While life expectancy continues to rise, healthspan is not keeping pace because current disease treatments often decrease mortality without preventing the decline in overall health. It is crucial to understand how the underlying processes of aging affect susceptibility to chronic disease and related conditions. Epigenetic mechanisms have arguably become an important frontier in geroscience. We and others have shown that epigenetic biomarkers tend to be more strongly related with chronological age than existing biomarkers of aging. Importantly, we have recently demonstrated that epigenetic biomarkers of aging are prognostic of all-cause mortality in later life and correlate with measures of physical and cognitive fitness in older age. These data suggest that epigenetic mechanisms may play a role in mediating the effect of age on disease susceptibility. In this planning grant we lay out th framework needed to design a large-scale study that tests the overall hypothesis that epigenetic changes during aging collectively underlie aging as a risk factor for chronic diseases and degenerative conditions. We will generate preliminary results by leveraging existing epigenetic and phenotypic data available to our team of co-investigators and collaborators. These resources include data from the ENCODE project, various epigenetic data generated in multiple tissues, and richly phenotyped cohorts, such as the Baltimore Longitudinal Study of Aging (BLSA), InCHIANTI, the Women's Health Initiative, and the Lothian Birth Cohorts. We will evaluate different platforms for measuring epigenetic age, DNA methylation levels, chromatin states, and non-coding RNAs in terms of their relevance to our overall hypothesis, data quality, coverage, and price. While there exists a large body of literature on epigenetics and aging, our proposal is novel in terms of its breadth and depth: we will lay the groundwork for a study that investigates multiple epigenetic processes (DNA methylation, histone modifications, non-coding RNAs), multiple human tissues, multiple chronic conditions, at multiple time points using multiple well characterized human cohort studies and state-of-the-art statistical and bioinformatics techniques. Using pilot data from these and other studies, we will assess the reliability and precision of cutting-edge epigenetic measures and to estimate the resources needed for a future study. We will also assess to what extent epigenetic features in accessible human tissues (e.g., blood, buccal epithelium) can serve as surrogates for affected tissues and cell types. By organizing two workshops at UCLA, we will establish a research network comprised of leading researchers in the fields of aging research, epigenetics, epidemiology, genomics, and systems biology.
In this planning grant we will conduct pilot studies to help design a human study that tests whether epigenetic changes underlie aging as a risk factor for chronic diseases and degenerative conditions.
|Horvath, Steve; Oshima, Junko; Martin, George M et al. (2018) Epigenetic clock for skin and blood cells applied to Hutchinson Gilford Progeria Syndrome and ex vivo studies. Aging (Albany NY) 10:1758-1775|
|Levine, Morgan E; Lu, Ake T; Quach, Austin et al. (2018) An epigenetic biomarker of aging for lifespan and healthspan. Aging (Albany NY) 10:573-591|
|Horvath, Steve; Stein, Dan J; Phillips, Nicole et al. (2018) Perinatally acquired HIV infection accelerates epigenetic aging in South African adolescents. AIDS 32:1465-1474|
|McEwen, Lisa M; Jones, Meaghan J; Lin, David Tse Shen et al. (2018) Systematic evaluation of DNA methylation age estimation with common preprocessing methods and the Infinium MethylationEPIC BeadChip array. Clin Epigenetics 10:123|
|Hofstatter, Erin W; Horvath, Steve; Dalela, Disha et al. (2018) Increased epigenetic age in normal breast tissue from luminal breast cancer patients. Clin Epigenetics 10:112|
|Lu, Ake T; Xue, Luting; Salfati, Elias L et al. (2018) GWAS of epigenetic aging rates in blood reveals a critical role for TERT. Nat Commun 9:387|
|Sehl, Mary E; Henry, Jill E; Storniolo, Anna Maria et al. (2017) DNA methylation age is elevated in breast tissue of healthy women. Breast Cancer Res Treat 164:209-219|
|Maierhofer, Anna; Flunkert, Julia; Oshima, Junko et al. (2017) Accelerated epigenetic aging in Werner syndrome. Aging (Albany NY) 9:1143-1152|
|Ambatipudi, Srikant; Horvath, Steve; Perrier, Flavie et al. (2017) DNA methylome analysis identifies accelerated epigenetic ageing associated with postmenopausal breast cancer susceptibility. Eur J Cancer 75:299-307|
|Chuang, Yu-Hsuan; Quach, Austin; Absher, Devin et al. (2017) Coffee consumption is associated with DNA methylation levels of human blood. Eur J Hum Genet 25:608-616|
Showing the most recent 10 out of 28 publications