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Table 2 Studies investigating the association between the epigenetic clock and the incidence of age-related diseases

From: The epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis

Paper Study (country) Characteristics: n, mean (SD) age, sex Outcome Sample; platform Clock* DNAmAge associations
[correlation with chronological age]
Adj.
[69] Cohort study
WHI
(USA)
2029, age 65.3 (7.1) 100% ♀
(post-menopause).
20 years FU
Lung cancer incidence; n = 43 Blood; 450 K IEAAH ↑ risk of lung cancer (HR 1.50; p = 0.003), especially septuagenarians (HR:2.51, p = 0.0008) and current smokers (HR 6.17, p = 0.0004)
[NS]
Age, ethnicity, smoking, and pack years
[70] Cohort study
NAS
(USA)
442, 71.7 (6.7), 0% ♀,
370 seen pre 2003,
306 in cohort 2003 to 2013.
3–5 years FU
Cancer incidence, n = 132 Buffy coat
(3 years FU); 450 K
IEAAHa ↑ cancer incidence (HR 1.06, p = 0.004 per year) in 2003–2013 cohort only
[NS]
Age, BMI, education, smoking, alcohol
[63] Case-control
EPIC
(10 countries)
902 Total, 52.3 (8.9), 100% ♀
451 cases
451 CT
Breast cancer Blood; 450 K IEAAH ↑ breast cancer (4%, p = 0.016). In stratified analysis, only significant for postmenopausal ♀
[0.76]
BMI, hormonal factors, various others
[64] Case-control
EPIC
(10 countries)
845 Total, 52 (7.4), 77.8% ♀
235 BC
166 CRC
Breast/colorectal cancer Blood; 450 K AAH
AAHa IEAAH
IEAAHa
In males, ↑ AAH in CRC (1.6 years older, p = 0.04)
NS all in females
[NS]
Cell %
[13] Seven case-control studies nested in MCCS
Case-control
(Australia)
6432 total, 27–76, 59% ♀
3216 cancer cases**
3216 CT
Median 8.3 years FU
Cancer Blood; 450 K All ↑ cancer risk (7 of 35 associations, p < 0.05, mainly kidney ↑ 35–63% and B cell lymphomas ↑15–27%).
[EAH: r = 0.73, EAHa:0.78]
Age and sex, matched, various others
[23] 10 cohorts (∆ ethnicities) WHI, BHS, PEG (USA), cohorts from Bolivia, Asia, and Africa Total 4296
(individual cohorts 41–1462),
2–92 (NS), between 0% and 100% ♀
Incident coronary heart disease (CHD), n = not stated Blood
(3× saliva)
450 K
(2 × 27 K)
IEAAH
EEAA
NS
[EAH assumed: r = 0.65 to 0.93 depending on cohort, 3 of 10 > 0.80]
Age, sex, cell %, education
[62] Cohort study
IS: BASICMAR
CT: REGICOR
(Spain)
IS: 82, 63.9 (10.3), 45.1% ♀
CT: 41, 62.8 (14.2), 48.8% ♀
Ischemic stroke Whole blood; 450 K AAH
AAHa
↑ stroke patients (AAHa: 2.5 years, p = 0.008; AAH NS), especially younger patients
[All samples, EAH: r = 0.87, EAHa:0.80]
Sex
[67] Two cohorts of ischemic stroke (IS) patients (Spain) Discovery:
551, 65–81 (NS), 41.9% ♀;
Replication:
85, 66–80 (NS), 29.4% ♀
IS outcome at 3 months (from 0 = no symptoms to 6 = death) Whole blood; 450 K AAHa ↑ worse 3-month stroke outcome (OR:1.04, p = 0.008 and OR 1.16, p < 0.001 in 2 cohorts).
[r = 0.81]
Age, sex, smoking, treatment, various others
[74] Cohort study
PIVUS
(Sweden)
832, 70 (NS), 50% ♀
10years FU
Incident CVD, n = 153 Whole blood; 450 K AAH
AAHa
↑ incident CVD (3.3% per year, p = 0.02) with AAH. AAHa NS
[NS]
Sex, smoking, BMI, various others
[16] Case-control
PEG
(USA)
Caucasians:
289 PD, 37–91 (NS), 43% ♀;
219 CT, 35–92 (NS), 47% ♀.
Hispanics:
46 PD, 37–83 (NS), 30% ♀
38 CT, 35–92 (NS), 53% ♀
Parkinson’s disease (PD) Blood; 450 k AAH
IEAAH EEAA
Associated with PD after logistic regression (AAH: p = 0.037; EEAA p = 0.031. Effect sizes not stated.
[Caucasians: r = 0.82, Hispanics: r = 0.81]
Age, sex, cell %, smoking, ethnicity, coffee, pesticides
[68] Cohort study
Betula
(Sweden)
16 maintain memory, 57.8 (3.6)
20 average, 58.0 (3.5)
16 decline, 57.9 (3.6), 50% ♀.
15 years FU
Dementia incidence, n = 7 Blood; 450 K AAH ↑ dementia incidence (β 0.16, p = 0.03). [r = 0.69] Age, sex
  1. AAH, age acceleration (Horvath); AAHa, age acceleration (Hannum); BASICMAR. Abbreviation: NS (Ministerio de Sanidad y Consumo, Instituto de Salud Carlos III); BC, breast cancer; Betula, longitudinal cohort study of memory, health and ageing; BHS, Bogalusa Heart Study; BL, baseline; CRC, colorectal cancer; CT, controls; CVD, cardiovascular disease; DNAmAge, DNA methylation age; EEAA, extrinsic epigenetic age acceleration (Hannum measurement); EAH, epigenetic age (Horvath); EAHa, epigenetic age (Hannum); EPIC, European Prospective Investigation into Cancer and Nutrition; FU, follow-up; IEAAH, intrinsic epigenetic age acceleration (Horvath); IEAAHa, intrinsic epigenetic age acceleration (Hannum); IS, ischemic stroke; MCCS, Melbourne Collaborative Cohort Study; NAS, US Department of Veterans Affairs’ Normative Ageing Study; NS, not shown; PEG, Parkinson’s disease, Environment, and Genes case-control study; PIVUS, Prospective Study of the Vasculature in Uppsala Seniors; REGICOR, Registre Gironi del Cor; WHI, Women’s Health Initiative (WHI)
  2. *Includes all five measures of interest to this review, including AAH, AAHa, IEAAH, IEAAHa, and EEAA
  3. **CRC, gastric, kidney, lung, prostate, urothelial, B cell lymphoma