A new epigenetic clock that uses easily collected cheek cells can accurately predict mortality.
We all age at different rates. While some supercentenarians may experience slower aging due to favorable genetics, numerous lifestyle and behavioral factors can accelerate the aging process. These include stress, poor sleep, inadequate nutrition, smoking, and alcohol consumption. Environmental influences like these leave their mark on our genome through epigenetic changes. By analyzing the epigenome at key genomic sites, it’s possible to measure molecular aging.
Over the past decade, scientists have developed several such ‘epigenetic clocks’, calibrated against chronological age and various lifestyle factors across large numbers of people. Most of these focused on DNA methylation in blood cells, which makes collection of samples onerous, as well as stressful for the patient. But earlier this year, scientists from the US developed a second-generation clock, called CheekAge, which is based on methylation data in easy-to-collect cells from inside the cheeks.
Now, in Frontiers in Aging, the team has shown for the first time that CheekAge can accurately predict the risk of mortality – and even if epigenetic data from another tissue is used as input.
“We also demonstrate that specific methylation sites are especially important for this correlation, revealing potential links between specific genes and processes and human mortality captured by our clock,” said Dr Maxim Shokhirev, the study’s first author and Head of Computational Biology and Data Science at the company Tally Health in New York.
CheekAge had been developed or ‘trained’ by correlating the fraction of methylation at approximately 200,000 sites with an overall score for health and lifestyle, reflecting presumed differences in physiological aging.
The biological clock is ticking
In the present study, Shokhirev and colleagues used statistical programming to see how well it predicted mortality from any cause in 1,513 women and men, born in 1921 and 1936 and followed throughout life by the Lothian Birth Cohorts (LBC) program of the University of Edinburgh. One of the LBC’s aims was to link differences in cognitive aging to lifestyle and psychosocial factors and biomedical, genetic, epigenetic, and brain imaging data. Every three years, the volunteers had their methylome in blood cells measured at approximately 450,000 DNA methylation sites. The last available methylation time point was used along with the mortality status to calculate CheekAge and its association with mortality risk. Data on mortality had been obtained from the Scottish National Health Service Central Register.
“[Our results show that] CheekAge is significantly associated with mortality in a longitudinal dataset and outcompetes first-generation clocks trained in datasets containing blood data,” concluded the authors.
Specifically, for every increase by a single standard deviation in CheekAge, the hazard ratio of all-cause mortality increased by 21%. This means that CheekAge is strongly associated with mortality risk in older adults.
“The fact that our epigenetic clock trained on cheek cells predicts mortality when measuring the methylome in blood cells suggests there are common mortality signals across tissues,” said Shokhirev.
“This implies that a simple, non-invasive cheek swab can be a valuable alternative for studying and tracking the biology of aging.”
Strongest predictors
The researchers looked at those methylation sites which were most strongly associated with mortality in greater detail. Genes located around or near these sites are potential candidates for impacting lifespan or the risk of age-related disease. For example, the gene PDZRN4, a possible tumor suppressor, and ALPK2, a gene implicated in cancer and heart health in animal models. Other genes that stood out had previously been implicated in the development of cancer, osteoporosis, inflammation, and metabolic syndrome.
“It would be intriguing to determine if genes like ALPK2 impact lifespan or health in animal models,” said Dr Adiv Johnson, the study’s last author and the Head of Scientific Affairs and Education at Tally Health.
“Future studies are also needed to identify what other associations besides all-cause mortality can be captured with CheekAge. For example, other possible associations might include the incidence of various age-related diseases or the duration of ‘healthspan’, the period of healthy life free of age-related chronic disease and disability.”
Reference: “CheekAge, a next-generation epigenetic buccal clock, is predictive of mortality in human blood” by Maxim N. Shokhirev, Daniel J. Kramer, Janie Corley, Simon R. Cox, Trinna L. Cuellar and Adiv A. Johnson, 26 August 2024, Frontiers in Aging.
DOI: 10.3389/fragi.2024.1460360
The study was funded by Tally Health, the Wellcome Trust, the Economic and Social Research Council, Age UK, the Biotechnology and Biological Sciences Research Council, the Medical Research Council, the Milton Damerel Trust, the University Of Edinburgh, and the Royal Society.