and Nutrition Examination Survey; CirS, Circadian Syndrome.

Measurement of α-klotho level

Serum α-klotho levels were measured using the enzyme-linked immunosorbent assay (ELISA) method, following the protocols provided by IBL International, Japan. Blood samples were collected from participants in a fasting state during morning hours to ensure consistency. The samples were immediately placed on dry ice and subsequently stored at -80°C until analysis. Each sample was analyzed in duplicate, and the final serum α-klotho value was determined by calculating the average of the two measurements, ensuring accuracy and reliability in the results [14]. The resulting data was then categorized into three groups (Q1, Q2, and Q3) based on the distribution of klotho levels, enabling the researchers to compare and analyze the levels of klotho within each group.

Assessment of CircS

An individual was categorized as having CircS if he/she had ≥ 4 of the following 7 components [15]: elevated waist circumference, elevated fasting glucose (or on medication), elevated triglycerides (or on lipid medication), reduced high-density lipoprotein cholesterol (HDL-C) (or on lipid medication), elevated blood pressure (or on antihypertensive medication), short sleep, and depression symptoms. Detailed components were defined as follows [16]: (1) Elevated waist circumference was defined by waist circumference ≥ 88 cm for women and ≥ 102 cm for men. (2) Elevated fasting glucose was defined by fasting glucose ≥ 100 mg/dL, or patients being treated with medication to lower blood sugar. (3) Elevated triglyceride was defined by serum triglycerides ≥ 150 mg/dL, or patients being treated with medication because of high blood cholesterol. (4) Reduced HDL-Cholesterol was defined by serum HDL-C < 40 mg/dL in men and < 50 mg/dL in women or patients being treated with medication because of high blood cholesterol. (5) Elevated blood pressure was defined by systolic blood pressure (SBP) ≥ 130 mmHg or a diastolic blood pressure (DBP) ≥ 85 mmHg, or patients being treated with antihypertensive medication. (6) Short sleep was defined by a sleep duration of < 6 h per day. (7) Depression symptoms were based on a score of ≥ 5 of the Patient Health Questionnaire (PHQ-9). It is a 9-item depression screening instrument that aims to evaluate the occurrence of depression symptoms within the preceding two weeks.

Covariates

In our study, we included several covariates that may influence the association between α-klotho and circadian syndrome. The demographic variables considered were age, sex, and race (categorized as Mexican American, other Hispanic, non-Hispanic White, non-Hispanic Black, and others). Marital status was recorded as either living alone or married/living with a partner, and the ratio of family income to poverty level (PIR) was classified into three categories: (1) less than 1.30; (2) 1.30–2.99; and (3) ≥ 3.00 [17]. Education level was divided into: (1) less than high school; (2) high school or GED; and (3) above high school. Smoking habits were categorized as follows: (1) never smoker (less than 100 cigarettes in a lifetime); (2) former smoker (≥ 100 cigarettes but not currently smoking); and (3) current smoker (≥ 100 cigarettes and currently smoking) [18]. Alcohol consumption status was classified into four groups: (1) never drinker (had < 12 drinks in a lifetime); (2) former drinker (had ≥ 12 drinks in one year but did not drink last year, or did not drink last year but had ≥ 12 drinks in a lifetime); (3) light-to-moderate drinker (less than 3 drinks per day for females, less than 4 drinks per day for males on average over the past year, or binge drinking [≥ 4 drinks on the same occasion for females, ≥ 5 drinks for males] on fewer than 5 days per month over the past year); and (4) heavy drinker (≥ 3 drinks per day for females, ≥ 4 drinks per day for males on average over the past year, or binge drinking on 5 or more days per month over the past year) [19].

Statistical analysis

Data were expressed as weighted proportions with 95% confidence intervals (CIs) for categorical variables and as weighted means ± standard error (SE) for continuous variables. Comparisons of baseline characteristics were performed using Student’s t-test or the nonparametric Mann-Whitney U test for continuous variables, alongside the Chi-square test or Fisher’s exact test for categorical variables. Additionally, multivariate linear regression models were employed to assess the relationship between serum α-klotho and CirS risk. The adjusted models were structured as follows: Crude model was unadjusted for covariates; Model 1 was adjusted for demographic factors (age, sex, race); Model 2 included further adjustments for lifestyle variables (PIR, education level, and marital status, smoking and alcohol consumption). Furthermore, subgroup analyses and interaction tests were conducted based on age, sex, race and lifestyle variables using multivariate linear regression with full adjustments. We employed restricted cubic splines (RCS) to investigate potential nonlinear associations between serum α-klotho levels and CirS risk, utilizing four knots at the 5th, 35th, 65th, 95th percentiles. All analyses were conducted using R software (version 4.3.2).

Baseline characteristics from NHANES participants

After screening and excluding participants with missing data from the NHANES dataset between 2007 and 2016, a total of 5,520 individuals aged 40 to 80 years were included in the analyses, with 51.2% females and 46.8% non-Hispanic White. There were 2893 (52.4%) individuals with CirS. The results (Table 1) indicated that serum α-klotho concentration was negatively correlated with the proportion of central obesity, elevated triglycerides, reduced HDL-C, elevated blood pressure, short sleep and CirS (all p < 0.01). In comparison to the lowest tertile group of α-lotho, the highest tertile group typically comprises young women and had a less propensity for smoking and alcohol consumption. Furthermore, different racial groups exhibited varying trends in relation to increasing α-klotho levels.

Table 1

Sample characteristics by quartiles of the α-klotho concentration among participants^a.
Charateristics	α-klotho Tertiles (pg/mL)			p.overall^b
	Q1 (< 704.1)	Q2 (704.1-923.8)	Q3 (> 923.8)
α-klotho (pg/ml)	577 ± 93.6	808 ± 61.9	1192 ± 315	0.000
Age(years)	58.8 ± 11.0	57.7 ± 10.7	57.1 ± 10.6	< 0.001
Gender (%)
Male	974 (52.9%)	910 (49.5%)	809 (44.0%)
Female	868 (47.1%)	928 (50.5%)	1031 (56.0%)
Race(%)				< 0.001
Mexican American	269 (14.6%)	287 (15.6%)	265 (14.4%)
Other Hispanic	179 (9.72%)	213 (11.6%)	217 (11.8%)
Non-Hispanic White	925 (50.2%)	898 (48.9%)	758 (41.2%)
Non-Hispanic Black	327 (17.8%)	271 (14.7%)	443 (24.1%)
others	142 (7.71%)	169 (9.19%)	157 (8.53%)
Marital status (%)				0.799
Living alone	652 (35.4%)	639 (34.8%)	659 (35.8%)
Married/living with partner	1190 (64.6%)	1199 (65.2%)	1181 (64.2%)
PIR				0.764
< 1.30	563 (30.6%)	532 (28.9%)	540 (29.3%)
1.30–2.99	558 (30.3%)	579 (31.5%)	557 (30.3%)
≥ 3.0	721 (39.1%)	727 (39.6%)	743 (40.4%)
Education				0.338
Below high school	489 (26.5%)	474 (25.8%)	479 (26.0%)
high school or GED	419 (22.7%)	413 (22.5%)	375 (20.4%)
Above high school	934 (50.7%)	951 (51.7%)	986 (53.6%)
Smoking (%)				< 0.001
Never	803 (43.6%)	928 (50.5%)	1030 (56.0%)
Former	621 (33.7%)	570 (31.0%)	504 (27.4%)
Current	418 (22.7%)	340 (18.5%)	306 (16.6%)
Alcohol				< 0.001
Never drinker	192 (10.4%)	240 (13.1%)	314 (17.1%)
Former drinker	397 (21.6%)	382 (20.8%)	401 (21.8%)
Light-to-moderate	863 (46.9%)	893 (48.6%)	865 (47.0%)
Heavy	390 (21.2%)	323 (17.6%)	260 (14.1%)
Central obesity	1238 (67.2%)	1169 (63.6%)	1151 (62.6%)	0.008
Elevated glucose	1192 (64.7%)	1146 (62.4%)	1161 (63.1%)	0.315
Elevated triglycerides	1049 (56.9%)	951 (51.7%)	839 (45.6%)	< 0.001
Reduced HDL-C	1009 (54.8%)	953 (51.8%)	873 (47.4%)	< 0.001
Elevated blood pressure	1240 (67.3%)	1156 (62.9%)	1147 (62.3%)	0.003
Short sleep	624 (33.9%)	600 (32.6%)	704 (38.3%)	0.001
Depression symptoms	481 (26.1%)	460 (25.0%)	453 (24.6%)	0.559
Circadian Syndrome	1041 (56.5%)	942 (51.3%)	910 (49.5%)	< 0.001

^a Data were presented as mean ± SD for continuous measures, and n (%) for categorical measures. ^b P values were based on ANOVA for continuous measures and Chi-squared test for categorical measures. Abbreviations: PIR, ratio of family income to poverty; HDL-C, high-density lipoprotein cholesterol.

Association between α-klotho and circadian syndrome

The relationship between serum α-klotho and CirS was examined using a logistic regression model adjusting for all covariates, as shown in Table 2. Compared to the first quartile of klotho, the Q2 group showed 16% decrease in CirS risk (OR = 0.84, 95%CI = 0.74–0.96, P = 0.012), and the Q3 group showed 21% decrease in CirS risk (OR = 0.79, 95%CI = 0.69–0.91, p < 0.001).

Table 2

Odds ratio (95%CI) for Circadian Syndrome by quartiles of the α-klotho concentration.
Exposure	Crude model		Model 1		Model 2
	95% CI	P -value	95% CI	P -value	95% CI	P -value
α-klotho tertiles
Q1	Ref		Ref		Ref
Q2	0.81 (0.71–0.92)	0.001	0.84 (0.73–0.96)	0.009	0.84 (0.74–0.96)	0.012
Q3	0.75 (0.66–0.86)	< 0.001	0.78 (0.69–0.90)	< 0.001	0.79 (0.69–0.91)	< 0.001
P for trend		< 0.001		< 0.001		0.001

Values are odds ratios (95%CI), and P-value from logistic regression. Crude model unadjusted for any covariates. Model 1 adjusted for gender, age, race. Model 2 further adjusted for marital status, PIR, education level, smoking, alcohol consumption. Abbreviations: CI, confidence interval; PIR, ratio of family income to poverty.

Subgroup analyses

The stability of the association between serum α-klotho and CirS was assessed through subgroup analysis and interaction testing. As shown in Table 3, the relationship between serum α-klotho and CirS was not entirely consistent in each subgroup. The results of the interaction test showed that alcohol consumption was a significant moderator of the association between serum α-klotho and CirS (P = 0.008 for the interaction test). In never drinker and former drinker subgroups, the serum α-klotho and CirS risk was negtively correlated. However, in light-to-moderate and heavy drinker subgroups, the association between serum α-klotho and CirS was not significant (P < 0.05).

Table 3

Subgroup analyses of the association between serum α-Klotho level (pg/ml) and odds ratio (95%CI) for Circadian Syndrome.
Subgroups	α-klotho tertiles			P for trend	P for interaction
	Q1	Q2	Q3
Gender (%)					0.087
Male	Ref	0.93 (0.77–1.12)	0.91 (0.75–1.11)	0.201
Female	Ref	0.76 (0.63–0.93)	0.68 (0.56–0.82)	< 0.001
Age					0.705
Young(40–59)	Ref	0.71 (0.59–0.86)	0.74 (0.62–0.90)	0.004
Old(60–80)	Ref	0.97 (0.79–1.18)	0.79 (0.65–0.97)	0.026
Race(%)					0.520
Mexican American	Ref	0.82 (0.58–1.17)	0.79 (0.55–1.14)	0.248
Other Hispanic	Ref	0.71 (0.46–1.09)	0.76 (0.49–1.16)	0.225
Non-Hispanic White	Ref	0.96 (0.79–1.16)	0.86 (0.70–1.05)	0.125
Non-Hispanic Black	Ref	0.76 (0.54–1.07)	0.66 (0.48–0.90)	0.008
others	Ref	0.59 (0.37–0.97)	0.62 (0.38–1.02)	0.053
Marital status (%)					0.377
Living alone	Ref	0.76 (0.61–0.96)	0.72 (0.57–0.91)	0.005
Married/living with partner	Ref	0.89 (0.75–1.05)	0.83 (0.70–0.98)	0.042
PIR					0.241
<1.30	Ref	0.72 (0.56–0.93)	0.69 (0.54–0.89)	0.003
1.30–2.99	Ref	0.76 (0.60–0.97)	0.79 (0.61–1.01)	0.085
≥ 3.0	Ref	1.04 (0.84–1.28)	0.86 (0.69–1.07)	0.285
Education					0.813
Below high school	Ref	0.80 (0.61–1.05)	0.75 (0.57–0.99)	0.064
high school or GED	Ref	0.87 (0.65–1.15)	0.74 (0.55–0.99)	0.034
Above high school	Ref	0.86 (0.72–1.04)	0.83 (0.69-1.00)	0.085
Smoking (%)					0.953
Never	Ref	0.76 (0.62–0.92)	0.78 (0.64–0.94)	0.036
Former	Ref	0.90 (0.71–1.15)	0.78 (0.61–0.99)	0.039
Current	Ref	0.97 (0.72–1.32)	0.81 (0.59–1.10)	0.173
Alcohol
Never drinker	Ref	0.73 (0.48–1.10)	0.62 (0.42–0.92)	0.023	0.008
Former drinker	Ref	0.72 (0.53–0.97)	0.59 (0.44–0.80)	< 0.001
Light-to-moderate	Ref	0.85 (0.70–1.03)	0.85 (0.70–1.04)	0.148
Heavy	Ref	1.04 (0.76–1.41)	1.03 (0.74–1.42)	0.815

Adjusted for gender, age, race,marital status, PIR, education level, smoking, alcohol consumption. Abbreviations: PIR, ratio of family income to poverty.

Non-linear relationship between serum α-klotho and circadian syndrome

A restricted cubic spline plot was employed to analyze the relationship between serum α-klotho levels and CirS (Fig. 2). After adjusting for all covariates, we observed a significant overall relationship between α-klotho and CirS. Interestingly, while the nonlinear association was not significant (P = 0.512), the overall association showed statistical significance (P = 0.003).

Figure 2. Association Between α-klotho and CirS Using a Restricted Cubic Spline Regression Model. Graphs show ORs for CirS according to α-klotho adjusted for sex, age, race, marital status, PIR, education, alcohol, smoking. Data were fitted by a logistic regression model, and the model was conducted with 4 knots at the 5th, 35th, 65th, 95th percentiles of α-klotho (reference is the 5th percentile). Solid lines indicate ORs, and shadow shape indicate 95% CIs. OR, odds ratio; PIR, ratio of family income to poverty; CI, confidence interval.

In this NHANES dataset analysis, we found that the prevalence of CircS was high, affecting over half of adults in the US. Our study indicated a clear negative correlation between serum α-klotho concentration and CirS. The interaction between α-klotho and alcohol consumption was significant (p = 0.008), meaning alcohol may influence the association between α-klotho and CirS.

CirS is a significant global health concern with substantial detrimental effects on human health. This condition arises from disruptions in the body's internal clock, leading to misalignments between an individual's biological rhythms and their external environment. Such disruptions can result from various factors, including lifestyle choices, work schedules, and environmental changes. The impact of CircS on health is multifaceted. Firstly, CircS has been linked to an increased risk of various metabolic disorders. Studies have shown that circadian rhythm disruption can lead to the development of conditions such as fatty liver, type 2 diabetes, and chronic gastroenteritisby affecting the body's metabolic and inflammatory responses [20]. Furthermore, circadian disruption has been identified as a common public health problem associated with a wide range of diseases, including metabolic disorders, neurodegenerative diseases, and cancer [21].

α-klotho is a protein that has been increasingly recognized for its significant role in metabolism and its association with various metabolic disorders such as diabetes, hypertension, non-alcoholic fatty liver disease (NAFLD), and MetS. In the context of diabetes, klotho has been shown to facilitate insulin release and promote β-cell health in the pancreas, exerting potent anti-diabetic and anti-obesogenic effects [22]. It inhibits insulin/insulin-like growth factor (IGF)-1 signaling, leading to a 'healthy insulin resistance' and beneficial effects on glycolipid metabolism and central energy homeostasis [23], suggesting that α-klotho plays a crucial role in maintaining glucose homeostasis. Regarding hypertension, α-klotho has been implicated in the regulation of blood pressure. It is known to inhibit the renin-angiotensin system, a key player in the development of hypertension [24]. Additionally, each ng/mL increase in Klotho was associated with a decrease in pulse pressure, an indicator of arterial stiffness [25], further highlighting its role in the cardiovascular system. In NAFLD, studies have found an association between low levels of α-klotho and NAFLD, with odds ratios ranging from 0.72 to 0.832. High levels of α-klotho, however, were associated with NAFLD-related fibrosis, indicating a complex relationship between Klotho and the progression of liver disease [26]. MetS is a cluster of conditions that increase the risk of heart disease, stroke, and diabetes. α-klotho has been linked to MetS through its effects on insulin resistance, inflammation, and oxidative stress, which are key components of MetS [27]. Beyond its metabolic roles, α-klotho has also been implicated in sleep and depression. There is evidence suggesting that α-klotho might serve as a neurobiological link between depression and dementia through the regulation of oxidative stress [28]. Given that sleep is closely linked to cognitive performance and emotional well-being, it is plausible that α-klotho may indirectly influence sleep through its effects on cognition and mood. For instance, α-klotho's neuroprotective properties could contribute to maintaining healthy sleep patterns by preserving the integrity of neural circuits involved in sleep regulation [29]. In summary, α-klotho may be associated with CirS. Unsurprisingly, our study utilizing clinical data has already demonstrated this association.

To our knowledge, this is the first time when serum α-klotho has been observed as a protective factor for patients with CirS. We innovatively examined the dose-response relationship between log10 (serum α-klotho) and CirS, aiming to identify the optimal control point for serum α-klotho levels. Our study suggest that high serum α-klotho levels may indicate improvement in CirS. Nevertheless, the present study has several limitations. First, we can only observe the correlation between α-klotho and CirS, but not confirm the causal relationship between the two factors in an observational study. Second, while data had been adjusted for the potential confounders in this study, some potential residual confounders could still not be taken into account. Finally, more prospective, longitudinal cohort studies with multiple repetitive sampling are needed to help to support our observations.

Author Contributions

Conceptualization, C.F. and Y.S.; methodology, Y.S.; software, Y.S.; validation, C.F.; formal analysis, C.F.; investigation, S.H.; data curation, C.X.; writing—original draft preparation, C.F.; writing—review and editing, Y.S.; supervision, C.F.; funding acquisition, C.F. All authors have read and agreed to the published version of the manuscript.

Acknowledgements

None

Consent for publication

Not applicable.

Funding

This research was funded by the National Natural Science Foundation of China (Grant Number 81900142, 82271621).

Availability of data and materials

All NHANES data for this study are publicly available and can be found here: https://wwwn.cdc.gov/nchs/nhanes.

Ethical approval and consent to participate

All participants submitted written informed consent and were approved by the National Ethics Board.

Competing interests

The authors declare no conflicts of interest.

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No competing interests reported.

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The association between serum alpha klotho and circadian syndrome: data from NHANES 2007–2016

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Abstract

Figures

Contributions to the literature

Introduction

Methods

Data source and participants

Measurement of α-klotho level

Assessment of CircS

Covariates

Statistical analysis

Results

Baseline characteristics from NHANES participants

Subgroup analyses

Non-linear relationship between serum α-klotho and circadian syndrome

Discussion

Declarations

References

Additional Declarations

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