GrimAge Outperforms Other Epigenetic Clocks

There are now a variety of epigenetic clocks, weighted combinations of the methylation status of various CpG sites on the genome in various different tissues. The epigenetic marks of DNA methylation change constantly in response to circumstances and cell activities, but some of these changes are characteristic of the aged tissue environment, and thus correlate well with the burden of damage and dysfunction that causes manifestations of aging. A person more greatly damaged will tend to exhibit an epigenetic age higher than chronological age, a phenomenon referred to as age acceleration.

Epigenetic clocks are derived from the analysis of large amounts of epigenetic data obtained from study population of different ages, rather than from any understanding of how and why age-related epigenetic changes take place. Cell metabolism and epigenetics are very complex, and it remains unclear in near all cases as to why specific changes occur, and how those changes relate to the underlying processes of aging. Still, one can certainly run the numbers to decide which of the clocks are better or worse than others when it comes to assessing the burden of aging.

The aging process is characterized by the presence of high interindividual variation between individuals of the same chronical age prompting a search for biomarkers that capture this heterogeneity. Epigenetic clocks measure changes in DNA methylation levels at specific CpG sites that are highly correlated with calendar age. The discrepancy resulting from the regression of DNA methylation age on calendar age is hypothesised to represent a measure of biological ageing with a positive or negative residual signifying age acceleration or deceleration respectively.

The present study examines the associations of four epigenetic clocks - Horvath, Hannum, PhenoAge, GrimAge - with a wide range of clinical phenotypes (walking speed, grip strength, Fried frailty, polypharmacy, Mini-Mental State Exam (MMSE), Montreal Cognitive Assessment (MOCA), Sustained Attention Reaction Time, 2-choice reaction time), and with all-cause mortality at up to 10-year follow-up, in a sample of 490 participants in the Irish Longitudinal Study on Ageing (TILDA).

Horvath Age Acceleration (AA) and HannumAA were not predictive of health; PhenoAgeAA was associated with 4 of 9 outcomes (walking speed, frailty, MOCA, MMSE) in minimally adjusted models, but not when adjusted for other social and lifestyle factors. GrimAgeAA by contrast was associated with 8 of 9 outcomes (all except grip strength) in minimally adjusted models, and remained a significant predictor of polypharmacy, frailty, and mortality in fully adjusted models. Results indicate that the GrimAge clock represents a step-improvement in the predictive utility of the epigenetic clocks for identifying age-related decline in an array of clinical phenotypes promising to advance precision medicine.


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