Under the assumption that aging is caused by dysfunction of specific biological mechanisms, it is reasonable to hypothesize that slowing aging should delay the onset of chronic diseases that typically affect older persons and improve their longevity and quality of life. Indeed, there is emerging evidence that factors associated with premature mortality are also involved in multiple pathologic conditions typical of aging. There is evidence that the study of aging and longevity requires a more comprehensive analysis of biological, environmental and phenotypic changes that occur with aging and how they are reflected by circulating and tissue biomarkers. A major limitation in this approach to date is that most studies of biomarkers rely on blood specimens, which may not recapitulate the biology of other tissues. In addition, although all cell types from the same person have exactly the same genetic code; information on epigenetic modifications, RNAm, and protein expression likely differ across cell types and at different points in time. Thus, global measures of these biomarkers in specific cell types can be affected by percentages of these cell types in the blood, and it is well known that such percentages change with aging and chronic diseases. More recently single cell biomarker assessment overcome such limitation and will be introduced in GESTALT in parallel with the measures already obtained.

In GESTALT, we will use cytapheresis to collect large number of PBMCs in the H group and we will draw blood to collect PBMCs in the NHF and F individuals dispersed over a wide age- range. The collection of large number of PBMCs is essential to obtain enough cells for each cell type to support measurements of the biomarkers of interest.

The information collected will be used to identify biomarkers that change with aging in healthy, non-healthy-or-frail and frail individuals, independent of changes in specific PBMCs cell types. We will also develop a statistical model that can be used by other studies of biomarkers to adjust their analysis for PBMCs cell type composition without having to perform complex and expensive measures, such as flow cytometry. The data collected in PBMCs will be compared to similar biomarker data obtained from muscle/fat and skin biopsies to understand to what extent biomarkers measured in the blood recapitulate similar changes that occur in different human tissues. Finally, once methodological limitations of measuring biomarkers in the blood have been addressed, we plan to assess the relationship of biomarkers assessed in specific circulating cell types, in the whole blood, bone marrow aspirate and in muscle/fat and skin biopsies to physiological measures that typically change with aging, including measures of body composition (anthropometrics, CT scan and MRI), energetics (spirometry at rest and during different degrees of exercise intensity), homeostatic equilibrium (hormones and inflammatory markers), neurological function (neurocognitive testing, brain MRI, nerve conduction studies). At even visits, we will focus on in depth characterization of phenotypes that are relevant for aging. Additionally, a modified schedule of testing will occur starting at Year 8. Year 8 Visit 4.5, which is between visits 4 and 5 and Year 18 Visit 8.5, which is between visits 8 and 9 and every 10 years thereafter. This strategy reduces the burden to participants but still allows delineating trajectories of essential variables and relate them longitudinally. The final goal is to develop new hypotheses about the biological nature of the aging process and how aging is associated with decline of physical and cognitive function.