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Vol.: (0123456789)GeroScience (2025) 48:2827–2850 https://doi.org/10.1007/s11357-025-01786-4ORIGINAL ARTICLETreatment of age?related decreases in GTP levels restores endocytosis and autophagyR. A. Santana · J. M. McWhirt · G. J. BrewerReceived: 27 March 2025 / Accepted: 30 June 2025 / Published online: 2 August 2025 © The Author(s) 2025Abstract Age-related declines in neuronal bio-energetic levels may limit vesicular traf f i cking and autophagic clearance of damaged organelles and proteins. Age-related ATP depletion would impact cognition dependent on ionic homeostasis, but limits on proteostasis powered by GTP are less clear. We used neurons isolated from aged 3xTg-AD Alzheimer’s model mice and a novel geneti-cally encoded fl uorescent GTP sensor (GEVAL) to evaluate live GTP levels in situ. We report an age-dependent reduction in ratiometric measurements of free/bound GTP levels in living hippocampal neurons. Free GTP colocalized in the mitochondria decreased with age accompanied by the accumula-tion of free GTP-labeled vesicular structures. The energy dependence of autophagy was demonstrated by depletion of GTP with rapamycin stimulation, while baf i lomycin inhibition of autophagy raised GTP levels. Twenty-four-hour supplementation of aged neurons with the NAD precursor nicotina-mide and the Nrf2 redox modulator EGCG restored GTP levels to youthful levels and mobilized endo-cytosis and lysosomal consumption for autophagy via the respective GTPases Rab7 and Arl8b. This vesicular mobilization promoted the clearance of intraneuronal Aβ aggregates, improved viabil-ity, and lowered protein oxidative nitration in AD model neurons. Our results reveal age- and AD-related neuronal GTP energy def i cits that impair autophagy and endocytosis. GTP def i cits were remediated by an external NAD precursor together with a Nrf2 redox modulator which suggests a translational path.Graphical Abstract Keywords Alzheimer · Neuron · Aging · Energetics · Redox · Nicotinamide · EGCG R. A. Santana · J. M. McWhirt · G. J. Brewer (*) Department of Biomedical Engineering, University of California Irvine, Irvine, CA 92697, USAe-mail: GJBrewer@uci.eduG. J. Brewer Center for Neurobiology of Learning and Memory, University of California Irvine, Irvine, CA 92697, USAG. J. Brewer Institute for Memory Impairments and Neurological Disorders, University of California Irvine, Irvine, CA 92697, USA