Publications
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Lautrup, Sofie Hindkjær; Cao, Shuqin; Long, Xi; Liu, Bonnie Hei Man; Doncel, Beatriz Escobar & Ferrante, Aristide
[Show all 16 contributors for this article]
(2026).
A combined artificial intelligence–wet lab approach identifies a pivotal role of the NAD+–mitophagy axis on aging and neurodegeneration.
Alzheimer's & Dementia.
ISSN 1552-5260.
22(8).
doi:
10.1002/alz.71680.
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Introduction: Emerging evidence points to a role of nicotinamide mononucleotide (NAD+) depletion and compromised mitophagy in aging and neurodegenerative diseases. We hypothesize that age-dependent impairment of the NAD+–mitophagy axis contributes to brain aging and neurodegeneration.
Methods: We analyzed transcriptomic data from 12 human brain regions across 77 integrated public datasets spanning major neurodegenerative diseases and controls to assess NAD+–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.
Results: The NAD+–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.
Discussion: Our study combines artificial intelligence-driven and experimental approaches to identify novel targets for neurodegeneration, revealing disruption of the NAD+–mitophagy axis as a central player in brain aging and AD.
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Wang, Heling; Duque, Gustavo; Siow, Richard; Medina, Tomás Alejandro Schmauck; Zhang, Jianying & Sandset, Per Morten
[Show all 39 contributors for this article]
(2024).
Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway–UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.
The journals of gerontology. Series A, Biological sciences and medical sciences.
ISSN 1079-5006.
79(4).
doi:
10.1093/gerona/glae029.
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Abstract Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.
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Pun, Frank W.; Leung, Geoffrey Ho Duen; Leung, Hoi Wing; Rice, Jared; Schmauck-Medina, Tomás Alejandro & Lautrup, Sofie Hindkjær
[Show all 17 contributors for this article]
(2023).
A comprehensive AI-driven analysis of large-scale omic datasets reveals novel dual-purpose targets for the treatment of cancer and aging.
Aging Cell.
ISSN 1474-9718.
22(12).
doi:
10.1111/acel.14017.
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As aging and tumorigenesis are tightly interconnected biological processes, targeting their common underlying driving pathways may induce dual-purpose anti-aging and anti-cancer effects. Our transcriptomic analyses of 16,740 healthy samples demonstrated tissue-specific age-associated gene expression, with most tumor suppressor genes downregulated during aging. Furthermore, a large-scale pan-cancer analysis of 11 solid tumor types (11,303 cases and 4431 control samples) revealed that many cellular processes, such as protein localization, DNA replication, DNA repair, cell cycle, and RNA metabolism, were upregulated in cancer but downregulated in healthy aging tissues, whereas pathways regulating cellular senescence were upregulated in both aging and cancer. Common cancer targets were identified by the AI-driven target discovery platform—PandaOmics. Age-associated cancer targets were selected and further classified into four groups based on their reported roles in lifespan. Among the 51 identified age-associated cancer targets with anti-aging experimental evidence, 22 were proposed as dual-purpose targets for anti-aging and anti-cancer treatment with the same therapeutic direction. Among age-associated cancer targets without known lifespan-regulating activity, 23 genes were selected based on predicted dual-purpose properties. Knockdown of histone demethylase KDM1A, one of these unexplored candidates, significantly extended lifespan in Caenorhabditis elegans. Given KDM1A's anti-cancer activities reported in both preclinical and clinical studies, our findings propose KDM1A as a promising dual-purpose target. This is the first study utilizing an innovative AI-driven approach to identify dual-purpose target candidates for anti-aging and anti-cancer treatment, supporting the value of AI-assisted target identification for drug discovery.
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Lu, Guang; Tan, Hayden Weng Siong; Schmauck-Medina, Tomás Alejandro; Wang, Liming; Chen, Jiaqing & Cho, Yik-Lam
[Show all 16 contributors for this article]
(2022).
WIPI2 positively regulates mitophagy by promoting mitochondrial recruitment of VCP.
Autophagy.
ISSN 1554-8627.
18(12),
p. 2865–2879.
doi:
10.1080/15548627.2022.2052461.
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The mammalian Atg18 ortholog WIPI2 is a key regulator of LC3 lipidation to promote autophagosome biogenesis during nonselective macroautophagy, while its functions in selective autophagy such as mitophagy remain largely unexplored. In this study, we explored the role of WIPI2 in PINK1-PRKN/parkin-mediated mitophagy. First, we found that WIPI2 is recruited to damaged mitochondria upon mitophagy induction. Second, loss of WIPI2 impedes mitochondrial damaging agents-induced mitophagy. Third, at molecular level, WIPI2 binds to and promotes AAA-ATPase VCP/p97 (valosin containing protein) to damaged mitochondria; and WIPI2 depletion blunts the recruitment of VCP to damaged mitochondria, leading to reduction in degradation of outer mitochondrial membrane (OMM) proteins and mitophagy. Finally, WIPI2 is implicated in cell fate decision as cells deficient in WIPI2 are largely resistant to cell death induced by mitochondrial damage. In summary, our study reveals a critical regulatory role of WIPI2 in mitochondrial recruitment of VCP to promote OMM protein degradation and eventual mitophagy.
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Xie, Chenglong; Zhuang, Xu-Xu; Niu, Zhangming; Ai, Ruixue; Lautrup, Sofie Hindkjær & Zheng, Shuangjia
[Show all 29 contributors for this article]
(2022).
Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow.
Nature Biomedical Engineering.
6(1),
p. 76–93.
doi:
10.1038/s41551-021-00819-5.
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Abstract A reduced removal of dysfunctional mitochondria is common to aging and age-related neurodegenerative pathologies such as Alzheimer’s disease (AD). Strategies for treating such impaired mitophagy would benefit from the identification of mitophagy modulators. Here we report the combined use of unsupervised machine learning (involving vector representations of molecular structures, pharmacophore fingerprinting and conformer fingerprinting) and a cross-species approach for the screening and experimental validation of new mitophagy-inducing compounds. From a library of naturally occurring compounds, the workflow allowed us to identify 18 small molecules, and among them two potent mitophagy inducers (Kaempferol and Rhapontigenin). In nematode and rodent models of AD, we show that both mitophagy inducers increased the survival and functionality of glutamatergic and cholinergic neurons, abrogated amyloid-β and tau pathologies, and improved the animals’ memory. Our findings suggest the existence of a conserved mechanism of memory loss across the AD models, this mechanism being mediated by defective mitophagy. The computational–experimental screening and validation workflow might help uncover potent mitophagy modulators that stimulate neuronal health and brain homeostasis.
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Aman, Yahyah; Schmauck-Medina, Tomás Alejandro; Hansen, M; Morimoto, RI; Simon, AK & Bjedov, I
[Show all 15 contributors for this article]
(2021).
Autophagy in healthy aging and disease.
Nature Aging.
1(8),
p. 634–650.
doi:
10.1038/s43587-021-00098-4.
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Autophagy is a fundamental cellular process that eliminates molecules and subcellular elements, including nucleic acids, proteins, lipids and organelles, via lysosome-mediated degradation to promote homeostasis, differentiation, development and survival. While autophagy is intimately linked to health, the intricate relationship among autophagy, aging and disease remains unclear. This Review examines several emerging features of autophagy and postulates how they may be linked to aging as well as to the development and progression of disease. In addition, we discuss current preclinical evidence arguing for the use of autophagy modulators as suppressors of age-related pathologies such as neurodegenerative diseases. Finally, we highlight key questions and propose novel research avenues that will likely reveal new links between autophagy and the hallmarks of aging. Understanding the precise interplay between autophagy and the risk of age-related pathologies across organisms will eventually facilitate the development of clinical applications that promote long-term health.
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Wang, Heling; Siow, Richard; Schmauck-Medina, Tomás Alejandro; Zhang, Jianying; Sandset, Per Morten & Filshie, Clare
[Show all 38 contributors for this article]
(2024).
Meeting Summary of The NYO3 5th NO-Age/AD Meeting and the 1st Norway-UK Joint Meeting on Aging and Dementia: Recent Progress on the Mechanisms and Interventional Strategies.
The journals of gerontology. Series A, Biological sciences and medical sciences.
ISSN 1079-5006.
79(4),
p. 1–10.
doi:
10.1093/gerona/glae029.
Full text in Research Archive
Show summary
Unhealthy aging poses a global challenge with profound healthcare and socioeconomic implications. Slowing down the aging process offers a promising approach to reduce the burden of a number of age-related diseases, such as dementia, and promoting healthy longevity in the old population. In response to the challenge of the aging population and with a view to the future, Norway and the United Kingdom are fostering collaborations, supported by a “Money Follows Cooperation agreement” between the 2 nations. The inaugural Norway–UK joint meeting on aging and dementia gathered leading experts on aging and dementia from the 2 nations to share their latest discoveries in related fields. Since aging is an international challenge, and to foster collaborations, we also invited leading scholars from 11 additional countries to join this event. This report provides a summary of the conference, highlighting recent progress on molecular aging mechanisms, genetic risk factors, DNA damage and repair, mitophagy, autophagy, as well as progress on a series of clinical trials (eg, using NAD+ precursors). The meeting facilitated dialogue among policymakers, administrative leaders, researchers, and clinical experts, aiming to promote international research collaborations and to translate findings into clinical applications and interventions to advance healthy aging.
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Schmauck-Medina, Tomás Alejandro; Patrick-Brown, Dawn Judith; Zhang, Shi-qi; Gilbert, Alexandra & Fang, Fei
(2022).
Molecular linkages among Aβ, tau, impaired mitophagy, and mitochondrial dysfunction in Alzheimer’s disease.
In Hamano, Tadanori & Mutoh, Tatsuro (Ed.),
Autophagy Dysfunction in Alzheimer's Disease and Dementia.
Academic Press.
ISSN 9780323899062.
p. 91–109.
Full text in Research Archive
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Schmauck-Medina, Tomás Alejandro; Molière, Adrian; Lautrup, Sofie Hindkjær; Zhang, Jianying; Chlopicki, Stefan & Madsen, Helena Borland
[Show all 21 contributors for this article]
(2022).
New hallmarks of ageing: a 2022 Copenhagen ageing meeting summary.
Aging.
14(16),
p. 6829–6839.
doi:
10.18632/aging.204248.
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Genomic instability, telomere attrition, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient-sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication were the original nine hallmarks of ageing proposed by López-Otín and colleagues in 2013. The proposal of these hallmarks of ageing has been instrumental in guiding and pushing forward research on the biology of ageing. In the nearly past 10 years, our in-depth exploration on ageing research has enabled us to formulate new hallmarks of ageing which are compromised autophagy, microbiome disturbance, altered mechanical properties, splicing dysregulation, and inflammation, among other emerging ones. Amalgamation of the ‘old’ and ‘new’ hallmarks of ageing may provide a more comprehensive explanation of ageing and age-related diseases, shedding light on interventional and therapeutic studies to achieve healthy, happy, and productive lives in the elderly.
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Back, Erica Caci; Kjendseth, Åsmund Røhr; Fang, Evandro Fei & Medina, Tomás Alejandro Schmauck
(2023).
The effects of Rapamycin on Lifespan and Healthspan in Caenorhabditis elegans atg-18 mutants.
Norges miljø- og biovitenskapelige universitet (NMBU).
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Aging is a biological process causing loss of physical integrity, reduced function, and higher vulnerability to death. Aging also increases the risk of major human diseases including cancer, diabetes, cardiovascular disorders, and neurodegenerative disorders like dementia. Research on aging and age-related diseases is important to improve human health during aging to minimize the global socioeconomic burden and challenges in healthcare. Autophagy is a cellular clearance pathway which promotes homeostasis in the cells and is proposed as a hallmark of aging. A disruption of autophagy is shown to accelerate age-related aggregation of proteins and shorten lifespan in several model organisms. An increase in autophagy e.g., by the autophagy-inducer rapamycin has shown suppressed protein aggregation as well as promoted health and longevity. Studies have shown that induction of autophagy by treatment with rapamycin in the widely used nematode Caenorhabditis elegans extends lifespan and healthspan parameters. This study aimed to investigate the effects of rapamycin treatment with a malfunctioning autophagy-machinery to see whether the treatment can affect lifespan and/or healthspan without affecting autophagy. C. elegans atg-18(gk378) with a loss-of-function mutation causing a malfunctional autophagy-machinery were investigated. Lifespan assay, as well as the healthspan assays pharyngeal pumping and thrashing were performed in the mutant and in a WT strain to examine the effects of the treatment. The lifespan assay showed a decreased lifespan for the mutants treated with rapamycin, suggesting that rapamycin might affect other mechanisms related to the process of aging with a negative effect. Considering that the thrashing assay might be a more reliable healthspan parameter than the pumping assay, rapamycin-treatment seemed to increase healthspan of the mutants as well as for the WT. To validate the effect of rapamycin on autophagy and the mammalian ATG-18 homolog WIPI2, HeLa cells with GFP-tagged WIPI2B were treated with rapamycin. Imaging of the cells clearly showed an increase in autophagy after 24 hours of treatment. Imaging as well as Western Blots suggested that 2 hours of treatment is not sufficient to show an effect of rapamycin-treatment. This study suggests that rapamycin decreases the lifespan of C. elegans atg-18(gk378) mutants, but to some degree promote healthier aging. The mechanisms seemingly affected by rapamycin in the C. elegans mutants may be interesting for further investigation. Not only in C. elegans, but also using other model organisms to investigate the replicability of the results in other models.
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Published
May 23, 2025 3:16 PM
- Last modified
June 18, 2025 2:01 PM
