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A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD<sup>+</sup>-mitophagy axis on aging and neurodegeneration.

Lautrup S, Cao SQ, Long X, Liu BHM, Escobar-Doncel B, Ferrante A, Frank J, Schmauck-Medina T, Leung GHD, Liang KX, Lu N, Veverova K, Vyhnalek M, Pun FW, Zhavoronkov A

Alzheimer's & dementia : the journal of the Alzheimer's Association · 2026

Stem-cell exhaustion Disabled macroautophagy C. elegans Human
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Abstract

<h4>Introduction</h4>Emerging evidence points to a role of nicotinamide mononucleotide (NAD<sup>+</sup>) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD<sup>+</sup>-mitophagy axis contributes to brain aging and neurodegeneration.<h4>Methods</h4>We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD<sup>+</sup>-mitophagy axis alterations, focusing on Alzheimer's disease (AD). Key targets were validated in Caenorhabditis elegans, a human Tau cell model, and induced pluripotent stem cell (iPSC)-derived cortical neurons.<h4>Results</h4>The NAD<sup>+</sup>-mitophagy axis is more severely dysregulated in neurodegeneration than in brain aging. Integrating computational and experimental approaches, we identified five AD-protective genes (ULK1, OPA1, LAMP2, MFN1, and ATP6V0E1) linked to synaptic resilience and/or reduced Tau pathology.<h4>Discussion</h4>Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD<sup>+</sup>-mitophagy axis as a central player in brain aging and AD.

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Provenance

Source
Europe PMC
DOI
10.1002/alz.71680
Canonical
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Fetched
2026-10-10 MST

Cite this

APA
S, L., SQ, C., X, L., BHM, L., B, E., A, F., J, F., T, S., GHD, L., KX, L., N, L., K, V., M, V., FW, P., A, Z., &amp; EF., F. (2026). A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD&lt;sup&gt;+&lt;/sup&gt;-mitophagy axis on aging and neurodegeneration. <em>Alzheimer's & dementia : the journal of the Alzheimer's Association</em>. https://doi.org/10.1002/alz.71680
Vancouver
S L, SQ C, X L, BHM L, B E, A F, et al. A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD&lt;sup&gt;+&lt;/sup&gt;-mitophagy axis on aging and neurodegeneration. Alzheimer's & dementia : the journal of the Alzheimer's Association. 2026. doi:10.1002/alz.71680.
BibTeX
@article{lautrup2026Acombi, title = {A combined artificial intelligence-wet lab approach identifies a pivotal role of the NAD&lt;sup&gt;+&lt;/sup&gt;-mitophagy axis on aging and neurodegeneration.}, author = {Lautrup S and Cao SQ and Long X and Liu BHM and Escobar-Doncel B and Ferrante A and Frank J and Schmauck-Medina T and Leung GHD and Liang KX and Lu N and Veverova K and Vyhnalek M and Pun FW and Zhavoronkov A and Fang EF.}, journal = {Alzheimer's & dementia : the journal of the Alzheimer's Association}, year = {2026}, doi = {10.1002/alz.71680}, }

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