An epigenetic aging analysis of randomized metformin and weight loss interventions in overweight postmenopausal breast cancer survivors

Nwanaji-Enwerem, Jamaji C.; Chung, Felicia Fei-Lei; Van der Laan, Lars; Novoloaca, Alexei; Cuenin, Cyrille; Johansson, Harriet; Bonanni, Bernardo; Hubbard, Alan E.; Smith, Martyn T.; Hartman, Sheri J.; Cardenas, Andres; Sears, Dorothy D.; Herceg, Zdenko

doi:10.1186/s13148-021-01218-y

Table 1 Estimated difference in epigenetic age biomarkers after 6 months of metformin and weight loss program interventions compared to placebo (N = 192)

From: An epigenetic aging analysis of randomized metformin and weight loss interventions in overweight postmenopausal breast cancer survivors

Aging biomarker models	Weight loss only (N = 48)		Metformin only (N = 48)		Weight loss plus metformin (N = 48)
Aging biomarker models	difference in DNA methylation biomarker (95% CI)	P	Difference in DNA methylation biomarker (95% CI)	P	difference in DNA methylation biomarker (95% CI)	P
EAA Hannum units: years
Unadjusted Intent to Treat	1.13 (− 0.46, 2.73)	0.16	0.25 (− 1.35, 1.84)	0.76	1.05 (− 0.55, 2.64)	0.20
Adjusted Intent to Treat	0.98 (− 0.48, 2.44)	0.19	0.47 (− 0.98, 1.91)	0.53	0.45 (− 1.04, 1.95)	0.55
Unadjusted High Adherence*	1.03 (− 0.95, 3.02)	0.30	0.43 (− 1.29, 2.16)	0.62	1.35 (− 0.58, 3.28)	0.17
Adjusted High Adherence*	− 0.04 (− 1.89, 1.81)	0.97	0.60 (− 0.98, 2.19)	0.45	0.61 (− 1.20, 2.43)	0.51
EAA Horvath units: years
Unadjusted Intent to Treat	0.96 (− 0.76, 2.68)	0.27	− 0.20 (− 1.93, 1.52)	0.81	− 0.25 (− 1.97, 1.48)	0.78
Adjusted Intent to Treat	0.74 (− 1.06, 2.53)	0.42	− 0.34 (− 2.11, 1.43)	0.70	− 0.59 (− 2.43, 1.25)	0.53
Unadjusted High Adherence*	− 0.26 (− 2.48, 1.97)	0.82	− 0.21 (− 2.15, 1.72)	0.83	0.38 (− 1.78, 2.55)	0.73
Adjusted High Adherence*	− 0.11 (− 2.49, 2.26)	0.93	− 0.26 (− 2.28, 1.77)	0.80	0.04 (− 2.29, 2.37)	0.97
EAA SkinBloodClock units: years
Unadjusted Intent to Treat	0.81 (− 0.54, 2.15)	0.24	− 0.68 (− 2.03, 0.66)	0.32	0.26 (− 1.08, 1.61)	0.70
Adjusted Intent to Treat	0.86 (− 0.48, 2.19)	0.21	− 0.69 (− 2.01, 0.63)	0.30	0.40 (− 0.96, 1.77)	0.56
Unadjusted High Adherence*	1.01 (− 0.67, 2.68)	0.24	− 0.99 (− 2.45, 0.46)	0.18	0.52 (− 1.10, 2.15)	0.53
Adjusted High Adherence*	0.77 (− 0.90, 2.43)	0.37	− 1.09 (− 2.52, 0.34)	0.13	0.52 (− 1.12, 2.16)	0.53
Intrinsic EAA (IEAA) units: years
Unadjusted Intent to Treat	0.74 (− 0.96, 2.44)	0.39	− 0.22 (− 1.91, 1.48)	0.80	− 0.36 (− 2.06, 1.34)	0.68
Adjusted Intent to Treat	0.74 (− 1.05, 2.53)	0.42	− 0.40 (− 2.17, 1.37)	0.66	− 0.63 (− 2.47, 1.20)	0.50
Unadjusted High Adherence*	− 0.38 (− 2.58, 1.82)	0.73	− 0.16 (− 2.08, 1.75)	0.87	0.12 (− 2.02, 2.26)	0.91
Adjusted High Adherence*	− 0.06 (− 2.45, 2.32)	0.96	− 0.33 (− 2.36, 1.70)	0.75	0.02 (− 2.32, 2.35)	0.99
Extrinsic EAA (EEAA) units: years
Unadjusted Intent to Treat	1.39 (− 0.66, 3.44)	0.18	0.13 (− 1.92, 2.19)	0.90	1.56 (− 0.49, 3.62)	0.13
Adjusted Intent to Treat	1.05 (− 0.55, 2.66)	0.20	0.60 (− 0.99, 2.18)	0.46	0.56 (− 1.08, 2.20)	0.50
Unadjusted High Adherence*	1.57 (− 0.94, 4.08)	0.22	0.42 (− 1.77, 2.60)	0.71	1.79 (− 0.66, 4.23)	0.15
Adjusted High Adherence*	− 0.12 (− 2.15, 1.90)	0.90	0.78 (− 0.95, 2.51)	0.38	0.70 (− 1.29, 2.68)	0.49
EAA PhenoAge units: years
Unadjusted Intent to Treat	1.92 (− 0.30, 4.14)	0.09	0.79 (− 1.43, 3.01)	0.48	0.40 (− 1.82, 2.63)	0.72
Adjusted Intent to Treat	2.02 (0.02, 4.03)	0.05	0.82 (− 1.16, 2.80)	0.41	− 0.12 (− 2.17, 1.93)	0.91
Unadjusted High Adherence*	3.32 (0.56, 6.08)	0.02	1.03 (− 1.37, 3.43)	0.40	0.58 (− 2.11, 3.27)	0.67
Adjusted High Adherence*	2.75 (0.18, 5.32)	0.04	0.98 (− 1.22, 3.17)	0.38	0.48 (− 2.04, 3.00)	0.70
EAA GrimAge units: years
Unadjusted Intent to Treat	0.76 (− 0.61, 2.12)	0.28	− 0.89 (− 2.26, 0.48)	0.20	0.26 (− 1.10, 1.63)	0.70
Adjusted Intent to Treat	0.76 (− 0.58, 2.10)	0.27	− 0.91 (− 2.24, 0.41)	0.18	− 0.39 (− 1.76, 0.98)	0.58
Unadjusted High Adherence*	1.61 (− 0.10, 3.33)	0.07	− 0.65 (− 2.14, 0.85)	0.39	0.45 (− 1.22, 2.12)	0.59
Adjusted High Adherence*	1.38 (− 0.33, 3.10)	0.11	− 0.74 (− 2.21, 0.73)	0.32	− 0.05 (− 1.73, 1.63)	0.95
DNAm TL Age Adjusted units: kb
Unadjusted Intent to Treat	− 0.07 (− 0.14, 0.01)	0.09	− 0.03 (− 0.10, 0.05)	0.52	− 0.02 (− 0.09, 0.06)	0.67
Adjusted Intent to Treat	− 0.04 (− 0.11, 0.02)	0.20	− 0.03 (− 0.10, 0.04)	0.41	0.01 (− 0.06, 0.08)	0.68
Unadjusted High Adherence*	− 0.10 (− 0.20, − 9.5e−4)	0.05	− 2.2e−4 (− 0.09, 0.08)	0.99	− 0.03 (− 0.13, 0.07)	0.53
Adjusted High Adherence*	− 0.06 (− 0.14, 0.03)	0.21	− 0.01 (− 0.08, 0.07)	0.80	0.01 (− 0.08, 0.09)	0.86
EpiTOC IR units: DNAm
Unadjusted Intent to Treat	5.7e−5 (− 5.9e−5, 1.7e−4)	0.34	5.7e−5 (− 5.9e−5, 1.7e−4)	0.34	1.1e−4 (− 5.0e−6, 2.3e−4)	0.06
Adjusted Intent to Treat	1.8e−5 (− 8.1e−5, 1.2e−4)	0.72	4.1e−5 (− 5.6e−5, 1.4e−4)	0.40	5.5e−5 (− 4.5e−5, 1.6e−4)	0.28
Unadjusted High Adherence*	3.0e−5 (− 1.2e−4, 1.8e−4)	0.69	8.9e−5 (− 3.8e−5, 2.2e−4)	0.17	9.0e−5 (− 5.2e−5, 2.3e−4)	0.21
Adjusted High Adherence*	6.6e−6 (− 1.17e−4, 1.3e−4)	0.92	8.5e−5 (− 2.1e−5, 1.9e−4)	0.12	5.1e−7 (− 1.2e−4, 1.2e−4)	0.99
EpiTOC2 IR units: cell divisions
Unadjusted Intent to Treat	3.78 (− 2.29, 9.85)	0.22	2.66 (− 3.41, 8.73)	0.39	5.91 (− 0.16, 11.98)	0.06
Adjusted Intent to Treat	1.43 (− 3.57, 6.44)	0.57	1.85 (− 3.10, 6.81)	0.46	2.73 (− 2.37, 7.84)	0.29
Unadjusted High Adherence*	2.79 (− 4.84, 10.42)	0.47	4.17 (− 2.47, 10.80)	0.22	4.82 (− 2.60, 12.24)	0.20
Adjusted High Adherence*	0.90 (− 5.46, 7.26)	0.78	4.07 (− 1.39, 9.53)	0.14	− 0.18 (− 6.41, 6.05)	0.95
MiAge IR units: cell divisions
Unadjusted Intent to Treat	0.28 (− 0.92, 1.45)	0.66	0.28 (− 0.90, 1.47)	0.64	0.69 (− 0.49, 1.88)	0.25
Adjusted Intent to Treat	− 0.14 (− 1.05, 0.77)	0.77	0.13 (− 0.77, 1.03)	0.78	0.37 (− 0.56, 1.30)	0.44
Unadjusted High Adherence*	0.24 (− 1.22, 1.70)	0.75	0.46 (− 0.81, 1.73)	0.47	0.67 (− 0.75, 2.09)	0.35
Adjusted High Adherence*	− 0.11 (− 1.26, 1.04)	0.85	0.49 (− 0.50, 1.48)	0.33	− 0.11 (− 1.24, 1.02)	0.85

Adjusted models include adjustments for number of days from randomization to end of study and leukocyte abundance/proportions
*Sample sizes for high adherence models are: placebo (N = 48), weight loss only (N = 23), metformin only (N = 36), and weight loss plus metformin (N = 25)
EAA = epigenetic age acceleration (residuals of regressing epigenetic age on chronological age)
IR = intrinsic rate of cell divisions (calculated by dividing mitotic clock measurements by chronological age)

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