Faster biological aging predicts lower cognitive test scores 7 years later

An analysis of the Framingham Heart Study data found that higher epigenetic aging metrics predicted lower scores on the digital Clock Drawing Test 7 years later. The strongest association was with DunedinPACE, a biomarker of the pace of biological aging. The research was published in Aging.

As people age, their DNA molecules undergo specific chemical changes. These changes mainly involve the addition or removal of methyl groups at CpG sites on the DNA molecule, a process known as DNA methylation. DNA methylation alters gene expression without changing the DNA sequence itself. CpG sites are locations on a DNA molecule where a cytosine nucleotide is directly followed by a guanine nucleotide.

Age-related changes in DNA methylation occur in systematic patterns, allowing researchers to use methylation levels at specific sites as a measure of a person’s biological age (i.e., how old that individual’s body appears to be based on physiological, molecular, or functional markers), called epigenetic age.

Scientists measure epigenetic age by analyzing methylation levels at selected DNA sites using blood or other tissue samples. Statistical models combine information from these sites to estimate a person’s epigenetic age. This estimated age can be compared to chronological age (i.e., how old a person actually is) to assess whether a person’s aging is accelerated or slowed. If epigenetic age is higher than chronological age, it suggests faster biological aging.

Systems for estimating epigenetic age are called epigenetic clocks. Epigenetic aging has been associated with health outcomes such as disease risk, functional decline, and mortality.

Study author Zexu Li and his colleagues wanted to explore the relationship between measures of epigenetic aging and performance on the digital Clock Drawing Test. The Clock Drawing Test is a brief neuropsychological screening test in which a person is asked to draw a clock showing a specific time. It is used to assess cognitive functions such as visuospatial ability, executive functioning, and memory, as a screening tool for detecting cognitive changes.

Previous studies suggested that accelerated epigenetic aging might be a risk factor for cognitive decline. Based on this, study authors hypothesized that accelerated epigenetic aging at one time point might be associated with worse performance on the digital Clock Drawing Test later in life.

These researchers analyzed data from 1,789 individuals who participated in the Framingham Heart Study. Participants’ average age was 65 years. 53% were women.

Study authors used data on epigenetic age estimated by four different epigenetic clocks—Horvath, Hannum, GrimAge, and PhenoAge—and one measure of the pace of biological aging, DunedinPACE. The epigenetic clocks estimate epigenetic age based on patterns of DNA methylation on selected CpG sites, while DunedinPACE estimates the pace of biological aging. All were developed using statistical or machine-learning-based models to predict specific aging-related outcomes. These clocks differ in the outcome they were created to predict.

For example, the Hannum clock was developed to predict chronological age, while GrimAge was optimized to predict time to death by incorporating DNA-methylation proxies for plasma proteins and smoking exposure. Data on participants’ performance on the digital Clock Drawing Test were collected approximately seven years after the epigenetic age and pace of biological aging estimates.

Results showed that higher epigenetic age acceleration at the start of the study was associated with lower digital Clock Drawing Test scores later. These associations were stronger in older individuals. The strongest association was with the DunedinPACE estimates. Associations were substantial with Horvath and PhenoAge clocks in older, but not in younger, participants. Additionally, some components of the GrimAge clock were associated with poorer cognitive performance.

“Our findings suggest that advanced biological aging, particularly as captured by DunedinPACE and GrimAge components, is significantly associated with poorer cognitive performance measured by dCDT [digital clock drawing test], especially in older adults, highlighting a potential link between systemic aging processes and cognitive decline**,” the** study authors concluded.

The study contributes to the scientific understanding of the links between cognitive performance and biological age. However, study authors note that the diversity of their participants was limited as all were non-Hispanic White. Results in more diverse groups might not be identical.

The paper, “Association of DNA methylation age acceleration with digital clock drawing test performance: the Framingham Heart Study,” was authored by Zexu Li, Huitong Ding, Mengyao Wang, Yi Li, Ting Fang Alvin Ang, Gurnani Ashita, Katherine A. Gifford, Cody Karjadi, Daniel Levy, Rhoda Au, and Chunyu Liu.