Comparing Some of the Most Widely Used Epigenetic Clocks

Epigenetic clocks assess biological age based on an algorithmic combination of the DNA methylation status at some number of CpG sites on the genome. Some changes in DNA methylation are characteristic of age, but at this time it is unknown as to how these changes relate to the underlying damage and dysfunction of age. Researchers here find that an epigenetic clock using few CpG sites performs about as well as those using many more sites when it comes to correlations with mortality risk. This is interesting, but it seems unlikely that a clock using a small number of sites will perform well as a way to assess whether or not a potential rejuvenation therapy is working. A specific rejuvenation therapy will likely address only one underlying cause of aging, and there is no reason to expect that any given small collection of CpG sites will react usefully to changes in that one cause of aging.

Three DNA methylation (DNAm) based algorithms, DNAm PhenoAge acceleration (AgeAccelPheno), DNAm GrimAge acceleration (AgeAccelGrim), and mortality risk score (MRscore), based on methylation in 513, 1030, and 10 CpGs, respectively, were established to predict health outcomes and mortality. In this study, we evaluated and compared the three DNAm algorithms and a frailty index (FI) in relation to prediction of mortality in a cohort of older adults. The three DNAm algorithms and the FI were positively correlated with each other and each of them was independently associated with all-cause and cause-specific mortality.

Whereas the first-generation epigenetic clocks were assessed solely by chronological age as the reference, PhenoAge and GrimAge were designed to better capture biological aging. Given that AgeAccelPheno and AgeAccelGrim are reflecting differences of estimated biological age and chronological age, their lack of correlation with chronological age in our study was predictable. Moreover, AgeAccelPheno and AgeAccelGrim were observed to be weakly correlated with FI.

In a previous study from the Lothian Birth Cohort 1936, higher DNAm GrimAge was associated with lower cognitive ability and brain vascular lesions in older age. Previous studies also reported that higher GrimAge and PhenoAge values were associated with an increase in physical function deficits and were correlated with poorer fitness, such as diminished grip strength and cardio-pulmonary function. Frailty is a consequence of a cumulative decline in many physiological systems and frail individuals are characterized by increased vulnerability to age-related disorders. The observed correlations of AgeAccelPheno and AgeAccelGrim with FI in the current study may reflect declines in multiple physiological systems beyond "normal aging".

One primary aim of developing DNAm biomarkers is finding an accurate, simple, and feasible method to predict mortality or lifespan. In that respect, MRscore, requiring methylation quantification at a much lower number of CpGs, by itself or in combination with some easy-to-determine frailty measure, such as FI, has potential capacity to be a practical and economic indicator for mortality risk stratification.


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