Abstract
Mitochondrial homeostasis is majorly maintained through mitochondrial autophagy (mitophagy). Recent research highlights the region- and cell type-specific nature of mitophagy during brain aging; however, these dynamics have largely remained unexplored in living brains. To address this gap, we conducted two-photon mt-Keima imaging in somatosensory cortical neurons and astrocytes in behaving male mice across two age groups, including 2–3-month-old (early-aged) and 18–20-month-old (old-aged) mice. We show reduced mitophagy in both cell types during aging, and we consistently found a higher level of mitophagy in astrocytes compared to neurons at the same age, in both age groups. Pharmacological augmentation of NAD+, a pivotal metabolite that induces mitophagy but normally declines in the aging brain, increased cellular mitophagy in both neurons and astrocytes in old-aged male mice at the dose and method of administration tested. Collectively, our data support an age-dependent reduction of mitophagy in neurons and astrocytes, at least in mouse somatosensory cortex, while NAD+ repletion offsets such reduction.
Acknowledgements
We thank Prof. Nuo Sun and Prof. Toren Finkel for providing the mt-Keima-based cell line with consent from the original owner. This work is supported by: Research Council of Norway (M.F.D.L.P. and B.E.D.’s PhD program is supported by Research Council of Norway #262552 and #334361, respectively; #262175), HELSE MIDT-NORGE (#28293, #40895), Felles forskningsutvalg (FFU, #34226), NTNU Discovery (#998012207, #102807120), Cure Alzheimer’s Fund (#282952), HELSE SØR-ØST (#2020001, #2021021, #2023093), Molecule AG/VITADAO (#282942), NordForsk Foundation (#119986), the National Natural Science Foundation of China (#81971327), Akershus University Hospital (#269901, #261973, #262960), the Civitan Norges Forskningsfond for Alzheimers sykdom (#281931), the Czech Republic-Norway KAPPA program (with Martin Vyhnálek, #TO01000215), the Rosa sløyfe/Norwegian Cancer Society & Norwegian Breast Cancer Society (#207819), HORIZON-TMA-MSCA-DN (#101073251, with Riekelt Houtkooper), Wellcome Leap’s Dynamic Resilience Program (jointly funded by Temasek Trust, #104617), and Childhood dementia project at Norwegian University of Science and Technology.
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Open access funding provided by NTNU Norwegian University of Science and Technology (incl St. Olavs Hospital - Trondheim University Hospital); Please verify relation to: NTNU Norwegian University of Science and Technology (incl St. Olavs Hospital - Trondheim University Hospital).
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W.T. is the owner of ProverBio Gene Consult AS (Organization number 936379117). E.F.F. is a co-owner of Fang-S Consultation AS (Organization number 931410717) and NO-Age AS (Organization number 933 219 127); he has an MTA with LMITO Therapeutics Inc (South Korea), a CRADA arrangement with ChromaDex (USA), a commercialization agreement with Molecule AG/VITADAO; he is a consultant to MindRank AI (China), NYO3 (Norway), and AgeLab (Vitality Nordic AS, Norway). Author E.F.F is an Editorial Board Member of journal npj Aging. E.F.F was not involved in the journal’s review of, or decisions related to, this manuscript. The other authors declare no competing financial or non-financial interests.
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Escobar-Doncel, B., Zhang, X., Ljøstad, Å. et al. Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging. npj Aging (2026). https://doi.org/10.1038/s41514-026-00414-5
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DOI: https://doi.org/10.1038/s41514-026-00414-5
