This proposal responds to Part B, """"""""Statistical Analysis of Biomarkers of Aging,"""""""" of RFA AG-91-17, """"""""Development of Biomarkers of Aging."""""""" Since 1988, several investigators in the NIA Biomarkers Initiative have been gathering biometric and psychometric data comparing diverse aspects of structure and function between rodents fed ad libitum and dietary-restricted animals. Collection of such data will continue over the period for which the present funding is requested. There result many megabytes of data representing a great diversity of aspects of biological structure and function measured in many different channels and on various schedules (longitudinally, at death, at sacrifice at fixed ages) in seven distinct genotypes for each sex. From this variety of experimental designs and measurements we propose to extract and calibrate assessments of gerontological age, or biomarkers, in a form suggesting generalizations to other species and to humans. The operationalization of """"""""biomarker"""""""" proposed for this project is a quasilinear composite, a weighted sum of smoothly transformed versions of raw measurements that covaries with a """"""""composite time"""""""" in a statistically optimal way. Composite time is a weighted contrast of time-since-birth with time-until-death, corresponding to the two criteria typically used to characterize biomarkers in the literature. Whenever the available data comprise a truly longitudinal design, these composites can be computed and validated, and various important gerontometric hypotheses calibrated or tested with their aid. These include the relative salience of each measurement included in the biomarker panels, the extent to which it leads or lags other members of the panel, the extent to which it discriminates the two dietary groups, the extent to which its sensitivity to gerontological age is shared between genotypes , and similar questions. These composite scores will be computed by the method of nonlinear Partial Least Squares. Composite biomarkers that emerge from the analysis of longitudinal data can be used to calibrate similar series of age-specific means emerging from the cross-sectional designs. The collection of potential biomarkers that results will be ordered along a few distinct dimensions of functional or gerontological age and will be assessed by both power to predict longevity and sensitivity to dietary restriction. Their synthesis into panels for future testing in primates and humans speaks directly to the overall programmatic intent of the Biomarkers Initiative.
| Miller, R A; Bookstein, F; Van der Meulen, J et al. (1997) Candidate biomarkers of aging: age-sensitive indices of immune and muscle function covary in genetically heterogeneous mice. J Gerontol A Biol Sci Med Sci 52:B39-47 |
