Background Obesity is a hallmark of aging in many Western societies, and is a precursor to numerous serious age-related diseases. Ghrelin (Ghrl), via its receptor (growth hormone secretagogue receptor, GHS-R), is shown to stimulate GH secretion and appetite. Surprisingly, our previous studies showed that Ghrl.sup.-/- mice have impaired thermoregulatory responses to cold and fasting stresses, while Ghsr.sup.-/- mice are adaptive. Methodology/Principal Findings To elucidate the mechanism, we analyzed the complete metabolic profiles of younger (3-4 months) and older (10-12 months) Ghrl.sup.-/- and Ghsr.sup.-/- mice. Food intake and locomotor activity were comparable for both null mice and their wild-type (WT) counterparts, regardless of age. There was also no difference in body composition between younger null mice and their WT counterparts. As the WT mice aged, as expected, the fat/lean ratio increased and energy expenditure (EE) decreased. Remarkably, however, older Ghsr.sup.-/- mice exhibited reduced fat/lean ratio and increased EE when compared to older WT mice, thus retaining a youthful lean and high EE phenotype; in comparison, there was no significant difference with EE in Ghrl.sup.-/- mice. In line with the EE data, the thermogenic regulator, uncoupling protein 1 (UCP1), was significantly up-regulated in brown adipose tissue (BAT) of Ghsr.sup.-/- mice, but not in Ghrl.sup.-/- mice. Conclusions Our data therefore suggest that GHS-R ablation activates adaptive thermogenic function(s) in BAT and increases EE, thereby enabling the retention of a lean phenotype. This is the first direct evidence that the ghrelin signaling pathway regulates fat-burning BAT to affect energy balance during aging. This regulation is likely mediated through an as-yet-unidentified new ligand of GHS-R.