Accelerated Biological Aging and a Nonlinear Risk Threshold for Sleep Apnea: Evidence from NHANES and Mediation by Oxidative-Metabolic Dysregulation

Jia Guo; Xiaona Wang; Ranran Zhao

doi:10.2478/rjim-2026-0010

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Accelerated Biological Aging and a Nonlinear Risk Threshold for Sleep Apnea: Evidence from NHANES and Mediation by Oxidative-Metabolic Dysregulation

Romanian Journal of Internal Medicine

AHEAD OF PRINT

By: Jia Guo, Xiaona Wang and Ranran Zhao

Open Access

|May 2026

Figures & Tables

Participant selection flowchart from the NHANES database. A total of 20,497 initial participants were assessed for eligibility. Participants were excluded sequentially due to: (1) missing sleep apnea data (n=7,882); (2) age under 18 years (n=893); and (3) missing PhenoAge data (n=6,821). The final analytical cohort consisted of 4,901 participants, who were stratified into sleep apnea (n=200) and non-sleep apnea (n=4,701) groups for subsequent analysis. Abbreviations: NHANES, National Health and Nutrition Examination Survey; PhenoAge, Phenotypic Age

Nonlinear Dose-Response Associations of Phenotypic Age with Sleep Apnea Risk: Overall and Subgroup Analyses. The restricted cubic spline analysis revealed a significant nonlinear association between PhenoAge and sleep apnea risk in the overall population in model 2 (P for nonlinearity < 0.001). A consistent inflection point was observed at a PhenoAge of 44.09 years (vertical dashed line) in the overall population, male, female, and obese subgroups (all P for nonlinearity < 0.05). In the non-obese subgroup, the association did not reach statistical significance for nonlinearity (P = 0.074), although a similar inflection pattern was visually apparent. Solid lines represent odds ratios, and shaded areas represent 95% confidence intervals. Black represents the overall population, blue represents males, red represents females, yellow represents the obese group, and green represents the non-obese group.

Mediation analysis of the effect of PhenoAge on sleep apnea risk through UHR (Model 2). This analysis used Model 2, with PhenoAge as the predictor (X), the uric acid-to-high-density lipoprotein cholesterol ratio (UHR) as the mediator (M), and sleep apnea risk as the outcome (Y). Based on bootstrap analysis, the figure presents point estimates and 95% confidence intervals for the average causal mediation effect (ACME, or indirect effect) and the average direct effect (ADE). The proportion mediated is reported where both ACME and ADE were statistically significant. Results are displayed for the overall population and stratified by sex (male, female), age (<40 / ≥40 years), and obesity status (obese, non-obese). A plus sign (+) denotes a positive path coefficient.

Segmented Logistic Regression Analysis of the Association Between PhenoAge and Sleep Apnea (SA) Risk_

Group	SA Cases / Total N	OR (95% CI)	P-value
Overall population
Low PhenoAge	57/2459	0.99(0.93–1.05)	0.705
High PhenoAge	143/2442	1.03(1.01–1.05)	0.003
Male
Low PhenoAge	37/1193	0.99(0.90–1.09)	0.816
High PhenoAge	92/1242	1.03(1.01–1.06)	0.009
Female
Low PhenoAge	20/1266	1.09(0.99–1.21)	0.079
High PhenoAge	51/1200	1.00(0.97–1.03)	0.944
Obese
Low PhenoAge	47/1048	1.06(0.98–1.14)	0.171
High PhenoAge	127/1335	1.02(1.00–1.04)	0.025
Non-obese
Low PhenoAge	10/1411	0.97(0.81–1.15)	0.700
High PhenoAge	16/1107	1.01(0.93–1.09)	0.824

Association Between PhenoAgeAccel and Sleep Apnea

Variable / Analysis	Crude Model	Model 1	Model 2
PhenoAgeAccel, year
OR (95% CI)	1.00(1.00–1.00)	1.04(1.02–1.06)	1.03(1.01–1.05)
P-value <0.001	<0.001	<0.001	0.004
PhenoAgeAccel, by category
EQ (n=1249)	1.00 (Ref.)	1.00 (Ref.)	1.00 (Ref.)
AC-1 (n=554)
OR (95% CI)	1.01(0.99–1.03)	1.38(0.84–2.27)	1.39(0.84–2.31)
P-value	0.316	0.206	0.202
AC-2 (n=884)
OR (95% CI)	1.04(1.02–1.06)	2.19(1.47–3.26)	1.98(1.31–3.00)
P-value	<0.001	<0.001	0.001
DC-1(n=1075)
OR (95% CI)	1.00(0.98–1.02)	0.94(0.61–1.46)	1.77(0.71–1.74)
P-value	0.947	0.783	0.658
DC-2 (n=1139)
OR (95% CI)	0.98(0.97–1.00)	0.52(0.31–0.86)	0.80(0.47–1.36)
P-value	0.051	0.011	0.459

Associations of PhenoAge with Sleep Apnea_

Variable / Analysis	Crude Model	Model 1	Model 2
PhenoAge, year
OR (95% CI)	1.00(1.00–1.00)	1.04(1.02–1.06)	1.03(1.01–1.04)
P-value	<0.001	<0.001	0.002
PhenoAge,by quartiles
Q1 (Lowest) (n=1226)	1.00 (Ref.)	1.00 (Ref.)	1.00 (Ref.)
Q2(n=1225)
OR (95% CI)	1.02(1.01–1.04)	4.02(2.11–7.67)	2.30(1.19–4.47)
P-value	0.016	<0.001	0.004
Q3(n=1225)
OR (95% CI)	1.04(1.03–1.06)	9.52(4.44–20.47)	4.00(1.79–8.93)
P-value	<0.001	<0.001	<0.001
Q4 (Highest) (n=1225)
OR (95% CI)	1.05(1.04–1.07)	17.15(6.53–45.06)	5.84(2.10–16.22)
P-value	<0.001	<0.001	<0.001

j_rjim-2026-0010_tab_006

Abbreviation	Full Term
AC-1 & 2	Acceleration Group-1 & 2
ACME	Average Causal Mediation Effect
ADE	Average Direct Effect
BMI	Body Mass Index
CAPI	Computer-Assisted Personal Interview
CI	Confidence Interval
CIH	Chronic Intermittent Hypoxia
CRP	C-Reactive Protein
DBP	Diastolic Blood Pressure
DC-1 & 2	Deceleration Group-1 & 2
EQ Group	Equality Group
FPG	Fasting Plasma Glucose
HbA1c	Glycated Hemoglobin
HDL-C	High-Density Lipoprotein Cholesterol
HOMA-IR	Homeostatic Model Assessment of Insulin Resistance
IQR	Interquartile Range
IR	Insulin Resistance
LDL-C	Low-Density Lipoprotein Cholesterol
MAP	Mean Arterial Pressure
MET	Metabolic Equivalent Task
MICE	Multiple Imputation by Chained Equations
MLR	Monocyte-to-Lymphocyte Ratio
NHANES	National Health and Nutrition Examination Survey
NLR	Neutrophil-to-Lymphocyte Ratio
NSA	Non-Sleep Apnea
OR	Odds Ratio
OSA	Obstructive Sleep Apnea
PA	Physical Activity
PhenoAge	Phenotypic Age
PhenoAgeAccel	Phenotypic Age Acceleration
PIR	Poverty-to-Income Ratio
Q1-Q4	First, Second, Third, Fourth Quartile
RCS	Restricted Cubic Spline
SA	Sleep Apnea
SBP	Systolic Blood Pressure
SII	Systemic Immune-Inflammation Index
SIRI	Systemic Inflammation Response Index
TC	Total Cholesterol
TG	Triglycerides
TyG index	Triglyceride-Glucose index
UA	Uric Acid
UHR	Uric Acid to High-Density Lipoprotein Cholesterol Ratio

Baseline Characteristics of the Study Participants by Sleep Apnea Status_

	Overall (n=4901)	SA-group (n=200)	NSA-group (n=4701)	P-value
Demographic characteristics
Age (years)	47.0(31.0–64.0)	55.0(42.3–66.0)	46.0(31.0–63.0)	<0.001
Gender, n(%)				<0.001
Male	2435(49.7)	129(64.5)	2306(49.1)
Femal	2466(50.3)	71(35.5)	2395(50.9)
Ethnic, n(%)				<0.001
Mexican American	955(19.5)	14(7.0)	941(20.0)
Other Hispanic	377(7.7)	12(6.0)	365(7.8)
Non-Hispanic White	2340(47.7)	123(61.5)	2217(47.2)
Non-Hispanic Black	1035(21.1)	46(23)	989(21.0)
Other	194(4.0)	5(2.5)	189(4.0)
PIR, n(%)				0.012
Low level	1354(29.6)	52(27.7)	1302(29.7)
Moderate level	1808(39.5)	60(31.9)	1748(39.8)
High level	1413(30.9)	76(40.4)	1337(30.5)
Education, n(%)				0.012
Less than high school	577(11.8)	13(6.5)	564(12.0)
High school or equivalent	2121(43.3)	80(40.0)	2041(43.5)
College or above	2197(44.9)	107(53.5)	2090(44.5)
Smoking status, n(%)				0.007
Current	1015(22.3)	45(22.7)	970(22.2)
Former	1200(26.3)	70(35.4)	1130(25.9)
Never	2344(51.4)	83(41.9)	2261(51.8)
Drinking status, n(%)				0.025
Current	2743(64.5)	106(57.9)	2637(64.8)
Former	912(21.5)	54(29.5)	858(21.1)
Never	596(14.0)	23(12.6)	573(14.1)
Body measurement indicators
Weight (kg)	78.6 (66.9–92.3)	101.4 (90.0–116.7)	77.9 (66.4–91.0)	<0.001
BMI (kg/m²)	27.8(24.3–32.1)	34.6(30.4–39.5)	27.6(24.1–31.7)	<0.001
BMI group, n(%)				<0.001
Underweight/normal	1123(23.3)	6(3.1)	1117(24.1)
Overweight	1360(28.2)	18(9.4)	1342(29)
Obese	2335(48.5)	167(87.4)	2168(46.9)
WC (cm)	97.4(87.2–107.8)	114.8(106.0–125.6)	96.8(86.9–107.0)	<0.001
Dietary and exercise indicators
Energy (kcal/d)	1918(1458–2478)	2078(1506–2808)	1914(1456–2472)	0.027
Protein (gm/d)	74.3(55.1–97.8)	78.0(58.2–111.1)	74.2(54.9–97.2)	0.008
Carbohydrate (gm/d)	233.6(175.3–307.5)	240.7(175.0–310.1)	233.2(175.3–307.4)	0.424
Fat (gm/d)	70.2(50.1–96.8)	82.1(57.8–115.5)	69.8(49.8–95.9)	<0.001
PA, n(%)				0.385
High-intensive	1108(22.9)	42(21.2)	1066(22.9)
Moderate-intensive	1423(29.4)	52(26.3)	1371(29.5)
Low-intensive	2314(47.8)	104(52.5)	2210(47.6)
Metabolic indicators
SBP (mmHg)	120.0(110.7–132.0)	124.0(113.5–136)	120.0(110.7–132.0)	0.006
DBP (mmHg)	68.7(60.7–76.0)	72.0(63.5–78.7)	68.7(60.7–76.0)	0.002
MAP (mmHg)	85.8(78.9–93.6)	88.8(82.3–96.0)	85.6(78.7–93.3)	<0.001
UA (umol/L)	321.2(261.7–380.7)	356.9(315.2–416.4)	321.2(261.7–374.7)	<0.001
TG (mmol/L)	1.28(0.88–1.90)	1.47(1.01–2.09)	1.26(0.87–1.89)	<0.001
TC (mmol/L)	4.97(4.27–5.72)	4.76(4.19–5.40)	4.97(4.28–5.74)	0.005
HDL-C (mmol/L)	1.34(1.11–1.63)	1.19(1.03–1.45)	1.34(1.11–1.63)	<0.001
LDL-C (mmol/L)	2.87(2.30–3.52)	2.81(2.22–3.37)	2.87(2.30–3.52)	0.086
FPG (mmol/L)	5.55(5.11–6.11)	5.80(5.33–6.76)	5.50(5.11–6.05)	<0.001
HbA1C (%)	5.4(5.1–5.8)	5.8(5.3–6.4)	5.4(5.1–5.8)	<0.001
HOME-IR	2.06(1.22–3.63)	3.44(1.95–7.00)	2.01(1.21–3.54)	<0.001
TyG index	7.29(6.87–7.73)	7.49(7.05–8.00)	7.28(6.86–7.72)	<0.001
UHR	0.103(0.076–0.139)	0.128(0.100–0.166)	0.102(0.075–0.137)	<0.001
Inflammatory indicators
CRP (mg/L)	2.1(0.9–5.1)	3.3(1.4–7.8)	2.0(0.9–5.0)	<0.001
NLR	1.95(1.44–2.64)	2.17(1.58–2.73)	1.95(1.44–2.63)	0.021
MLR	0.26(0.21–0.33)	0.28(0.21–0.37)	0.26(0.21–0.33)	0.095
SII	509.8(361.6–730.2)	533.1(379.8–716.1)	508.4(360.0–731.7)	0.450
SIRI	1.01(0.68–1.49)	1.15(0.79–1.55)	1.00(0.68–1.49)	0.008
Biological age
PhenoAge (years)	43.9(27.8–61.7)	54.5(42.8–68.9)	43.2(27.4–61.2)	<0.001
PhenoAgeAccel (years)	−1.28(−4.77–2.97)	1.54(−2.90–6.43)	−1.37(−4.82–2.82)	<0.001

Subgroup Analysis of the Associations Between PhenoAge and Sleep Apnea_

	SA Cases / Total N	OR [95%CI]	P-Value	P-Interaction
Overall	200/4901	1.03(1.01–1.04)	0.002	-
Gender				0.433
Male	129/2435	1.03(1.01–1.06)	0.006
Female	71/2466	1.01(0.99–1.04)	0.307
Age				0.001
<40 years	36/1887	0.99(0.93–1.05)	0.705
≥40 years	164/3014	1.03(1.01–1.05)	0.003
Obesity status				0.144
Non-obese	26/2518	0.99(0.90–1.09)	0.822
Obese	174/2383	1.03(1.01–1.05)	0.003

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DOI: https://doi.org/10.2478/rjim-2026-0010 | Journal eISSN: 2501-062X | Journal ISSN: 1220-4749

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Language: English

Submitted on: Mar 7, 2026

Published on: May 18, 2026

Published by: N.G. Lupu Internal Medicine Foundation

In partnership with: Paradigm Publishing Services

Publication frequency: 4 issues per year

Keywords:

UHR,

Related subjects:

Internal medicine, other,

Cardiology,

Gastroenterology,

Rheumatology

© 2026 Jia Guo, Xiaona Wang, Ranran Zhao, published by N.G. Lupu Internal Medicine Foundation
This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License.

AHEAD OF PRINT

Accelerated Biological Aging and a Nonlinear Risk Threshold for Sleep Apnea: Evidence from NHANES and Mediation by Oxidative-Metabolic Dysregulation

Figures & Tables

Figure 1.

Figure 2.

Figure 3.

Segmented Logistic Regression Analysis of the Association Between PhenoAge and Sleep Apnea (SA) Risk_

Association Between PhenoAgeAccel and Sleep Apnea

Associations of PhenoAge with Sleep Apnea_

j_rjim-2026-0010_tab_006

Baseline Characteristics of the Study Participants by Sleep Apnea Status_

Subgroup Analysis of the Associations Between PhenoAge and Sleep Apnea_

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