Serotonin 5HT(1A)-binding sites can be detected in living human brain with the positron-emitting antagonist [(11)C]WAY-100635. Previous measurements of the availability of [(11)C]WAY-binding sites in normal aging are equivocal, in part because of the greatly variable binding of this ligand. To test the null hypothesis that the binding potential (pB) of 5HT(1A) sites remains constant with age; 19 healthy volunteers aged 23-73 years (8 women, 11 men) underwent positron emission tomography. To determine pBs, we applied a novel tissue reference method of analysis, Estimation of Reversible Ligand Binding and Receptor Density (ERLiBIiRD) (Gjedde, 2003; Rosa-Neto et al, 2004), which extrapolates measures of specific binding to an estimated steady-state. We compared these estimates in the two age groups with results obtained with the conventional Logan Plot and Simplified Reference Tissue Method (SRTM) applied to both regions of interest-based as parametric analyses. The regional distribution of specific binding of free sites [(11)C]WAY-100635 was similar to that reported in previous studies, with the highest pBs in limbic structures and the raphé nuclei. Although the results of the three methods differed, pBs in the elderly subjects consistently were lower than those of young subjects. Thus, the correlation between pB and age applied to regions-of-interest revealed significant decline of pB at the rate of 3 or 4% per decade, and a 10% decline of the global mean 5HT(1A) receptor-pB in elderly relative to young subjects. The results demonstrate that the number of available 5HT(1A)-binding sites declines with age.