Project Summary/Abstract Life expectancy at age 65 increased steadily in the United States over the past half-century. There is great uncertainty, however, regarding the extent to which this increase was accompanied by the compression of morbidity/disability due to Alzheimer’s disease (AD), AD-related dementias (ADRD), and stroke—the leading causes of cognitive impairment (CI) among the elderly—or to heart disease, cancer, diabetes, obesity, arthritis, and fractures—the leading causes of non-cognitive disablement in basic activities of daily living (ADL) among the elderly. Given the aging of the U.S. population and the increasing costs of health care and long-term care above age 65, addressing this uncertainty is of profound public health importance. The 1982–1994 National Long Term Care Survey (NLTCS) produced the first reports of major improvements in ADL and instrumental ADL (IADL) disability rates above age 65. While ADL/IADL improvements continued through 2004 in the NLTCS, dramatically larger improvements occurred for severe cognitive impairment—including AD/ADRD—during 1984– 2004. Moreover, multiple reports from the Health and Retirement Study (HRS) indicated that the favorable trends in severe cognitive impairment continued, but at a slower pace, through 2012; similar reports from the National Health and Aging Trends Study (NHATS) provided additional independent evidence of continuing improvement during 2011–2015. We propose to conduct comprehensive analyses of genetic and non-genetic modulators of the compression of morbidity/disability in the NLTCS, HRS, NHATS, and Long Life Family Study (LLFS), using morbidity/disability criteria consistent with the HIPAA ADL and CI triggers, to test two major hypotheses: (1) that modifiable non-genetic risk factors account for the recent temporal changes in the incidence, prevalence, and continuance of cognitive and physical impairments; and (2) that constitutional genetic and epigenetic factors modulate individual differences in lifetime morbidity/disability incidence, prevalence, and continuance of cognitive and physical impairments. We will analyze the roles of modifiable non-genetic risk factors in longevity, co-morbidity, functional health (ADL/IADL), and severe cognitive impairment (Aim 1). We will complete the SNP array analysis of 2,680 biospecimen samples (918 currently done) and conduct DNA methylation analysis of 639 blood samples in the NLTCS. De-identified NLTCS genetic and epigenetic data will be released using NIAGADS protocols. We will use SNP and DNA methylation data to conduct genetic and epigenetic association analyses with phenotypes of aging, health, longevity, physical disability, and severe cognitive impairment (Aim 2). We will analyze associations of phenotypes of long healthy life with candidate polymorphisms within two highly relevant coupled gene networks—Insulin/IGF1 signaling (incl. FOXO3A and IGFR) and mTOR pathways—linked to aging and longevity across different species a...