BACKGROUND We previously derived a whole-body resting energy expenditure (REE) prediction model by using organ and tissue mass measured by magnetic resonance imaging combined with assumed stable, specific resting metabolic rates of individual organs and tissues. Although the model predicted REE well in young persons, it overpredicted REE by approximately 11% in elderly adults. This overprediction may occur because of a decline in the fraction of organs and tissues as cell mass with aging. OBJECTIVE The aim of the present study was to develop a cellular-level REE prediction model that would be applicable across the adult age span. Specifically, we tested the hypothesis that REE can be predicted from a combination of organ and tissue mass, the specific resting metabolic rates of individual organs and tissues, and the cellular fraction of fat-free mass. DESIGN Fifty-four healthy subjects aged 23-88 y had REE, organ and tissue mass, body cell mass, and fat-free mass measured by indirect calorimetry, magnetic resonance imaging, whole-body (40)K counting, and dual-energy X-ray absoptiometry, respectively. RESULTS REE predicted by the cellular-level model was highly correlated with measured REE (r = 0.92, P < 0.001). The mean difference between measured REE (x+/- SD: 1487 +/- 294 kcal/d) and predicted REE (1501 +/- 300 kcal/d) for the whole group was not significant, and the difference between predicted and measured REE was not associated with age (r = 0.009, NS). CONCLUSION The present approach establishes an REE-body composition link with the use of a model at the cellular level. The combination of 2 aging-related factors (ie, decline in both the mass and the cellular fraction of organs and tissues) may account for the lower REE observed in elderly adults.