UC San Diego

In the United States, the number of individuals who are 90 and older is expected to quadruple from 1.9 million in 2010 to 7.6 million individuals in 2050. Aging into the later years is often accompanied by time spent with mobility and cognitive impairments, multiple morbidity and disability in activities of daily living. Impairments in either the physical or mental domains contribute to declines in one’s intrinsic capacity to maintain high functioning and wellbeing.The pace of biological aging differs across older adults of the same chronological age. Faster biological aging is linked to greater accumulation of multiple morbidities, lower physical and cognitive functioning, and earlier death. Epigenetic age, a biomarker of aging, is a composite measure of DNA methylation across specific cytosine-guanine dinucleotide sites (CpG sites) associated with chronologic or phenotypic age. Epigenetic age acceleration, as measured by epigenetic clocks, is postulated to identify whether individuals are aging faster or slower when compared to their chronologic age. There have been no prospective studies that have examined the relationships between genome wide DNA methylation or epigenetic age acceleration with multiple morbidity at a specified older age or survival to 90 years of age with intact mobility and cognitive functioning. The first chapter of this dissertation reviews the epidemiological evidence on DNA methylation and epigenetic clocks and their relationships with longevity, mobility, cognitive functioning and multiple morbidity. The second chapter assesses the associations between four DNA methylation clocks that measure epigenetic age acceleration and exceptional longevity, defined as survival to age 90 with intact mobility and cognitive function. The third chapter utilizes an epigenome wide association study to identify specific CpG sites and regions that are associated with exceptional longevity. The fourth chapter evaluates associations between the four DNA methylation clocks and multiple morbidity among women when they reach 90 years of age. The final chapter summarizes and integrates the key findings from this dissertation and highlights future directions for research on the potential of DNA methylation and epigenetic clocks to expand knowledge of the etiology of healthy longevity and to identify targets for intervention to improve healthy aging.