Table 3 Studies investigating the association between the epigenetic clock and mortality

[17]

Meta-analysis of 4 cohorts:

LBC1921 and LBC1936 (Scotland),

FHS and NAS

(USA)

LBC1921: 446, age 79.1 (0.6), 60% ♀; LBC1936: 920, age 69.5 (0.8), 49% ♀;

FHS: 2635, age 66.3 (8.9), 54% ♀;

NAS: 657, age 72.9 (6.9), 0% ♀.

2–15 years FU

All-cause mortality, n = 862

Blood; 450 K

IEAAH¹

IEAAHa¹

16% and 9% ↑ mortality risk for a 5-year higher IEAAHa and IEAA respectively (p < 0.05).

[EAH: r = 0.75, EAHa:0.83]

Chronological age, sex, smoking, education, childhood IQ, social class, hypertension, diabetes, cardiovascular disease, and APOE status.

[18]

Meta-analysis of 12 cohorts: WHI (× 3), NAS, ARIC, FHS, BLSA (USA);

LBC1921 and 1936

(Scotland);

KORA (Germany); InCHIANTI (Italy); Rotterdam (Netherlands)

Overall 12,284.

Age range 52–79, % ♀ not stated.

From 4 to 21 years FU

All-cause mortality, n = 2704

Blood; 450 K

AAH

AAHa

IEAAH

EEAA

All measures of age acceleration are significantly associated with ↑ mortality risk (p ≤ 5.4e-05). EEAA outperformed all measures with the smallest p value.

[EAH: r = 0.15–0.87,

EAHa: r = 0.13–0.89, all depending on cohort, 10 of 26 > 0.80]

Age, BMI, various others

[72]

Twin study

LSADT

(Denmark)

LSADT: 86 same-sex twins,

aged 73–82, 72% ♀

All-cause mortality

n = 55

Blood; 450 K

AAH

AAHa

35% ↑ mortality risk per 5-year ↑ in AA-Horvath (P = 0.02). 2-fold ↑ mortality risk for the twin with the oldest biological age. AAHa NS

[EAH: r = 0.97]

Age, sex, cell composition, twin pairing.

[75]

Cohort study

LBC1921 and LBC1936 (Scotland)

LBC1921: 414, age 79.1 (0.6), 58% ♀, 13 years FU

LBC1936: 920, age 69.5 (0.8), 49%♀,

6 years FU

All-cause mortality, n = 280 and 135

Whole blood; 450 K

AAHa

25% ↑ mortality risk for each 1 SD ↑ in AAHa (p = 0.0001) (Pooled result)

[NS]

Age (at baseline), sex

[76]

Cohort Study

Louisiana Healthy Ageing Study Cohort (USA)

262, age 86 (10), 60.7% ♀, all Caucasian. Average 4.4 years FU

All-cause mortality, n = 206

Blood; 450 K

AAH

NS

[r = 0.63]

Age, cell %

[77]

Cohort Study

NAS

(USA)

241, age 52.6 (10.7), 13% ♀.

White non-Hispanic.

6.5 years FU, average 3.4 years

All-cause mortality, n = 17

Buffy coat; 450 K

AAHa

13% ↑ mortality risk over FU (p = 0.03).

[r = 0.90]

Age (baseline), sex, cell %, PTSD, ancestry

[11]

Seven case-control studies nested in MCCS

Case-control(Australia)

2818 healthy controls matched to cancer cases, age 27–76, 39% ♀. Median 10.7 years FU

All-cause mortality, n = 831;

cancer, n = 240; CVD, n = 203; other-cause mortality, n = 249.

Blood; 450 K

All

5–8% ↑ risk of all-cause mortality per 5-year ↑ Horvath (both predictor types). 11–14% ↑ risk of cancer-related mortality (all predictors). NS with the risk of CVD or other-cause mortality (all predictors).

[EAH: r = 0.73, EAHa:0.76]

Age, various others

[13]

Seven case-control studies nested in MCCS

Case-control(Australia)

3216 cancer cases (different types) and controls, 27–76, 59% ♀. Median 8.3 years FU

All-cause mortality, n = 1726;

cancer-related,

n = 1271;

other causes of death,

n = 309.

Blood; 450 K

All

4–14% ↑ risk of all-cause, cancer-related and other causes of death per 5-year ↑ Hannum (all 3 predictors). Horvath NS predictive of mortality (all measured types).

[EAH: r = 0.73, EAHa:0.78]

Age and sex, matched. Various others

[70]

Cohort study

NAS

(USA)

442 males, age 71.7 (6.7),

370 seen pre-2003,

306 in cohort 2003 to 2013.

3–5 year FU

Cancer mortality,

n = 34

Buffy coat (3 years FU); 450 K

IEAAHa

17% ↑ cancer mortality per year (p = 0.001) in 2003–2013 cohort only.

[NS]

Age at first blood draw, BMI, education, smoking, alcohol, and top 3 principal components

[78]

Cohort study

ESTHER

(Germany)

1863 total, aged 62.5 (6.6).

1260 survivors, 57.2% ♀,

602 cases (316 selected, 43.7% ♀ and 286 deceased in sub-sample, 39.5% ♀).

Maximum 13 years FU

All-cause mortality, n = 602;

cancer-causing mortality, n = 235;

CVD-related mortality, n = 194.

Blood, baseline; 450 K

AAH AAHa

22–23% ↑ risk of all-cause and cancer-causing mortality per 5-year ↑ in AA-Horvath (p < 0.05). AA-Horvath NS with CVD mortality when the model was fully adjusted. NS AA-Hannum with any of the 3 measures of mortality

[r = 0.77, 0.73)

[EAH: r = 0.73, EAHa: r = 0.77]

Age, sex, BMI, various others

[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 < 0.001 and OR: 1.06, p = 0.007 in 2 cohorts).

[r = 0.81]

Biological age, sex, recanalization treatment, and basal NIHSS, various others