Rise or fall? Reconciling contested directions in human gut hormone aging

Gut hormones govern appetite and postprandial glucose handling, and both functions deteriorate with age - yet the human literature cannot agree on the direction of the underlying hormonal changes. Incretin secretion is reported both to rise and to fall in older adults; ghrelin to decline, to be unchanged, and to be elevated; and the anorexia of aging is attributed variously to excess satiety signaling and to deficient basal hunger. This mini-review examines these three controversies, identifies the design features that give rise to them, and argues that they are largely reconcilable. Across all three, disputes about magnitude resolve when the outcome measured is instead the fidelity of coupling between nutrient ingestion and hormonal response: elevated GLP-1 coexists with an impaired incretin effect because it is compensation for β-cell failure, not preserved sensing; ghrelin concentrations may be normal while prandial rhythm is abolished; and older adults with low appetite show exaggerated anorexigenic responses despite unchanged subjective appetite. We further note that the human gut-hormone literature and the rapidly advancing rodent literature on age-related intestinal stem cell misdifferentiation have developed in near isolation, and that they currently disagree on whether the aged gut contains more or fewer enteroendocrine cells. Resolving these controversies requires studies that measure hormone concentrations and functional coupling in the same individuals, as well as longitudinal designs that extend beyond incretins.