Clonal Hematopoiesis of Indeterminate Potential in Aging and Exceptional Longevity in Older Women

This application is responsive to Notice of Special Interest: Women’s Health Research, which seeks research to to extend healthy lifespan among older women. There are currently 1.4 million women in the U.S. ages 90 and older, which is expected to quadruple by 2050. While women’s lifespans are increasing, their healthspans, or years of healthy life, have not been rising. Identification of novel strategies to extend healthspan is important for older women, who live longer than men but experience a greater number of years lived with chronic diseases and physical impairment. Age is the strongest known risk factor for chronic diseases; yet, the mechanisms through which aging confers this risk are unknown. Evidence is emerging that clonal hematopoiesis of indeterminate potential (CHIP), an age-related phenomenon in which cells undergo somatic mutations that lead to overgrowth (“clones”) of a genetically distinct subpopulation of blood cells, is a risk factor for chronic diseases and mortality. However, several questions related to the epidemiology of CHIP and aging remain unanswered. In particular, the extent to which CHIP increases risk of multimorbidity and mobility impairment, conditions that are highly prevalent in older women, is unknown. Moreover, the impact of CHIP on exceptional longevity has been vastly understudied, as few cohorts have adequate numbers of long-lived survivors. Further, the mechanistic pathways through which CHIP influences disease and healthspan are unclear. We plan to use a large sample of ~10,000 older women from the deeply phenotyped Women’s Health Initiative (WHI) cohort who already have undergone deep targeted CHIP sequencing, including ~7,000 with longitudinal CHIP data at two time points 14-19 years apart. We will supplement the existing WHI CHIP resource by obtaining new baseline CHIP measures using our highly sensitive targeted gene sequencing method to study exceptional longevity prospectively in a total sample of 15,314 women (30% African American, 14% Hispanic, 11% Asian, and 38% White). In Aim 1, we will examine associations of baseline CHIP and longitudinal CHIP changes with multimorbidity and mobility impairment. In Aim 2, we will determine associations of CHIP with exceptional longevity (survival to ages 90, 95, and 100) and exceptionally healthy aging (survival to age 90 with intact mobility and free of cardiovascular disease, cancer, type 2 diabetes, and cognitive impairment/dementia). In Aim 3, we will use epigenomic and proteomic data to identify novel biological pathways that lie in the causal pathway between CHIP and outcomes from Aims 1 and 2. Our study will have a transformative impact by: (1) evaluating the potential for CHIP to be used as a novel, blood-based aging biomarker to predict risk of age-related diseases to advance precision medicine in older adults; and (2) identifying mechanistic pathways through which CHIP impacts disease risk and healthspan, which may identify novel therapeutic targets to concomitantly delay or prevent multiple chronic diseases and preserve mobility in older adults. Key findings will be replicated and extended to men in the extensively phenotyped UK Biobank and Jackson Heart Study. Project Number: 1R01AG092395-01A1 | Fiscal Year: 2026 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: ALEXANDER REINER (+1 co-PI) | Institution: FRED HUTCHINSON CANCER CENTER, SEATTLE, WA | Award Amount: $785,867 | Activity Code: R01 | Study Section: Aging, Injury, Musculoskeletal, and Rheumatologic Disorders Study Section[AIMR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11298116