Fei Fang-Stavem

• Fang EF, Scheibye-Knudsen M, Brace L, Kassahun H, SenGupta T, Nilsen H, Mitchell JR, Croteau DL, Bohr VA (2014). Defective Mitophagy in XPA via PARP1 hyperactivation and NAD+/SIRT1 reduction, Cell, 157 (4): 882-896. This paper offers first evidence that compromised mitophagy exacerbates accelerated aging
• Fang EF, Kassahun H, Croteau DL, Scheibye-Knudsen M, Marosi K, Lu H, Shamanna RA, Kalyanasundaram S, Bollineni RC, Wilson MA, Iser WB, Wollman BN, Morevati M, Li J, Kerr JS, Lu Q, Waltz TB, Tian J, Sinclair DA, Mattson MP, Nilsen H, Bohr VA (2016). NAD+ replenishment improves lifespan and healthspan in Ataxia telangiectasia models via mitophagy and DNA repair, Cell Metabolism, 24, 566-581. This feature article of the issue describes NAD+ induces mitophagy through DCT-1
• Fang EF, Palikaras K, Sun N, Fivenson EM, Spangler RD, Kerr JS, Cordonnier SA, Hou Y, Dombi E, Kassahun H, Tavernarakis N, Poulton J, Nilsen H, Bohr VA. In Vitro and In Vivo Detection of Mitophagy in Human Cells, C. Elegans, and Mice, JOVE, 2017, In press. This method paper summarizes mitophagy detection methods in cross-species model systems
• Fang EF, Scheibye-Knudsen M, Chua KF, Mattson MP, Croteau DL, Bohr VA (2016). Nuclear DNA damage signalling to mitochondria in ageing, Nature Rev Mol Cell Bio, 17(5):308-321. This review paper proposes a novel concept to the aging theory
• Fang EF, Lautrup S, Hou Y, Demarest TG, Croteau DL, Mattson MP, Bohr VA. NAD+ in aging: Molecular mechanisms and translational implicationis. Trends Mol Med. 2017, in press. This Feature review summarizes latest progress of NAD+ in aging, and suggests compromised autophagy as the 10th hall marker of aging. 
• Kerr JS, Adriaanse BA, Greig NH, Mattson MP, Cader MZ, Bohr VA*, Fang EF*. Mitophagy and Alzheimer’s disease: Cellular and molecular mechanisms, Trends in Neurosciences, 40(3):151-166 (*Corresponding author). This review proposes compromised mitophagy as a new concept in AD etiology.
•  Fang EF*, Hou Y, Palikaras K, et al, Mattson MP, Tavernarakis N, Bohr VA*. ­­Mitophagy inhibits Aβ and p-Tau pathologies and cognitive deficits in experimental models of Alzheimer’s disease. Nature Neuroscience, 2019, 22(3):401-412 (* corresponding author).Highlighted in Nature Reviews Drug Discovery ;     News in VG (the largest newspaper in Norway, 12 Feb 2019 Issue );   News in NRKHighlighted in ALZFORUM ; University of Copenhagen; National Institute on Ageing ; ScienceNordic;  NHI news;   NHI Facebook
• Lautrup S, Sinclair DA, Mattson MP, Fang EF*. NAD⁺ in Brain Aging and Neurodegenerative Disorders. Cell Metabolism, 2019.
• Aman, Y., T. Schmauck-Medina, M. Hansen, R. I. Morimoto, A. K. Simon, I. Bjedov, K. Palikaras, A. Simonsen, T. Johansen, N. Tavernarakis, D. C. Rubinsztein, L. Partridge, G. Kroemer, J. Labbadia*, Fang EF* (2021). "Autophagy in healthy ageing and disease." Nature Aging 1: 634-650.
• Xie, C., X. X. Zhuang, Z. Niu, R. Ai, S. Lautrup, S. Zheng, Y. Jiang, R. Han, T. SenGupta, S. Cao, M. J. Lagartos-Donate, C. Z. Cai, L. M. Xie, D. Caponio, W. W. Wang, T. Schmauck-Medina, J. Zhang, H. L. Wang, G. Lou, X. Xiao, W. Zheng, K. Palikaras, G. Yang, K. A. Caldwell, G. A. Caldwell, H. M. Shen, H. Nilsen, J. H. Lu* and Fang E.F*. "Amelioration of Alzheimer’s disease pathology by mitophagy inducers identified via machine learning and a cross-species workflow." Nature Biomed Eng., 2022.
• Presterud R, Deng WH, Wennerström AB, Burgers T, Gajera B, Mattsson K, Solberg A, Fang EF, Nieminen AI, Stray-Pedersen A, Nilsen H. Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia. Mov Disord. 2023. （A 2-year NR-based (longest by Nov 2023) clinical trial in treating A-T patients with significant benefits）.
• Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease. Kateřina Veverová, Jan Laczó, Alžběta Katonová, Hana Horáková, Veronika Matušková, Francesco Angelucci, Martina Laczó, Zuzana Nedelská, Jakub Hort, He-Ling Wang, Jianying Zhang, Liu Shi, Fang EF*, Vyhnálek V*. Autophagy, 2024. One of the top 11 discoveries in all fields in the Czech Republic in 2024 • Czech Neuropsychophamacological Society awarded it as the best clinical study of 2024.
• Cao SQ, Jiménez-Loygorri JI, Qiu Y, Kang YJ, Do KV, Smith AE, Huang J, Pan JP, Mao L, Li A, Yang H, Aman Y, Lagartos MJD, Lautrup SH, Chen A, Liang KX, Zhang H, Yi J, Jin X, Cheung TC, Apokotou O, Papastefanaki F, Matsas R, McEwan WA, Cheng F, Cho H, Chen G, Su H, Palikaras K, Luo OJ, Zhao QH, Ding D, van Duijn C, Tavernarakis N, Boya P*, Tencomnao T*, Fang EF*. The Mitochondrial Guardian α-Amyrin Mitigates Alzheimer's Disease Pathology via Modulation of the DLK-SARM1-ULK1 Axis. Adv Sci (Weinh). 2026.
• Fang EF^#,*, Fang Y#,*, Chen G, Wang HL, Zhang J, Wu C, Liao J, Xie C, Liu X, Wang K, Liu Y, Yang G, Wang Q, He LT, Li J, Chen HZ, Kang L, Jiang Y, Su H, Jiang H, He N, Tao J, Leng SX, Siow RC, Liu C, Khan HTA, Liu Y, Kato H, Sasaki T, Kim JI, Maier AB, Zhang L, Rasmussen LJ, Woo J, Wu J*, Zou H*. Adapting health, economic and social policies to address population aging in China. Nature Aging. 2025.
• Zhang J, Wang HL, Lautrup S, Nilsen HL, Treebak JT, Watne LO, Selbæk G, Wu LE, Omland T, Pirinen E, Cheung TC, Wang J, Ziegler M, Tysnes OB, Zapata-Pérez R, Bruzzone S, Canto C, Deleidi M, Janssens GE, Houtkooper RH, Scheibye-Knudsen M, Koshizaka M, Yokote K, Verdin E, Bohr VA, Tzoulis C, Sinclair DA, Fang EF. Emerging strategies, applications and challenges of targeting NAD+ in the clinic. Nature Aging. 2025.
• Ambrosio F, Artyomov MN, Austad SN, Barzilai N, Belmonte JCI, Belsky DW, Benayoun BA, Brunet A, Dönertaş HM, Dubal DB, Fang EF, Feige JN, Fried LP, Furman D, Gao X, Gladyshev VN, Gorbunova V, Gorospe M, Han JJ, Hansson O, Hara E, Horvath S, Ip NY, Kuchel GA, Kaeberlein M, Lamming DW, Levy BR, Liu GH, Lee J, Moffitt TE, Minamino T, Partridge L, Raina P, Rando TA, Rowe JW, Schwartz M, Scott AJ, Sierra F, Sinclair DA, Teunissen CE, Vellas B, Verdin E, Walker KA, Webb AE, Wyss-Coray T, Xu M, Yu JT, Zhavoronkov A, Aman Y, Kriebs A, Ren Q, Walters H, Thuault S. Past, present and future perspectives on the science of aging. Nature Aging. 2026.
• Lagartos-Donate MJ*, Escobar-Doncel B, Zhang SQ, Pan JP, Villaseca González N, Anisimov A, Montaldo NP, Jensen V, Mao L, Li B, Banzon-Pereira N, Shi L, Cao SQ, Caponio D, Wang P, Nair RR, Luo OJ, Chen G, Nevado-Holgado AJ, Buckley N, Nilsen HL, Fang EF*. Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD. Brain. 2026.

• Schmauck-Medina T, Lautrup S, Di Francesco A, Mitchell SJ, Clemmensen C, Partridge L, Roth GS, Anderson RM, Mattison JA, de Cabo R, Speakman JR, Richardson A, Ingram DK, Weindruch R, Mattson MP*, Fang EF*. Dietary restriction in aging and longevity. Nature Aging. 2026.

  All publications 

• https://pubmed.ncbi.nlm.nih.gov/?term=fang+ef&sort=date 

• 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. Full text in Research Archive Show summary

  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.

• Pan, Junping; Zhang, Jianying; Wang, Ping Jie; Chen, Guobing & Fang-Stavem, Fei (2026). Mitophagy mitigates tau acetylation via the ULK1-NAD⁺/SIRT1 axis in Alzheimer’s disease. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2026.2689031. Full text in Research Archive
• Doncel, Beatriz Escobar; Zhang, Xiaoyi; Ljøstad, Åsne; Puebla, Mario Fernández de la; Shreyas, Rao & Fjeldstad, Synnøve Algrøy [Show all 11 contributors for this article] (2026). Two-photon in vivo imaging reveals cell type-specific mitophagy dynamic changes in mouse somatosensory cortex during aging. npj Aging. 12. doi: 10.1038/s41514-026-00414-5. Full text in Research Archive Show summary

  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.

• Suaste, Veronica; Presterud, Rebecca; Wennerström, Anna Berit; Wang, Heling; Zhang, Jianying & Lund, Solveig Osnes [Show all 16 contributors for this article] (2026). Transcriptional Profiling Shows Dampening of Interferon Gene Signatures by NAD Augmentation in Ataxia-Telangiectasia. International Journal of Molecular Sciences. ISSN 1661-6596. 27(13). doi: 10.3390/ijms27135652. Full text in Research Archive Show summary

  Ataxia-Telangiectasia (A-T) is a multisystem disorder caused by loss of A-T mutated (ATM) protein activity, characterized clinically by immunodeficiency and cerebellar ataxia. ATM is a master regulator of DNA damage responses and loss of ATM function is accompanied by persistent activation of PARP1 leading to depletion of intracellular NAD+ and dysfunction of a series of cellular signalling pathways dependent on NAD+, providing a mechanistic rationale for NAD+ augmentation therapy. We performed a clinical trial of NAD+ augmentation with nicotinamide riboside (NR) over 24 months in A-T patients where we observed improved coordination and eye movements in A-T patients. Here, by using peripheral blood mononuclear cells, we performed longitudinal transcriptome profiling to define molecular signatures of A-T and to assess pathway-level responses to NR supplementation. A-T patients exhibited reproducible transcriptomic alterations involving immune, vascular, and inflammatory pathways. NAD+ augmentation was associated with suppression of interferon response genes and modulation of networks correlated with neurological improvement. These findings establish systemic molecular signatures of A-T and identify potential blood-based biomarkers that reflect disease processes and therapeutic response, supporting the use of NAD+ augmentation as a disease-modifying strategy in A-T by dampening interferon signalling.

• Dong, Yu; Xiao, Xianglu; Zhuang, Xu Xu; Wu, Wenfan; Fang-Stavem, Fei & Yang, Guang [Show all 8 contributors for this article] (2026). AI-Driven discovery of brain-penetrant mTOR-independent autophagy enhancers for Alzheimer’s disease. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2026.2679639. Full text in Research Archive
• Huang, Ze Bo; Lin, Jin Yi; Cheng, Ling Jun; Wu, Yong; Gao, Xiang Zheng & Zhang, Yichi [Show all 15 contributors for this article] (2026). STING-OPTN signaling confers cytoprotection through TBK1-dependent mitophagy. Cell reports. 45(6). doi: 10.1016/j.celrep.2026.117515. Full text in Research Archive
• Cao, Shuqin; Jiménez-Loygorri, Juan Ignacio; Qiu, Yunguang; Kang, You Jung; Do, Khanh Van & Smith, Annabel E. [Show all 37 contributors for this article] (2026). The Mitochondrial Guardian α-Amyrin Mitigates Alzheimer's Disease Pathology via Modulation of the DLK-SARM1-ULK1 Axis. Advanced Science. 13(24). doi: 10.1002/advs.202512374. Full text in Research Archive Show summary

  ABSTRACT High consumption of colorful fruits and vegetables correlates with low dementia risk, but the exact molecules and the underlying biological mechanisms governing their bioactive profiles are largely unknown. Using a 10‐year observational cohort study coupled with an AI‐driven systems pharmacology platform, we identified a natural triterpenoid compound found in colorful fruits and vegetables, α‐Amyrin (αA), as a therapeutic candidate for Alzheimer's disease (AD). The efficacy of αA in treating the symptoms of AD, such as Tau tangles, damaged mitochondria, and memory loss, was examined using cross‐species models; αA retained memory in AD‐like animal models while also strongly inhibiting Tau pathology, especially p‐Tau217, in a cellular ‘Tau seeding’ system and in Tau[P301S] mice, followed by validation using a human 3D microfluidic system. At molecular level, αA is a robust mitochondrial regulator, enhancing mitochondrial stress resilience and activation of mitophagy. Mechanistically, αA inhibits dual leucine zipper kinase (DLK), leading to the inhibition of DLK‐Sterile Alpha and TIR Motif Containing 1 (SARM1)‐dependent neurodegeneration; this inhibition frees unc‐51 Like Autophagy Activating Kinase 1 (ULK1) from the ULK1‐SARM1 complex, allowing it to participate in autophagy/mitophagy. αA also shows strong translational potential with a 10.1 h half‐life and the ability to cross the blood‐brain barrier. Our results indicate that αA may act as a mitochondrial guardian against AD via modulating the DLK‐SARM1‐ULK1‐autophagy/mitophagy axis while further preclinical and clinical studies are warranted.

• Pan, Junping; Wang, Ping-Jie; Zhang, Jianying; Knapskog, Anne-Brita; Watne, Leiv Otto & Wang, He-Ling [Show all 40 contributors for this article] (2026). Reduced ULK1 links impaired autophagy and mitophagy to Alzheimer’s disease pathology. Nature Aging. 6(5), p. 1079–1102. doi: 10.1038/s43587-026-01108-z. Full text in Research Archive
• Dekan, Aleksandr; Lore, Sierra; Yoon, Ye Eun; Sjöholm, Aisyah; Tyshkovskiy, Alexander & Terskikh, Alexey [Show all 105 contributors for this article] (2026). Toward actionable interventions in human aging (12th ARDD meeting, 2025). Aging. 18, p. 282–302. doi: 10.18632/aging.206368. Full text in Research Archive
• Dong, Yu; Xiao, Xianglu; Zhuang, Xu Xu; Wu, Wenfan; Wang, Zi Ying & Zhang, Shuang [Show all 29 contributors for this article] (2026). DeepDrugDiscovery identifies blood–brain barrier permeable autophagy enhancers for Alzheimer’s disease. Nature Biomedical Engineering. doi: 10.1038/s41551-026-01667-x. Full text in Research Archive
• Wang, Pingjie; Tan, Yang; Fan, Zhe; He, Shilin; Chen, Chunxiao & Sun, Ying [Show all 12 contributors for this article] (2026). High-Sugar Consumption Induces Anxiety-Like Behavior via Activating the Glutamatergic Neurons in the Nucleus of the Solitary Tract in Mice. Biology (Basel). 15(8). doi: 10.3390/biology15080646. Full text in Research Archive
• Lin, Jin Yi; Huang, Ze Bo; Fang-Stavem, Fei & Lu, Guang (2026). STUB1-VCP/p97 limits PINK1 overaccumulation to safeguard mitophagy and memory. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2026.2658848. Full text in Research Archive
• Lagartos, Maria Jose Donate; Doncel, Beatriz Escobar; Zhang, Shi-qi; Pan, Junping; González, Noemí Villaseca & Anisimov, Aleksander [Show all 22 contributors for this article] (2026). Loss of REST associated with Alzheimer's disease pathology is ameliorated by NAD+. Brain. ISSN 0006-8950. 149(4), p. 1208–1223. doi: 10.1093/brain/awaf261. Full text in Research Archive Show summary

  Downregulation and inactivation of the Repressor Element 1-Silencing Transcription factor (REST) is shown in Alzheimer’s disease (AD) and likely contributes to its progression, but the exact molecular mechanism linking REST reduction to AD remains unclear. We examined changes in REST expression in the entorhinal cortex and hippocampus across different Braak stages of tauopathy. We show that alterations in REST expression and sub-cellular localization are partially responsible for AD pathology, as REST overexpression improves cognition, reduces amyloid-β and phosphorylated Tau deposition, and restores mitochondrial and synaptic homeostasis. Mechanistically, the NAD+/SIRT1 axis modulates REST expression through chromatin remodelling in the promoter region of REST, leading to changes in the expression of REST target genes involved in mitophagy and synaptic function. These findings reveal a new mechanism of action for NAD+ and highlight REST as a promising therapeutic target for AD therapy.

• Li, Ang; Xiao, Xianglu; Liu, Guopan; Li, Krinos; Ling, Yixia & Deng, Shenglong [Show all 14 contributors for this article] (2026). Isoginkgetin protects against degeneration of ALS motor neurons via regulating the GSK-3β–TFEB signaling axis. Pharmacological Research. ISSN 1043-6618. 227. doi: 10.1016/j.phrs.2026.108172. Full text in Research Archive
• Lin, Jin Yi; Huang, Ze Bo; Zhang, Shi-qi; Wu, Yong; Cheng, Ling Jun & Gao, Xiangzheng [Show all 17 contributors for this article] (2026). STUB1-VCP/p97 complex regulates mitophagy via fine-tuning of PINK1 levels. Cell reports. 45(4). doi: 10.1016/j.celrep.2026.117183. Full text in Research Archive
• He, Haijun; Ai, Ruixue; Fang-Stavem, Fei & Palikaras, Konstantinos (2025). The Rab3 family proteins in age-related neurodegeneration: unraveling molecular pathways and potential therapeutic targets. npj Aging. 11(1). doi: 10.1038/s41514-025-00257-6. Full text in Research Archive
• Ai, Ruixue; Mao, Lipeng; Jin, Xurui; Campos-Marques, Carlos; Zhang, Shi-qi & Pan, Junping [Show all 33 contributors for this article] (2025). NAD+ reverses Alzheimer’s neurological deficits via regulating differential alternative RNA splicing of EVA1C. Science Advances. 11(45). doi: 10.1126/sciadv.ady9811. Full text in Research Archive Show summary

  Dysfunctional alternative splicing events (ASEs) in RNA are markers of aging and Alzheimer’s disease (AD). As a key neuronal resilience metabolite, the oxidized nicotinamide adenine dinucleotide (NAD+) slows down AD progression in preclinical studies with several clinical trials ongoing. However, the underlying molecular mechanisms around how NAD+ enhances neuronal resilience, especially whether it has any effect on ASEs, have remained elusive. This study shows that NAD+ augmentation corrects the ASEs of many genes via a key protein, EVA1C (epithelial V-like antigen 1 homolog C), which is involved in neuronal development and activities. EVA1C is reduced in the hippocampus in patients with AD compared to cognitively normal ones. NAD+-induced memory retention is partially dependent on EVA1C, as adeno-associated virus–based Eva1c knockdown in the hippocampal CA1 region annuls NAD+-induced memory improvement in pathological Tau–bearing mice. We propose that NAD+ reduces AD pathologies, at least partially, via amplification of the NAD+-EVA1C splicing axis, pointing to a potential splice-switching therapy for AD.

• Li, Ang; Huang, Sen; Cao, Shuqin; Lin, Jinyi; Zhao, Linping & Yu, Feng [Show all 23 contributors for this article] (2025). Isoginkgetin antagonizes ALS pathologies in its animal and patient iPSC models via PINK1-Parkin-dependent mitophagy. EMBO Molecular Medicine. ISSN 1757-4676. 17(11), p. 3139–3173. doi: 10.1038/s44321-025-00323-2. Full text in Research Archive Show summary

  Damaged mitochondria initiate mitochondrial dysfunction-associated senescence, which is considered to be a critical cause for amyotrophic lateral sclerosis (ALS). Thus, mitophagic elimination of damaged mitochondria provides a promising strategy in ALS treatment. Here, through screening of a large natural compound library (n = 9555), we have identified isoginkgetin (ISO), a bioflavonoid from Ginkgo biloba, as a robust and specific mitophagy inducer. ISO enhances PINK1–Parkin-dependent mitophagy via stabilization of the PINK1/TOM complex. In a translational perspective, ISO antagonizes ALS pathology in C. elegans and mouse models; intriguingly, ISO improves mitochondrial function and antagonizes motor neuron pathologies in three ALS patient-derived induced pluripotent stem cell systems (C9, SOD1, and TDP-43), highlighting a potential broad application to ALS patients of different genetic background. At the molecular level, ISO inhibits ALS pathologies in a PINK1–Parkin-dependent manner, as depletion or inhibition of PINK1 or Parkin blunts its benefits. These results support the hypothesis that mitochondrial dysfunction is a driver of ALS pathology and that defective mitophagy is a druggable therapeutic target for ALS.

• Fang-Stavem, Fei; Fang, Yuan; Chen, Guobing; Wang, He-Ling; Zhang, Jianying & Wu, Chenkai [Show all 36 contributors for this article] (2025). Adapting health, economic and social policies to address population aging in China. Nature Aging. 5, p. 2176–2187. doi: 10.1038/s43587-025-00999-8. Full text in Research Archive Show summary

  Despite its rapid economic rise over the past four decades, China now grapples with the challenge of accommodating and supporting its expanding aging population. In 2020, 18% of its population were over age 60, and 2.5% were over age 80, projected to rise to 39% and 10%, respectively, by 2050. This demographic shift places China at the forefront of diverse individual, familial and societal challenges. Here, we review these challenges in the context of emerging breakthroughs in basic and translational research, shifts in healthcare paradigms, evolving socioeconomic and political dynamics, and policy innovations. We synthesize China’s current policies toward promoting healthy longevity in the general population, focusing on social health insurance, long-term care insurance, community and home-based care and palliative care, as well as gerontological research, public health prevention, nutritional and medical interventions, while identifying strengths and gaps. Finally, we propose suggestions to promote a more inclusive, resilient and happier aging society within China’s distinctive sociopolitical and cultural context. China’s dramatic demographic shift toward population aging raises challenges at the individual, familial and societal levels. Fang et al. review these challenges and emerging policies designed to promote healthy longevity in China.

• Zhang, Jianying; Wang, Heling; Lautrup, Sofie Hindkjær; Nilsen, Hilde; Treebak, Jonas T. & Watne, Leiv Otto [Show all 28 contributors for this article] (2025). Emerging strategies, applications and challenges of targeting NAD+ in the clinic. Nature Aging. 5(9), p. 1704–1731. doi: 10.1038/s43587-025-00947-6. Full text in Research Archive Show summary

  Beyond their classical functions as redox cofactors, recent fundamental and clinical research has expanded our understanding of the diverse roles of nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) in signaling pathways, epigenetic regulation and energy homeostasis. Moreover, NAD and NADP influence numerous diseases as well as the processes of aging, and are emerging as targets for clinical intervention. Here, we summarize safety, bioavailability and efficacy data from NAD+-related clinical trials, focusing on aging and neurodegenerative diseases. We discuss the established NAD+ precursors nicotinic acid and nicotinamide, newer compounds such as nicotinamide riboside and nicotinamide mononucleotide, and emerging precursors. We also discuss technological advances including in industrial-scale production and real-time detection, which are facilitating NAD+ research and clinical translation. Finally, we emphasize the need for further large-scale studies to determine optimal dose, administration routes and frequency, as well as long-term safety and interindividual variability in response.

• Xing, Xiaodan; Tang, Chunling; Murdoch, Siofra; Papanastasiou, Giorgos; Guo, Yunzhe & Xiao, Xianglu [Show all 13 contributors for this article] (2025). Artificial immunofluorescence in a flash: Rapid synthetic imaging from brightfield through residual diffusion. Neurocomputing. ISSN 0925-2312. 612. doi: 10.1016/j.neucom.2024.128715. Full text in Research Archive Show summary

  Immunofluorescent (IF) imaging is crucial for visualising biomarker expressions, cell morphology and assessing the effects of drug treatments on sub-cellular components. IF imaging needs extra staining process and often requiring cell fixation, therefore it may also introduce artefacts and alter endogenous cell morphology. Some IF stains are expensive or not readily available hence hindering experiments. Recent diffusion models, which synthesise high-fidelity IF images from easy-to-acquire brightfield (BF) images, offer a promising solution but are hindered by training instability and slow inference times due to the noise diffusion process. This paper presents a novel method for the conditional synthesis of IF images directly from BF images along with cell segmentation masks. Our approach employs a Residual Diffusion process that enhances stability and significantly reduces inference time. We performed a critical evaluation against other image-to-image synthesis models, including UNets, GANs, and advanced diffusion models. Our model demonstrates significant improvements in image quality (𝑝 < 0.05 in MSE, PSNR, and SSIM), inference speed (26 times faster than competing diffusion models), and accurate segmentation results for both nuclei and cell bodies (0.77 and 0.63 mean IOU for nuclei and cell true positives, respectively). This paper is a substantial advancement in the field, providing robust and efficient tools for cell image analysis.

• Feng, Yayan; Cao, Shuqin; Shi, Yi; Sun, Anna; Flanagan, Margaret E. & Leverenz, James B. [Show all 12 contributors for this article] (2025). Human herpesvirus-associated transposable element activation in human aging brains with Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 21(2). doi: 10.1002/alz.14595. Full text in Research Archive Show summary

  INTRODUCTION Human herpesvirus (HHV) has been linked to Alzheimer's disease (AD), but the underlying mechanisms remain unknown. METHODS We leveraged functional genomics data from Religious Orders Study or the Rush Memory and Aging Project (ROS/MAP) and Mount Sinai Brain Bank (MSBB) brain biobanks and single-cell RNA-sequencing data from HHV-infected forebrain organoids to investigate HHV-infection-associated transposable element (TE) dysregulation underlying AD etiologies. RESULTS We identified widespread TE dysregulation in HHV-positive human AD brains, including an astrocyte-specific upregulation of LINE1 subfamily TEs in HHV-positive human AD brains. We further pinpointed astrocyte-specific LINE1 upregulation that could potentially regulate target gene NEAT1 expression via long-range enhancer-promoter chromatin interactions. This LINE1 dysregulation can be partially reversed by the usage of anti-HHV drugs (valacyclovir and acyclovir) in a virus-infected human brain organoid model. Finally, we demonstrated that valacyclovir rescued tau-associated neuropathology and alleviated LINE1 activation in an experimental tau aggregation model. DISCUSSION Our analysis provides associations linking molecular, clinical, and neuropathological AD features with HHV infection, which warrants future clinical validation.

• Veverová, Kateřina; Katonová, Alžběta; Horáková, Hana; Laczó, Jan; Angelucci, Francesco & Hort, Jakub [Show all 9 contributors for this article] (2025). Distinctive autophagy/mitophagy biomarker profiles in frontotemporal lobar degeneration and Alzheimer’s disease. Acta neuropathologica communications. 13(1). doi: 10.1186/s40478-025-01954-9. Full text in Research Archive Show summary

  Maintaining cellular homeostasis by removing damaged and senescent mitochondria, a process termed mitophagy, is crucial in preventing Alzheimer’s disease (AD) and represents a promising therapeutic target. Our previous research revealed altered mitophagy biomarkers, such as increased CSF and serum PINK1 and serum BNIP3L and decreased serum TFEB levels, indicating impaired autophagy-lysosomal degradation in the AD continuum. However, the role of autophagy/mitophagy in frontotemporal lobar degeneration (FTLD) remains unclear. This study investigated the biomarkers of autophagy/mitophagy and lysosomal biogenesis (PINK1, ULK1, BNIP3L, and TFEB) in biofluids (CSF and serum) from 308 biomarker-defined individuals across the FTLD continuum (FTLD-dementia, n = 29; FTLD-MCI, n = 33) and compared them with those across the AD continuum (MCI-AD, n = 100; AD-dementia, n = 100) and cognitively unimpaired (CU) controls (n = 46) recruited from Czech Brain Aging Study. Additionally, we compared the mitophagy biomarkers across different FTLD clinical subtypes (frontal, semantic and nonfluent variant) with CU, and explored the association between mitophagy biomarkers and clinical phenotypes of FTLD (biomarkers of tau, biomarkers of neurodegeneration, cognition and ATN profile). Our findings indicated a significantly lower CSF PINK1 and ULK1 levels in FTLD compared to AD, with FTLD dementia showing particularly low CSF PINK1 levels compared to AD-dementia. Conversely, CSF ULK1 levels were higher in FTLD-MCI compared to AD-dementia. Serum analyses revealed lower PINK1 and higher TFEB levels in FTLD dementia compared to AD dementia. This study provides compelling evidence of distinct alterations in autophagy/mitophagy biomarkers between FTLD and AD, indicating that these neurodegenerative diseases may affect the cellular waste disposal system through different pathways. This is the first study to explore mitophagy biomarkers in human CSF and serum in FTLD, opening avenues for further research and potential clinical applications.

• Ai, Ruixue; Xiao, Xianglu; Deng, Shenglong; Yang, Nan; Xing, Xiaodan & Watne, Leiv [Show all 16 contributors for this article] (2025). Artificial intelligence in drug development for delirium and Alzheimer's disease. Acta Pharmaceutica Sinica B (APSB). ISSN 2211-3835. 15(9), p. 4386–4410. doi: 10.1016/j.apsb.2025.04.026. Full text in Research Archive
• Lautrup, Sofie Hindkjær; Zhang, Shi-qi; Funayama, Shinichiro; Lirussi, Lisa; Visnovska, Martina & Cheung, Hoi-Hung [Show all 19 contributors for this article] (2025). Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation. Aging. 17(4), p. 937–959. doi: 10.18632/aging.206236. Full text in Research Archive
• 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. Full text in Research Archive Show summary

  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.

• Zhou, Yujia; Pang, Nengzhi; Li, Wenli; Li, Qiuyan; Luo, Jing & Gu, Yingying [Show all 19 contributors for this article] (2024). Inhibition of ethanol-induced eNAMPT secretion attenuates liver ferroptosis through BAT-Liver communication. Redox Biology. 75. doi: 10.1016/j.redox.2024.103274. Full text in Research Archive Show summary

  Background & aims Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) has long been recognized as an adipokine. However, the exact role of eNAMPT in alcoholic liver disease (ALD) and its relevance to brown adipose tissue (BAT) remain largely unknown. This study aimed to evaluate the impact of eNAMPT on liver function and the underlying mechanisms involved in BAT-Liver communication. Methods Serum eNAMPT levels were detected in the serum of both ALD patients and mice. Chronic and binge ethanol feeding was used to induce alcoholic liver injury in mice. An eNAMPT antibody, a coculture model of brown adipocytes and hepatocytes, and BAT-specific Nampt knockdown mice were used to investigate the role of eNAMPT in ALD. Results Serum eNAMPT levels are elevated in ALD patients and are significantly positively correlated with the liver injury index. In ALD mice, neutralizing eNAMPT reduced the elevated levels of circulating eNAMPT induced by ethanol and attenuated liver injury. In vitro experiments revealed that eNAMPT induced hepatocyte ferroptosis through the TLR4-dependent mitochondrial ROS-induced ferritinophagy pathway. Furthermore, ethanol stimulated eNAMPT secretion from brown adipocytes but not from other adipocytes. In the coculture model, ethanol-induced release of eNAMPT from brown adipocytes promoted hepatocyte ferroptosis. In BAT-specific Nampt-knockdown mice, ethanol-induced eNAMPT secretion was significantly reduced, and alcoholic liver injury were attenuated. These effects can be reversed by intraperitoneal injection of eNAMPT. Conclusion Inhibition of ethanol-induced eNAMPT secretion from BAT attenuates liver injury and ferroptosis. Our study reveals a previously uncharacterized critical role of eNAMPT-mediated BAT-Liver communication in ALD and highlights its potential as a therapeutic target.

• Rice, Jared; Lautrup, Sofie Hindkjær & Stavem, Fei Fang (2024). NAD+ Boosting Strategies. Subcellular biochemistry. ISSN 0306-0225. 107, p. 63–90. doi: 10.1007/978-3-031-66768-8_4. Full text in Research Archive
• Hong, Yu; Zhang, Zhuoyuan; Yangzom, Tsering; Chen, Anbin; Lundberg, Bjørn Christian & Fang, Fei [Show all 12 contributors for this article] (2024). The NAD+ Precursor Nicotinamide Riboside Rescues Mitochondrial Defects and Neuronal Loss in iPSC derived Cortical Organoid of Alpers' Disease. International Journal of Biological Sciences. 20(4), p. 1194–1217. doi: 10.7150/ijbs.91624. Full text in Research Archive Show summary

  Alpers' syndrome is an early-onset neurodegenerative disorder usually caused by biallelic pathogenic variants in the gene encoding the catalytic subunit of polymerase-gamma (POLG), which is essential for mitochondrial DNA (mtDNA) replication. The disease is progressive, incurable, and inevitably it leads to death from drug-resistant status epilepticus. The neurological features of Alpers' syndrome are intractable epilepsy and developmental regression, with no effective treatment; the underlying mechanisms are still elusive, partially due to lack of good experimental models. Here, we generated the patient derived induced pluripotent stem cells (iPSCs) from one Alpers' patient carrying the compound heterozygous mutations of A467T (c.1399G>A) and P589L (c.1766C>T), and further differentiated them into cortical organoids and neural stem cells (NSCs) for mechanistic studies of neural dysfunction in Alpers' syndrome. Patient cortical organoids exhibited a phenotype that faithfully replicated the molecular changes found in patient postmortem brain tissue, as evidenced by cortical neuronal loss and depletion of mtDNA and complex I (CI). Patient NSCs showed mitochondrial dysfunction leading to ROS overproduction and downregulation of the NADH pathway. More importantly, the NAD+ precursor nicotinamide riboside (NR) significantly ameliorated mitochondrial defects in patient brain organoids. Our findings demonstrate that the iPSC model and brain organoids are good in vitro models of Alpers' disease; this first-in-its-kind stem cell platform for Alpers' syndrome enables therapeutic exploration and has identified NR as a viable drug candidate for Alpers' disease and, potentially, other mitochondrial diseases with similar causes.

• Wang, Heling; Zhang, Jianying; Cao, Shuqin; Lagartos, Maria Jose Donate; Zhang, Shi-qi & Lautrup, Sofie Hindkjær [Show all 10 contributors for this article] (2024). A luminescent-based protocol for NAD+/NADH detection in C. elegans, mice, and human whole blood. STAR Protocols. 5(4). doi: 10.1016/j.xpro.2024.103428. Full text in Research Archive Show summary

  Here, we present a NAD+/NADH detection assay for evaluating NAD+, NADH, and NAD+/NADH ratio across diverse biological models, including Caenorhabditis elegans, mouse muscle tissue, mouse whole blood, and human whole blood. We describe steps for sample collection and preparation from different models as well as detection and calculation of NAD+ and NADH levels. This protocol is applicable for quantifying cellular/tissue NAD+ and NADH levels across different biological models.

• Yi, Juan; Wang, Heling; Lu, Guang; Zhang, Hailong; Wang, Lina & Li, Zhen-Yu [Show all 11 contributors for this article] (2024). Spautin-1 promotes PINK1-PRKN-dependent mitophagy and improves associative learning capability in an alzheimer disease animal model. Autophagy. ISSN 1554-8627. 20(12), p. 2655–2676. doi: 10.1080/15548627.2024.2383145. Full text in Research Archive Show summary

  Spautin-1 is a well-known macroautophagy/autophagy inhibitor via suppressing the deubiquitinases USP10 and USP13 and promoting the degradation of the PIK3C3/VPS34-BECN1 complex, while its effect on selective autophagy remains poorly understood. Mitophagy is a selective form of autophagy for removal of damaged and superfluous mitochondria via the autophagy-lysosome pathway. Here, we report a surprising discovery that, while spautin-1 remains as an effective autophagy inhibitor, it promotes PINK1-PRKN-dependent mitophagy induced by mitochondrial damage agents. Mechanistically, spautin-1 facilitates the stabilization and activation of the full-length PINK1 at the outer mitochondrial membrane (OMM) via binding to components of the TOMM complex (TOMM70 and TOMM20), leading to the disruption of the mitochondrial import of PINK1 and prevention of PARL-mediated PINK1 cleavage. Moreover, spautin-1 induces neuronal mitophagy in Caenorhabditis elegans (C. elegans) in a PINK-1-PDR-1-dependent manner. Functionally, spautin-1 is capable of improving associative learning capability in an Alzheimer disease (AD) C. elegans model. In summary, we report a novel function of spautin-1 in promoting mitophagy via the PINK1-PRKN pathway. As deficiency of mitophagy is closely implicated in the pathogenesis of neurodegenerative disorders, the pro-mitophagy function of spautin-1 might suggest its therapeutic potential in neurodegenerative disorders such as AD.

• Lautrup, Sofie Hindkjær; Hou, Yujun; Fang, Fei & Bohr, Vilhelm A. (2024). Roles of NAD+ in Health and Aging. Cold Spring Harbor Perspectives in Medicine. 14(1). doi: 10.1101/cshperspect.a041193. Full text in Research Archive
• Knapskog, Anne-Brita; Edwin, Trine Holt; Ueland, Per Magne; Ulvik, Arve; Fang, Fei & Eldholm, Rannveig Sakshaug [Show all 11 contributors for this article] (2024). Sex-specific associations of kynurenic acid with neopterin in Alzheimer’s disease. Alzheimer's Research & Therapy. 16(1). doi: 10.1186/s13195-024-01531-7. Full text in Research Archive Show summary

  Background: Sex differences in neuroinflammation could contribute to women’s increased risk of Alzheimer’s disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation of the kynurenine pathway (KP) contributes to neuroinflammation and there is some evidence of sex differences in KP metabolism. However, the sex-specific associations between KP metabolism and biomarkers of AD and neuroinflammation need to be explored further. Methods: Here we investigate sex differences in cerebrospinal fluid concentrations of seven KP metabolites and sex-specific associations with established AD biomarkers and neopterin, an indicator of neuroinflammation. This study included 311 patients with symptomatic AD and 105 age-matched cognitively unimpaired (CU) controls, followed for up to 5 years. Results: We found sex differences in KP metabolites in the AD group, with higher levels of most metabolites in men, while there were no sex differences in the CU group. In line with this, more KP metabolites were significantly altered in AD men compared to CU men, and there was a trend in the same direction in AD women. Furthermore, we found sex-specific associations between kynurenic acid and the kynurenic acid/quinolinic acid ratio with neopterin, but no sex differences in the associations between KP metabolites and clinical progression. Discussion: In our cohort, sex differences in KP metabolites were restricted to AD patients. Our results suggest that dysregulation of the KP due to increased inflammation could contribute to higher AD risk in women.

• Liang, Xiao; Chen, Anbin; Kianian, Atefeh; Kristiansen, Cecilie Katrin; Yangzom, Tsering Yangzom Tsering & Palmer, Jessica Furriol [Show all 13 contributors for this article] (2024). Activation of Neurotoxic Astrocytes Due to Mitochondrial Dysfunction Triggered by POLG Mutation. International Journal of Biological Sciences. 20(8), p. 2860–2880. doi: 10.7150/ijbs.93445. Full text in Research Archive Show summary

  Mitochondrial diseases are associated with neuronal death and mtDNA depletion. Astrocytes respond to injury or stimuli and damage to the central nervous system. Neurodegeneration can cause astrocytes to activate and acquire toxic functions that induce neuronal death. However, astrocyte activation and its impact on neuronal homeostasis in mitochondrial disease remain to be explored. Using patient cells carrying POLG mutations, we generated iPSCs and then differentiated these into astrocytes. POLG astrocytes exhibited mitochondrial dysfunction including loss of mitochondrial membrane potential, energy failure, loss of complex I and IV, disturbed NAD+/NADH metabolism, and mtDNA depletion. Further, POLG derived astrocytes presented an A1-like reactive phenotype with increased proliferation, invasion, upregulation of pathways involved in response to stimulus, immune system process, cell proliferation and cell killing. Under direct and indirect co-culture with neurons, POLG astrocytes manifested a toxic effect leading to the death of neurons. We demonstrate that mitochondrial dysfunction caused by POLG mutations leads not only to intrinsic defects in energy metabolism affecting both neurons and astrocytes, but also to neurotoxic damage driven by astrocytes. These findings reveal a novel role for dysfunctional astrocytes that contribute to the pathogenesis of POLG diseases.

• Lyu, Yu-Xuan; Fu, Qiang; Wilczok, Dominika; Ying, Kejun; King, Aaron & Antebi, Adam [Show all 126 contributors for this article] (2024). Longevity biotechnology: bridging AI, biomarkers, geroscience and clinical applications for healthy longevity. Aging. 16(20), p. 12955–12976. doi: 10.18632/aging.206135. Full text in Research Archive
• Fu, Leiwen; Tian, Tian; Wang, Bingyi; Lu, Zhen; Bian, Junye & Zhang, Weijie [Show all 12 contributors for this article] (2024). Global, regional, and national burden of HIV and other sexually transmitted infections in older adults aged 60–89 years from 1990 to 2019: results from the Global Burden of Disease Study 2019. The Lancet Healthy Longevity. 5(1), p. e17–e30. doi: 10.1016/S2666-7568(23)00214-3. Full text in Research Archive Show summary

  Background Sexually active older adults are often more susceptible to HIV and other sexually transmitted infections (STIs) due to various health conditions (especially a weakened immune system) and low use of condoms. We aimed to assess the global, regional, and national burdens and trends of HIV and other STIs in older adults from 1990 to 2019. Methods We retrieved data from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 on the incidence and disability-adjusted life-years (DALYs) of HIV and other STIs (syphilis, chlamydia, gonorrhoea, trichomoniasis, and genital herpes) for older adults aged 60–89 years in 204 countries and territories from 1990 to 2019. Estimated annual percentage changes in the age-standardised incidence and DALY rates of HIV and other STIs, by age, sex, and Socio-demographic Index (SDI), were calculated to quantify the temporal trends. Spearman correlation analysis was used to examine the relationship between age-standardised rates and SDI. Findings In 2019, among older adults globally, there were an estimated 77 327 (95% uncertainty interval 59 443 to 97 648) new cases of HIV (age-standardised incidence rate 7·6 [5·9 to 9·6] per 100 000 population) and 26 414 267 (19 777 666 to 34 860 678) new cases of other STIs (2607·1 [1952·1 to 3440·8] per 100 000). The age-standardised incidence rate decreased by an average of 2·02% per year (95% CI –2·38 to –1·66) for HIV and remained stable for other STIs (–0·02% [–0·06 to 0·01]) from 1990 to 2019. The number of DALYs globally in 2019 was 1 905 099 (95% UI 1 670 056 to 2 242 807) for HIV and 132 033 (95% UI 83 512 to 225 630) for the other STIs. The age-standardised DALY rate remained stable from 1990 to 2019, with an average change of 0·97% (95% CI –0·54 to 2·50) per year globally for HIV but decreased by an annual average of 1·55% (95% CI –1·66 to –1·43) for other STIs. Despite the global decrease in the age-standardised incidence rate of HIV in older people from 1990 to 2019, many regions showed increases, with the largest increases seen in eastern Europe (average annual change 17·84% [14·16 to 21·63], central Asia (14·26% [11·35 to 17·25]), and high-income Asia Pacific (7·52% [6·54 to 8·51]). Regionally, the age-standardised incidence and DALY rates of HIV and other STIs decreased with increases in the SDI. Interpretation Although the incidence and DALY rates of HIV and STIs either declined or remained stable from 1990 to 2019, there were regional and demographic disparities. Health-care providers should be aware of the effects of ageing societies and other societal factors on the risk of HIV and other STIs in older adults, and develop age-appropriate interventions. The disparities in the allocation of health-care resources for older adults among regions of different SDIs should be addressed. Funding Natural Science Foundation of China, Fujian Province's Third Batch of Flexible Introduction of High-Level Medical Talent Teams, Science and Technology Innovation Team (Tianshan Innovation Team) Project of Xinjiang Uighur Autonomous Region, Cure Alzheimer's Fund, Helse Sør-Øst, the Research Council of Norway, Molecule/VitaDAO, NordForsk Foundation, Akershus University Hospital, the Civitan Norges Forskningsfond for Alzheimers Sykdom, the Czech Republic-Norway KAPPA programme, and the Rosa Sløyfe/Norwegian Cancer Society & Norwegian Breast Cancer Society.

• Hou, Yujun; Chu, Xixia; Park, Jae-Hyeon; Zhu, Qing; Hussain, Mansoor & Li, Zhiquan [Show all 13 contributors for this article] (2024). Urolithin A improves Alzheimer's disease cognition and restores mitophagy and lysosomal functions. Alzheimer's & Dementia. ISSN 1552-5260. 20(6), p. 4212–4233. doi: 10.1002/alz.13847. Full text in Research Archive Show summary

  BACKGROUND Compromised autophagy, including impaired mitophagy and lysosomal function, plays pivotal roles in Alzheimer's disease (AD). Urolithin A (UA) is a gut microbial metabolite of ellagic acid that stimulates mitophagy. The effects of UA's long-term treatment of AD and mechanisms of action are unknown. METHODS We addressed these questions in three mouse models of AD with behavioral, electrophysiological, biochemical, and bioinformatic approaches. RESULTS Long-term UA treatment significantly improved learning, memory, and olfactory function in different AD transgenic mice. UA also reduced amyloid beta (Aβ) and tau pathologies and enhanced long-term potentiation. UA induced mitophagy via increasing lysosomal functions. UA improved cellular lysosomal function and normalized lysosomal cathepsins, primarily cathepsin Z, to restore lysosomal function in AD, indicating the critical role of cathepsins in UA-induced therapeutic effects on AD. CONCLUSIONS Our study highlights the importance of lysosomal dysfunction in AD etiology and points to the high translational potential of UA.

• Veverová, Kateřina; Laczó, Jan; Katonová, Alžběta; Horáková, Hana; Matušková, Veronika & Angelucci, Francesco [Show all 14 contributors for this article] (2024). Alterations of human CSF and serum-based mitophagy biomarkers in the continuum of Alzheimer disease. Autophagy. ISSN 1554-8627. 20(8), p. 1868–1878. doi: 10.1080/15548627.2024.2340408. Full text in Research Archive Show summary

  Defective mitophagy is consistently found in postmortem brain and iPSC-derived neurons from Alzheimer disease (AD) patients. However, there is a lack of extensive examination of mitophagy status in serum or cerebrospinal fluid (CSF), and the clinical potential of mitophagy biomarkers has not been tested. We quantified biomarkers of mitophagy/autophagy and lysosomal degradation (PINK1, BNIP3L and TFEB) in CSF and serum from 246 individuals, covering mild cognitive impairment due to AD (MCI-AD, n = 100), dementia due to AD (AD-dementia, n = 100), and cognitively unimpaired individuals (CU, n = 46), recruited from the Czech Brain Aging Study. Cognitive function and brain atrophy were also assessed. Our data show that serum and CSF PINK1 and serum BNIP3L were higher, and serum TFEB was lower in individuals with AD than in corresponding CU individuals. Additionally, the magnitude of mitophagy impairment correlated with the severity of clinical indicators in AD patients. Specifically, levels of PINK1 positively correlated with phosphorylated (p)-MAPT/tau (181), total (t)-MAPT/tau, NEFL (neurofilament light chain), and NRGN (neurogranin) levels in CSF and negatively with memory, executive function, and language domain. Serum TFEB levels negatively correlated with NEFL and positively with executive function and language. This study reveals mitophagy impairment reflected in biofluid biomarkers of individuals with AD and associated with more advanced AD pathology.

• Omholt, Stig William; Lejneva, Raissa; Lagartos, Maria Jose Donate; Caponio, Domenica; Fang, Fei & Kobro-Flatmoen, Asgeir (2024). Bnip3 expression is strongly associated with reelin-positive entorhinal cortex layer II neurons. Brain Structure and Function. ISSN 1863-2653. 229, p. 1617–1629. doi: 10.1007/s00429-024-02816-1. Full text in Research Archive Show summary

  In layer II of the entorhinal cortex, the principal neurons that project to the dentate gyrus and the CA3/2 hippocampal fields markedly express the large glycoprotein reelin (Re + ECLII neurons). In rodents, neurons located at the dorsal extreme of the EC, which border the rhinal fissure, express the highest levels, and the expression gradually decreases at levels successively further away from the rhinal fissure. Here, we test two predictions deducible from the hypothesis that reelin expression is strongly correlated with neuronal metabolic rate. Since the mitochondrial turnover rate serves as a proxy for energy expenditure, the mitophagy rate arguably also qualifies as such. Because messenger RNA of the canonical promitophagic BCL2 and adenovirus E1B 19-kDa-interacting protein 3 (Bnip3) is known to be highly expressed in the EC, we predicted that Bnip3 would be upregulated in Re + ECLII neurons, and that the degree of upregulation would strongly correlate with the expression level of reelin in these neurons. We confirm both predictions, supporting that the energy requirement of Re + ECLII neurons is generally high and that there is a systematic increase in metabolic rate as one moves successively closer to the rhinal fissure. Intriguingly, the systematic variation in energy requirement of the neurons that manifest the observed reelin gradient appears to be consonant with the level of spatial and temporal detail by which they encode information about the external environment.

• Tian, Yuyao; Lautrup, Sofie Hindkjær; Law, Patrick Wai Nok; Dinh, Ngoc-Duy; Fang, Fei & Chan, Wai-Yee (2024). WRN loss accelerates abnormal adipocyte metabolism in Werner syndrome. Cell & Bioscience. 14(1). doi: 10.1186/s13578-023-01183-4. Full text in Research Archive Show summary

  Background Metabolic dysfunction is one of the main symptoms of Werner syndrome (WS); however, the underlying mechanisms remain unclear. Here, we report that loss of WRN accelerates adipogenesis at an early stage both in vitro (stem cells) and in vivo (zebrafish). Moreover, WRN depletion causes a transient upregulation of late-stage of adipocyte-specific genes at an early stage. Methods In an in vivo study, we generated wrn−/− mutant zebrafish and performed histological stain and Oil Red O staining to assess the fat metabolism. In an in vitro study, we used RNA-seq and ATAC-seq to profile the transcriptional features and chromatin accessibility in WRN depleted adipocytes. Moreover, we performed ChIP-seq to further study the regulatory mechanisms of metabolic dysfunction in WS. Results Our findings show that mechanistically WRN deficiency causes SMARCA5 upregulation. SMARCA5 is crucial in chromatin remodeling and gene regulation. Additionally, rescuing WRN could normalize SMARCA5 expression and adipocyte differentiation. Moreover, we find that nicotinamide riboside (NR) supplementation restores adipocyte metabolism in both stem cells and zebrafish models. Conclusions Our findings unravel a new mechanism for the influence of WRN in the early stage of adipogenesis and provide a possible treatment for metabolic dysfunction in WS. These data provide promising insights into potential therapeutics for ageing and ageing-related diseases.

• Presterud, Rebecca; Deng, Wei Hai; Wennerström, Anna Berit; Burgers, Geertruida Aleida Wilhelmina; Gajera, Bharat & Mattsson, Kirsten G. [Show all 11 contributors for this article] (2023). Long-Term Nicotinamide Riboside Use Improves Coordination and Eye Movements in Ataxia Telangiectasia. Movement Disorders. ISSN 0885-3185. p. 1–11. doi: 10.1002/mds.29645. Full text in Research Archive Show summary

  Background: Supplementation of nicotinamide riboside (NR) ameliorates neuropathology in animal models of ataxia telangiectasia (A-T). In humans, short-term NR supplementation showed benefits in neurological outcome. Objectives: The study aimed to investigate the safety and benefits of long-term NR supplementation in individuals with A-T. Methods: A single-arm, open-label clinical trial was performed in individuals with A-T, receiving NR over a period of 2 years. Biomarkers and clinical examinations were used to assess safety parameters. Standardized and validated neuromotor tests were used to monitor changes in neurological symptoms. Using generalized mixed models, test results were compared to expected disease progression based on historical data. Results: NAD+ concentrations increased rapidly in peripheral blood and stabilized at a higher level than baseline. NR supplementation was well tolerated for most participants. The total scores in the neuromotor test panels, as evaluated at the 18-month time point, improved for all but one participant, primarily driven by improvements in coordination subscores and eye movements. A comparison with historical data revealed that the progression of certain neuromotor symptoms was slower than anticipated. Conclusions: Long-term use of NR appears to be safe and well tolerated, and it improves motor coordination and eye movements in patients with A-T of all ages. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

• Dong, Yu; Zhuang, Xu-Xu; Wang, Yi-Ting; Tan, Jieqiong; Feng, Du & Li, Min [Show all 11 contributors for this article] (2023). Chemical mitophagy modulators: Drug development strategies and novel regulatory mechanisms. Pharmacological Research. ISSN 1043-6618. 194. doi: 10.1016/j.phrs.2023.106835. Full text in Research Archive Show summary

  Maintaining mitochondrial homeostasis is a potential therapeutic strategy for various diseases, including neurodegenerative diseases, cardiovascular diseases, metabolic disorders, and cancer. Selective degradation of mitochondria by autophagy (mitophagy) is a fundamental mitochondrial quality control mechanism conserved from yeast to humans. Indeed, small-molecule modulators of mitophagy are valuable pharmaceutical tools that can be used to dissect complex biological processes and turn them into potential drugs. In the past few years, pharmacological regulation of mitophagy has shown promising therapeutic efficacy in various disease models. However, with the increasing number of chemical mitophagy modulator studies, frequent methodological flaws can be observed, leading some studies to draw unreliable or misleading conclusions. This review attempts (a) to summarize the molecular mechanisms of mitophagy; (b) to propose a Mitophagy Modulator Characterization System (MMCS); (c) to perform a comprehensive analysis of methods used to characterize mitophagy modulators, covering publications over the past 20 years; (d) to provide novel targets for pharmacological intervention of mitophagy. We believe this review will provide a panorama of current research on chemical mitophagy modulators and promote the development of safe and robust mitophagy modulators with therapeutic potential by introducing high methodological standards.

• Xiong, Xi; He, Haijun; Ye, Qianqian; Qian, Shuangjie; Zhou, Shuoting & Feng, Feifei [Show all 8 contributors for this article] (2023). Alzheimer's disease diagnostic accuracy by fluid and neuroimaging ATN framework. CNS Neuroscience & Therapeutics. ISSN 1755-5930. doi: 10.1111/cns.14357. Full text in Research Archive Show summary

  Abstract Objectives The ATN's different modalities (fluids and neuroimaging) for each of the Aβ (A), tau (T), and neurodegeneration (N) elements are used for the biological diagnosis of Alzheimer's disease (AD). We aim to identify which ATN category achieves the highest potential for diagnosis and predictive accuracy of longitudinal cognitive decline. Methods Based on the availability of plasma ATN biomarkers (plasma‐derived Aβ 42/40 , p‐tau181, NFL, respectively), CSF ATN biomarkers (CSF‐derived Aβ 42 /Aβ 40 , p‐tau181, NFL), and neuroimaging ATN biomarkers (18F‐florbetapir (FBP) amyloid‐PET, 18F‐flortaucipir (FTP) tau‐PET, and fluorodeoxyglucose (FDG)‐PET), a total of 2340 participants were selected from ADNI. Results Our data analysis indicates that the area under curves (AUCs) of CSF‐A, neuroimaging‐T, and neuroimaging‐N were ranked the top three ATN candidates for accurate diagnosis of AD. Moreover, neuroimaging ATN biomarkers display the best predictive ability for longitudinal cognitive decline among the three categories. To note, neuroimaging‐T correlates well with cognitive performances in a negative correlation manner. Meanwhile, participants in the “N” element positive group, especially the CSF‐N positive group, experience the fastest cognitive decline compared with other groups defined by ATN biomarkers. In addition, the voxel‐wise analysis showed that CSF‐A related to tau accumulation and FDG–PET indexes more strongly in subjects with MCI stage. According to our analysis of the data, the best three ATN candidates for a precise diagnosis of AD are CSF‐A, neuroimaging‐T, and neuroimaging‐N. Conclusions Collectively, our findings suggest that plasma, CSF, and neuroimaging biomarkers differ considerably within the ATN framework; the most accurate target biomarkers for diagnosing AD were the CSF‐A, neuroimaging‐T, and neuroimaging‐N within each ATN modality. Moreover, neuroimaging‐T and CSF‐N both show excellent ability in the prediction of cognitive decline in two different dimensions.

• Li, Wenli; Zhou, Yujia; Pang, Nengzhi; Hu, Qianrong; Li, Qiuyan & Sun, Yan [Show all 15 contributors for this article] (2023). NAD Supplement Alleviates Intestinal Barrier Injury Induced by Ethanol Via Protecting Epithelial Mitochondrial Function. Nutrients. 15(1). doi: 10.3390/nu15010174. Full text in Research Archive Show summary

  Background: The epithelial tight junction is an important intestinal barrier whose disruption can lead to the release of harmful intestinal substances into the circulation and cause damage to systemic injury. The maintenance of intestinal epithelial tight junctions is closely related to energy homeostasis and mitochondrial function. Nicotinamide riboside (NR) is a NAD booster that can enhance mitochondrial biogenesis in liver. However, whether NR can prevent ethanol-induced intestinal barrier dysfunction and the underlying mechanisms remain unclear. Methods: We applied the mouse NIAAA model (chronic plus binge ethanol feeding) and Caco-2 cells to explore the effects of NR on ethanol-induced intestinal barrier dysfunction and the underlying mechanisms. NAD homeostasis and mitochondrial function were measured. In addition, knockdown of SirT1 in Caco-2 cells was further applied to explore the role of SirT1 in the protection of NR. Results: We found that ethanol increased intestinal permeability, increased the release of LPS into the circulation and destroyed the intestinal epithelial barrier structure in mice. NR supplementation attenuated intestinal barrier injury. Both in vivo and in vitro experiments showed that NR attenuated ethanol-induced decreased intestinal tight junction protein expressions and maintained NAD homeostasis. In addition, NR supplementation activated SirT1 activity and increased deacetylation of PGC-1α, and reversed ethanol-induced mitochondrial dysfunction and mitochondrial biogenesis. These effects were diminished with the knockdown of SirT1 in Caco-2 cells. Conclusion: Boosting NAD by NR alleviates ethanol-induced intestinal epithelial barrier damage via protecting mitochondrial function in a SirT1-dependent manner.

• 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. Full text in Research Archive Show summary

  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.

• Pang, Nengzhi; Hu, Qianrong; Zhou, Yujia; Xiao, Ying; Li, Wenli & Ding, Yijie [Show all 16 contributors for this article] (2023). Nicotinamide Adenine Dinucleotide Precursor Suppresses Hepatocellular Cancer Progression in Mice. Nutrients. 15(6). doi: 10.3390/nu15061447. Full text in Research Archive Show summary

  Targeting Nicotinamide adenine dinucleotide (NAD) metabolism has emerged as a promising anti-cancer strategy; we aimed to explore the health benefits of boosting NAD levels with nicotinamide riboside (NR) on hepatocellular carcinoma (HCC). We established three in vivo tumor models, including subcutaneous transplantation tumor model in both Balb/c nude mice (xenograft), C57BL/6J mice (allograft), and hematogenous metastatic neoplasm in nude mice. NR (400 mg/kg bw) was supplied daily in gavage. In-situ tumor growth or noninvasive bioluminescence were measured to evaluate the effect of NR on the HCC process. HepG2 cells were treated with transforming growth factor-β (TGF-β) in the absence/presence of NR in vitro. We found that NR supplementation alleviated malignancy-induced weight loss and metastasis to lung in nude mice in both subcutaneous xenograft and hematogenous metastasis models. NR supplementation decreased metastasis to the bone and liver in the hematogenous metastasis model. NR supplementation also significantly decreased the size of allografted tumors and extended the survival time in C57BL/6J mice. In vitro experiments showed that NR intervention inhibited the migration and invasion of HepG2 cells triggered by TGF-β. In summary, our results supply evidence that boosting NAD levels by supplementing NR alleviates HCC progression and metastasis, which may serve as an effective treatment for the suppression of HCC progression.

• Knapskog, Anne Brita; Aksnes, Mari; Edwin, Trine Holt; Ueland, Per Magne; Ulvik, Arve & Fang, Fei [Show all 11 contributors for this article] (2023). Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease. Alzheimer's & Dementia. ISSN 1552-5260. 19(12), p. 5573–5582. doi: 10.1002/alz.13162. Full text in Research Archive Show summary

  INTRODUCTION The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic acid act on the N-methyl-D-aspartate receptor, a possible therapeutic target in treating AD. METHODS In our longitudinal case–control study, KP metabolites in the cerebrospinal fluid were analyzed in 311 patients with AD and 105 cognitively unimpaired controls. RESULTS Patients with AD exhibited higher concentrations of KA (β = 0.18, P < 0.01) and picolinic acid (β = 0.20, P < 0.01) than the controls. KA was positively associated with tau pathology (β = 0.29, P < 0.01), and a higher concentration of KA was associated with the slower progression of dementia. DISCUSSION The higher concentrations of neuroprotective metabolites KA and picolinic acid suggest that the activation of the KP's neuroprotective branch is an adaptive response in AD and may be a promising target for intervention and treatment. Highlights Patients with Alzheimer's disease (AD) exhibited higher concentrations of kynurenic acid and picolinic acid than controls. Higher concentrations of kynurenic acid were associated with slower progression of AD. Potential neurotoxic kynurenines were not increased among patients with AD. Activation of the kynurenine pathway's neuroprotective branch may be an adaptive response in AD.

• Stock, Amanda J.; Ayyar, Saipriya; Kashyap, Amogh; Wang, Yunong; Yanai, Hagai & Starost, Matthew F. [Show all 16 contributors for this article] (2023). Boosting NAD ameliorates hematopoietic impairment linked to short telomeres in vivo. GeroScience. ISSN 2509-2715. 45, p. 2213–2228. doi: 10.1007/s11357-023-00752-2. Full text in Research Archive Show summary

  Abstract Short telomeres are a defining feature of telomere biology disorders (TBDs), including dyskeratosis congenita (DC), for which there is no effective general cure. Patients with TBDs often experience bone marrow failure. NAD, an essential metabolic coenzyme, is decreased in models of DC. Herein, using telomerase reverse transcriptase null ( Tert −/− ) mice with critically short telomeres, we investigated the effect of NAD supplementation with the NAD precursor, nicotinamide riboside (NR), on features of health span disrupted by telomere impairment. Our results revealed that NR ameliorated body weight loss in Tert −/− mice and improved telomere integrity and telomere dysfunction-induced systemic inflammation. NR supplementation also mitigated myeloid skewing of Tert −/− hematopoietic stem cells. Furthermore, NR alleviated villous atrophy and inflammation in the small intestine of Tert −/− transplant recipient mice. Altogether, our findings support NAD intervention as a potential therapeutic strategy to enhance aspects of health span compromised by telomere attrition.

• Ye, Peiwu; Fang, Qiuyuan; Hu, Xupang; Zou, Wenjuan; Huang, Miaodan & Ke, Minjing [Show all 23 contributors for this article] (2023). TRPM2 as a conserved gatekeeper determines the vulnerability of DA neurons by mediating ROS sensing and calcium dyshomeostasis. Progress in Neurobiology. ISSN 0301-0082. 231. doi: 10.1016/j.pneurobio.2023.102530. Full text in Research Archive Show summary

  Different dopaminergic (DA) neuronal subgroups exhibit distinct vulnerability to stress, while the underlying mechanisms are elusive. Here we report that the transient receptor potential melastatin 2 (TRPM2) channel is preferentially expressed in vulnerable DA neuronal subgroups, which correlates positively with aging in Parkinson’s Disease (PD) patients. Overexpression of human TRPM2 in the DA neurons of C. elegans resulted in selective death of ADE but not CEP neurons in aged worms. Mechanistically, TRPM2 activation mediates FZO-1/CED-9-dependent mitochondrial hyperfusion and mitochondrial permeability transition (MPT), leading to ADE death. In mice, TRPM2 knockout reduced vulnerable substantia nigra pars compacta (SNc) DA neuronal death induced by stress. Moreover, the TRPM2-mediated vulnerable DA neuronal death pathway is conserved from C. elegans to toxin-treated mice model and PD patient iPSC-derived DA neurons. The vulnerable SNc DA neuronal loss is the major symptom and cause of PD, and therefore the TRPM2-mediated pathway serves as a promising therapeutic target against PD.

• Morevati, Marya; Fang, Fei; Mace, Maria L.; Kanbay, Mehmet; Gravesen, Eva & Nordholm, Anders [Show all 8 contributors for this article] (2022). Roles of NAD+ in Acute and Chronic Kidney Diseases. International Journal of Molecular Sciences. ISSN 1661-6596. 24(1), p. 1–26. doi: 10.3390/ijms24010137. Full text in Research Archive Show summary

  Nicotinamide adenine dinucleotide (oxidized form, NAD+) is a critical coenzyme, with functions ranging from redox reactions and energy metabolism in mitochondrial respiration and oxidative phosphorylation to being a central player in multiple cellular signaling pathways, organ resilience, health, and longevity. Many of its cellular functions are executed via serving as a co-substrate for sirtuins (SIRTs), poly (ADP-ribose) polymerases (PARPs), and CD38. Kidney damage and diseases are common in the general population, especially in elderly persons and diabetic patients. While NAD+ is reduced in acute kidney injury (AKI) and chronic kidney disease (CKD), mounting evidence indicates that NAD+ augmentation is beneficial to AKI, although conflicting results exist for cases of CKD. Here, we review recent progress in the field of NAD+, mainly focusing on compromised NAD+ levels in AKI and its effect on essential cellular pathways, such as mitochondrial dysfunction, compromised autophagy, and low expression of the aging biomarker αKlotho (Klotho) in the kidney. We also review the compromised NAD+ levels in renal fibrosis and senescence cells in the case of CKD. As there is an urgent need for more effective treatments for patients with injured kidneys, further studies on NAD+ in relation to AKI/CKD may shed light on novel therapeutics.

• Cao, Shuqin; Aman, Yahyah; Fang, Fei & Tencomnao, Tewin (2022). P. edulis Extract Protects Against Amyloid-β Toxicity in Alzheimer’s Disease Models Through Maintenance of Mitochondrial Homeostasis via the FOXO3/DAF-16 Pathway. Molecular Neurobiology. ISSN 0893-7648. 59(9), p. 5612–5629. doi: 10.1007/s12035-022-02904-5. Full text in Research Archive
• Tian, Yuyao; Wang, Wuming; Lautrup, Sofie Hindkjær; Zhao, Hui; Li, Xiang & Law, Patrick Wai Nok [Show all 10 contributors for this article] (2022). WRN promotes bone development and growth by unwinding SHOX-G-quadruplexes via its helicase activity in Werner Syndrome. Nature Communications. 13(1). doi: 10.1038/s41467-022-33012-6. Full text in Research Archive Show summary

  Abstract Werner Syndrome (WS) is an autosomal recessive disorder characterized by premature aging due to mutations of the WRN gene. A classical sign in WS patients is short stature, but the underlying mechanisms are not well understood. Here we report that WRN is indispensable for chondrogenesis, which is the engine driving the elongation of bones and determines height. Zebrafish lacking wrn exhibit impairment of bone growth and have shorter body stature. We pinpoint the function of WRN to its helicase domain. We identify short-stature homeobox (SHOX) as a crucial and direct target of WRN and find that the WRN helicase core regulates the transcriptional expression of SHOX via unwinding G-quadruplexes. Consistent with this, shox −/− zebrafish exhibit impaired bone growth, while genetic overexpression of SHOX or shox expression rescues the bone developmental deficiency induced in WRN / wrn -null mutants both in vitro and in vivo. Collectively, we have identified a previously unknown function of WRN in regulating bone development and growth through the transcriptional regulation of SHOX via the WRN helicase domain, thus illuminating a possible approach for new therapeutic strategies.

• Charmipilas, N; Fang, Fei & Palikaras, Konstantinos (2022). Mitophagy and Neuroinflammation: A Compelling Interplay. Neuropharmacology. ISSN 0028-3908. 21(7), p. 1477–1481. doi: 10.2174/1570159X20666220628153632. Full text in Research Archive
• Sengupta, Tanima; Lefol, Yohan Pierre; Lirussi, Lisa; Morales, Veronica Suaste; Lüders, Torben & Gupta, Swapnil [Show all 10 contributors for this article] (2022). Krill oil protects dopaminergic neurons from age-related degeneration through temporal transcriptome rewiring and suppression of several hallmarks of aging. Aging. 14(21), p. 8661–8687. doi: 10.18632/aging.204375. Full text in Research Archive Show summary

  There is accumulating evidence that interfering with the basic aging mechanisms can enhance healthy longevity. The interventional/therapeutic strategies targeting multiple aging hallmarks could be more effective than targeting one hallmark. While health-promoting qualities of marine oils have been extensively studied, the underlying molecular mechanisms are not fully understood. Lipid extracts from Antarctic krill are rich in long-chain omega-3 fatty acids choline, and astaxanthin. Here, we used C. elegans and human cells to investigate whether krill oil promotes healthy aging. In a C. elegans model of Parkinson´s disease, we show that krill oil protects dopaminergic neurons from aging-related degeneration, decreases alpha-synuclein aggregation, and improves dopamine-dependent behavior and cognition. Krill oil rewires distinct gene expression programs that contribute to attenuating several aging hallmarks, including oxidative stress, proteotoxic stress, senescence, genomic instability, and mitochondrial dysfunction. Mechanistically, krill oil increases neuronal resilience through temporal transcriptome rewiring to promote anti-oxidative stress and anti-inflammation via healthspan regulating transcription factors such as SNK-1. Moreover, krill oil promotes dopaminergic neuron survival through regulation of synaptic transmission and neuronal functions via PBO-2 and RIM-1. Collectively, krill oil rewires global gene expression programs and promotes healthy aging via abrogating multiple aging hallmarks, suggesting directions for further pre-clinical and clinical explorations.

• Watne, Leiv Otto; Pollmann, Christian Thomas; Neerland, Bjørn Erik; Paulsen, Else Quist; Halaas, Nathalie Bodd & Idland, Ane-Victoria [Show all 20 contributors for this article] (2022). Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients. Journal of Clinical Investigation. ISSN 0021-9738. 133(2). doi: 10.1172/JCI163472. Full text in Research Archive Show summary

  Background: The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response to inflammation. Delirium (acute confusion) is a common complication of acute illness and is associated with increased risk of dementia and mortality. However, the molecular mechanism underlying delirium, particularly in relation to the KP, remain elusive. Methods: We undertook a multi-center observational study with 586 hospitalized patients (248 with delirium) and investigated associations between delirium and KP metabolites measured in cerebrospinal fluid (CSF) and serum by targeted metabolomics. We also explored associations between KP metabolites and markers of neuronal damage and one-year mortality. Results: In delirium, we found concentrations of the neurotoxic metabolite quinolinic acid in CSF (CSF-QA, OR 2.26 [1.78, 2.87], p

• Zeng, Xiangxiang; Wang, Fei; Luo, Yuan; Kang, Seung-gu; Tang, Jian & Lightstone, Felice C. [Show all 10 contributors for this article] (2022). Deep generative molecular design reshapes drug discovery. Cell Reports Medicine. 3(12), p. 1–13. doi: 10.1016/j.xcrm.2022.100794. Full text in Research Archive Show summary

  Recent advances and accomplishments of artificial intelligence (AI) and deep generative models have established their usefulness in medicinal applications, especially in drug discovery and development. To correctly apply AI, the developer and user face questions such as which protocols to consider, which factors to scrutinize, and how the deep generative models can integrate the relevant disciplines. This review summarizes classical and newly developed AI approaches, providing an updated and accessible guide to the broad computational drug discovery and development community. We introduce deep generative models from different standpoints and describe the theoretical frameworks for representing chemical and biological structures and their applications. We discuss the data and technical challenges and highlight future directions of multimodal deep generative models for accelerating drug discovery.

• 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. Full text in Research Archive Show summary

  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.

• Ye, Qinghao; Gao, Yuan; Ding, Weiping; Niu, Zhangming; Wang, Chengjia & Jiang, Yinghui [Show all 11 contributors for this article] (2022). Robust weakly supervised learning for COVID-19 recognition using multi-center CT images. Applied Soft Computing. ISSN 1568-4946. 116. doi: 10.1016/j.asoc.2021.108291. Full text in Research Archive Show summary

  The world is currently experiencing an ongoing pandemic of an infectious disease named coronavirus disease 2019 (i.e., COVID-19), which is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Computed Tomography (CT) plays an important role in assessing the severity of the infection and can also be used to identify those symptomatic and asymptomatic COVID-19 carriers. With a surge of the cumulative number of COVID-19 patients, radiologists are increasingly stressed to examine the CT scans manually. Therefore, an automated 3D CT scan recognition tool is highly in demand since the manual analysis is time-consuming for radiologists and their fatigue can cause possible misjudgment. However, due to various technical specifications of CT scanners located in different hospitals, the appearance of CT images can be significantly different leading to the failure of many automated image recognition approaches. The multi-domain shift problem for the multi-center and multi-scanner studies is therefore nontrivial that is also crucial for a dependable recognition and critical for reproducible and objective diagnosis and prognosis. In this paper, we proposed a COVID-19 CT scan recognition model namely coronavirus information fusion and diagnosis network (CIFD-Net) that can efficiently handle the multi-domain shift problem via a new robust weakly supervised learning paradigm. Our model can resolve the problem of different appearance in CT scan images reliably and efficiently while attaining higher accuracy compared to other state-of-the-art methods.

• 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. Full text in Research Archive Show summary

  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.

• Luo, Oscar Junhong; Lei, Wen; Zhu, Guodong; Ren, Zhiyao; Xu, Yudai & Xiao, Chanchan [Show all 26 contributors for this article] (2022). Multidimensional single-cell analysis of human peripheral blood reveals characteristic features of the immune system landscape in aging and frailty. Nature Aging. 2(4), p. 348–364. doi: 10.1038/s43587-022-00198-9. Full text in Research Archive
• Naranjo-Galindo, Francisco José; Ai, Ruixue; Fang, Evandro Fei; Nilsen, Hilde Loge & SenGupta, Tanima (2022). C. elegans as an Animal Model to Study the Intersection of DNA Repair, Aging and Neurodegeneration. Frontiers in Aging. 3. doi: 10.3389/fragi.2022.916118. Full text in Research Archive Show summary

  Since its introduction as a genetic model organism, Caenorhabditis elegans has yielded insights into the causes of aging. In addition, it has provided a molecular understanding of mechanisms of neurodegeneration, one of the devastating effects of aging. However, C. elegans has been less popular as an animal model to investigate DNA repair and genomic instability, which is a major hallmark of aging and also a cause of many rare neurological disorders. This article provides an overview of DNA repair pathways in C. elegans and the impact of DNA repair on aging hallmarks, such as mitochondrial dysfunction, telomere maintenance, and autophagy. In addition, we discuss how the combination of biological characteristics, new technical tools, and the potential of following precise phenotypic assays through a natural life-course make C. elegans an ideal model organism to study how DNA repair impact neurodegeneration in models of common age-related neurodegenerative diseases.

• Ma, Huijing; Ye, Qinghao; Ding, Weiping; Jiang, Yinghui; Wang, Minhao & Niu, Zhangming [Show all 14 contributors for this article] (2021). Can Clinical Symptoms and Laboratory Results Predict CT Abnormality? Initial Findings Using Novel Machine Learning Techniques in Children With COVID-19 Infections. Frontiers in Medicine. 8. doi: 10.3389/fmed.2021.699984. Full text in Research Archive
• Zhang, Yalun; Zhang, Yi; Aman, Yahyah; Ng, Cheung Toa; Chau, Wing-Hin & Zhang, Zhigang [Show all 21 contributors for this article] (2021). Amyloid-β toxicity modulates tau phosphorylation through the PAX6 signalling pathway. Brain. ISSN 0006-8950. 144(9), p. 2759–2770. doi: 10.1093/brain/awab134. Full text in Research Archive
• Zong, Le; Tanaka-Yano, Mayuri; Park, Bongsoo; Yanai, Hagai; Turhan, Ferda T. & Croteau, Deborah L. [Show all 10 contributors for this article] (2021). NAD+ augmentation with nicotinamide riboside improves lymphoid potential of Atm−/− and old mice HSCs. npj Aging and Mechanisms of Disease. 7(1), p. 1–9. doi: 10.1038/s41514-021-00078-3. Full text in Research Archive Show summary

  NAD+ supplementation has significant benefits in compromised settings, acting largely through improved mitochondrial function and DNA repair. Elevating NAD+ to physiological levels has been shown to improve the function of some adult stem cells, with implications that these changes will lead to sustained improvement of the tissue or system. Here, we examined the effect of elevating NAD+ levels in models with reduced hematopoietic stem cell (HSC) potential, ATM-deficient and aged WT mice, and showed that supplementation of nicotinamide riboside (NR), a NAD+ precursor, improved lymphoid lineage potential during supplementation. In aged mice, this improved lymphoid potential was maintained in competitive transplants and was associated with transcriptional repression of myeloid gene signatures in stem and lineage-committed progenitor cells after NR treatment. However, the altered transcriptional priming of the stem cells toward lymphoid lineages was not sustained in the aged mice after NR removal. These data characterize significant alterations to the lineage potential of functionally compromised HSCs after short-term exposure to NR treatment.

• Munson, Michael Joseph; Mathai, Benan J.; Ng, Matthew; Moncho, Laura Cristina Trachsel; Ballina, Laura R de la & Schultz, Sebastian W. [Show all 13 contributors for this article] (2021). GAK and PRKCD are positive regulators of PRKN-independent mitophagy. Nature Communications. 12(1). doi: 10.1038/s41467-021-26331-7. Full text in Research Archive Show summary

  The mechanisms involved in programmed or damage-induced removal of mitochondria by mitophagy remains elusive. Here, we have screened for regulators of PRKN-independent mitophagy using an siRNA library targeting 197 proteins containing lipid interacting domains. We identify Cyclin G-associated kinase (GAK) and Protein Kinase C Delta (PRKCD) as regulators of PRKN-independent mitophagy, with both being dispensable for PRKN- dependent mitophagy and starvation-induced autophagy. We demonstrate that the kinase activity of both GAK and PRKCD are required for efficient mitophagy in vitro, that PRKCD is present on mitochondria, and that PRKCD facilitates recruitment of ULK1/ATG13 to early autophagic structures. Importantly, we demonstrate in vivo relevance for both kinases in the regulation of basal mitophagy. Knockdown of GAK homologue (gakh-1) in C. elegans or knockout of PRKCD homologues in zebrafish led to significant inhibition of basal mitophagy, highlighting the evolutionary relevance of these kinases in mitophagy regulation.

• 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. Full text in Research Archive Show summary

  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.

• Gudmundsrud, Ruben; Skjånes, Tarjei Hartmann; Gilmour, Brian Christopher; Caponio, Domenica; Lautrup, Sofie Hindkjær & Fang, Fei (2021). Crosstalk among DNA Damage, Mitochondrial Dysfunction, Impaired Mitophagy, Stem Cell Attrition, and Senescence in the Accelerated Ageing Disorder Werner Syndrome. Cytogenetic and Genome Research. ISSN 1424-8581. 161(6-7), p. 297–304. doi: 10.1159/000516386. Full text in Research Archive Show summary

  Werner syndrome (WS) is an accelerated ageing disease caused by multiple mutations in the gene encoding the Werner DNA helicase (WRN). The major clinical features of WS include wrinkles, grey hair, osteoporosis, and metabolic phenomena such as atherosclerosis, diabetes, and fatty liver, and resemble those seen in normal ageing, but occur earlier, in middle age. Defective DNA repair resulting from mutations in WRN explain the majority of the clinical features of WS, but the underlying mechanisms driving the larger metabolic dysfunction remain elusive. Recent studies in animal models of WS and in WS patient cells and blood samples suggest the involvement of impaired mitophagy, NAD&lt;sup&gt;+&lt;/sup&gt; depletion, and accumulation of damaged mitochondria in metabolic dysfunction. This mini-review summarizes recent progress in the understanding of the molecular mechanisms of metabolic dysfunction in WS, with the involvement of DNA damage, mitochondrial dysfunction, mitophagy reduction, stem cell impairment, and senescence. Future studies on NAD&lt;sup&gt;+&lt;/sup&gt; and mitophagy may shed light on potential therapeutic strategies for the WS patients.

• Reiten, Ole Kristian; Wilvang, Martin Andreas; Mitchell, Sarah J.; Hu, Zeping & Fang, Fei (2021). Preclinical and clinical evidence of NAD+ precursors in health, disease, and ageing. Mechanisms of Ageing and Development. ISSN 0047-6374. 199. doi: 10.1016/j.mad.2021.111567. Full text in Research Archive
• Kobro-Flatmoen, Asgeir; Lagartos-Donate, Maria Jose; Aman, Yahyah; Edison, Paul; Witter, Menno & Fang, Fei (2021). Re-emphasizing early Alzheimer's disease pathology starting in select entorhinal neurons, with a special focus on mitophagy. Ageing Research Reviews. ISSN 1568-1637. 67, p. 1–17. doi: 10.1016/j.arr.2021.101307. Full text in Research Archive Show summary

• Chen, Anbin; Kristiansen, Cecilie Katrin; Hong, Yu; Kianian, Atefeh; Fang, Fei & Sullivan, Gareth John [Show all 10 contributors for this article] (2021). Nicotinamide riboside and metformin ameliorate mitophagy defect in induced pluripotent stem cell-derived astrocytes with POLG mutations. Frontiers in Cell and Developmental Biology. 9, p. 1–20. doi: 10.3389/fcell.2021.737304. Full text in Research Archive Show summary

  Mitophagy specifically recognizes and removes damaged or superfluous mitochondria to maintain mitochondrial homeostasis and proper neuronal function. Defective mitophagy and the resulting accumulation of damaged mitochondria occur in several neurodegenerative diseases. Previously, we showed mitochondrial dysfunction in astrocytes with POLG mutations, and here, we examined how POLG mutations affect mitophagy in astrocytes and how this can be ameliorated pharmacologically. Using induced pluripotent stem cell (iPSC)-derived astrocytes carrying POLG mutations, we found downregulation of mitophagy/autophagy-related genes using RNA sequencing-based KEGG metabolic pathway analysis. We confirmed a deficit in mitochondrial autophagosome formation under exogenous stress conditions and downregulation of the mitophagy receptor p62, reduced lipidation of LC3B-II, and decreased expression of lysosome protein lysosomal-associated membrane protein 2A (LAMP2A). These changes were regulated by the PINK1/Parkin pathway and AKT/mTOR/AMPK/ULK1 signaling pathways. Importantly, we found that double treatment with nicotinamide riboside (NR) and metformin rescued mitophagy defects and mitochondrial dysfunction in POLG-mutant astrocytes. Our findings reveal that impaired mitophagy is involved in the observed mitochondrial dysfunction caused by POLG mutations in astrocytes, potentially contributing to the phenotype in POLG-related diseases. This study also demonstrates the therapeutic potential of NR and metformin in these incurable mitochondrial diseases.

• Xu, Chong; Wu, Jialin; Wu, Yiqun; Ren, Zhichu; Yao, Yuyuan & Chen, Guobing [Show all 12 contributors for this article] (2021). TNF-α-dependent neuronal necroptosis regulated in Alzheimer’s disease by coordination of RIPK1-p62 complex with autophagic UVRAG. Theranostics. 11(19), p. 9452–9469. doi: 10.7150/THNO.62376. Full text in Research Archive
• Qiu, Congling; Qiu, C.; Xiao, Chanchan; Xiao, C; Wang, Zhigang & Wang, Z [Show all 34 contributors for this article] (2021). CD8+ T-Cell Epitope Variations Suggest a Potential Antigen HLA-A2 Binding Deficiency for Spike Protein of SARS-CoV-2. Frontiers in Immunology. 12. doi: 10.3389/fimmu.2021.764949. Full text in Research Archive Show summary

  We identified SARS-CoV-2 specific antigen epitopes by HLA-A2 binding affinity analysis and characterized their ability to activate T cells. As the pandemic continues, variations in SARS-CoV-2 virus strains have been found in many countries. In this study, we directly assess the immune response to SARS-CoV-2 epitope variants. We first predicted potential HLA-A*02:01-restricted CD8 + T-cell epitopes of SARS-CoV-2. Using the T2 cell model, HLA-A*02:01-restricted T-cell epitopes were screened for their binding affinity and ability to activate T cells. Subsequently, we examined the identified epitope variations and analyzed their impact on immune response. Here, we identified specific HLA-A2-restricted T-cell epitopes in the spike protein of SARS-CoV-2. Seven epitope peptides were confirmed to bind with HLA-A*02:01 and potentially be presented by antigen-presenting cells to induce host immune responses. Tetramers containing these peptides could interact with specific CD8 + T cells from convalescent COVID-19 patients, and one dominant epitope (n-Sp1) was defined. These epitopes could activate and generate epitope-specific T cells in vitro , and those activated T cells showed cytolytic activity toward target cells. Meanwhile, n-Sp1 epitope variant 5L&amp;gt;F significantly decreased the proportion of specific T-cell activation; n-Sp1 epitope 8L&amp;gt;V variant showed significantly reduced binding to HLA-A*02:01 and decreased proportion of n-Sp1-specific CD8 + T cell, which potentially contributes to the immune escape of SARS-CoV-2. Our data indicate that the variation of a dominant epitope will cause the deficiency of HLA-A*02:01 binding and T-cell activation, which subsequently requires the formation of a new CD8 + T-cell immune response in COVID-19 patients.

• Klionsky, Daniel J.; Abdel-Aziz, Amal Kamal; Abdelfatah, Sara; Abdellatif, Mahmoud Khaled; Abdoli, Asghar & Abudu, Yakubu Princely [Show all 50 contributors for this article] (2021). Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition). Autophagy. ISSN 1554-8627. 17(1), p. 1–382. doi: https:/www.tandfonline.com/doi/full/10.1080/15548627.2020.1797280. Full text in Research Archive
• Wang, Heling; Lautrup, Sofie Hindkjær; Caponio, Domenica; Zhang, Jianying & Fang, Fei (2021). Dna damage‐induced neurodegeneration in accelerated ageing and alzheimer’s disease. International Journal of Molecular Sciences. ISSN 1661-6596. 22(13), p. 1–17. doi: 10.3390/ijms22136748. Full text in Research Archive Show summary

  DNA repair ensures genomic stability to achieve healthy ageing, including cognitive maintenance. Mutations on genes encoding key DNA repair proteins can lead to diseases with accelerated ageing phenotypes. Some of these diseases are xeroderma pigmentosum group A (XPA, caused by mutation of XPA), Cockayne syndrome group A and group B (CSA, CSB, and are caused by mutations of CSA and CSB, respectively), ataxia-telangiectasia (A-T, caused by mutation of ATM), and Werner syndrome (WS, with most cases caused by mutations in WRN). Except for WS, a common trait of the aforementioned progerias is neurodegeneration. Evidence from studies using animal models and patient tissues suggests that the associated DNA repair deficiencies lead to depletion of cellular nicotinamide adenine dinucleotide (NAD+), resulting in impaired mitophagy, accumulation of damaged mitochondria, metabolic derailment, energy deprivation, and finally leading to neuronal dysfunction and loss. Intriguingly, these features are also observed in Alzheimer’s disease (AD), the most common type of dementia affecting more than 50 million individuals worldwide. Further studies on the mechanisms of the DNA repair deficient premature ageing diseases will help to unveil the mystery of ageing and may provide novel therapeutic strategies for AD.

• Aman, Yahyah; Frank, Johannes; Lautrup, Sofie Hindkjær; Matysek, Adrian; Niu, Zhangming & Yang, Guang [Show all 13 contributors for this article] (2020). The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications. Mechanisms of Ageing and Development. ISSN 0047-6374. 185, p. 1–11. doi: 10.1016/j.mad.2019.111194. Full text in Research Archive Show summary

  Nicotinamide adenine dinucleotide (NAD+) is an important natural molecule involved in fundamental biological processes, including the TCA cycle, OXPHOS, β-oxidation, and is a co-factor for proteins promoting healthy longevity. NAD+ depletion is associated with the hallmarks of ageing and may contribute to a wide range of age-related diseases including metabolic disorders, cancer, and neurodegenerative diseases. One of the central pathways by which NAD+ promotes healthy ageing is through regulation of mitochondrial homeostasis via mitochondrial biogenesis and the clearance of damaged mitochondria via mitophagy. Here, we highlight the contribution of the NAD+-mitophagy axis to ageing and age-related diseases, and evaluate how boosting NAD+ levels may emerge as a promising therapeutic strategy to counter ageing as well as neurodegenerative diseases including Alzheimer’s disease. The potential use of artificial intelligence to understand the roles and molecular mechanisms of the NAD+-mitophagy axis in ageing is discussed, including possible applications in drug target identification and validation, compound screening and lead compound discovery, biomarker development, as well as efficacy and safety assessment. Advances in our understanding of the molecular and cellular roles of NAD+ in mitophagy will lead to novel approaches for facilitating healthy mitochondrial homoeostasis that may serve as a promising therapeutic strategy to counter ageing-associated pathologies and/or accelerated ageing.

• Okur, Mustafa Nazir; Fang, Evandro Fei; Fivenson, Elayne M.; Tiwari, Vinod; Croteau, Deborah L. & Bohr, Vilhelm A. (2020). Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling. Aging Cell. ISSN 1474-9718. doi: 10.1111/acel.13268. Full text in Research Archive Show summary

  Cockayne syndrome (CS) is a rare premature aging disease, most commonly caused by mutations of the genes encoding the CSA or CSB proteins. CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12 years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription‐coupled nucleotide excision repair (TC‐NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross‐species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD+ supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD+ precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD+ restoration.

• Wong, Jack Ho; Ng, Tzi Bun; Chan, Helen Hei Ling; Liu, Qin; Man, Gene Chi Wai & Zhang, Chris Zhiyi [Show all 18 contributors for this article] (2020). Mushroom extracts and compounds with suppressive action on breast cancer: evidence from studies using cultured cancer cells, tumor-bearing animals, and clinical trials. Applied Microbiology and Biotechnology. ISSN 0175-7598. p. 1–29. doi: 10.1007/s00253-020-10476-4. Full text in Research Archive Show summary

  This article reviews mushrooms with anti-breast cancer activity. The mushrooms covered which are better known include the following: button mushroom Agaricus bisporus, Brazilian mushroom Agaricus blazei, Amauroderma rugosum, stout camphor fungus Antrodia camphorata, Jew’s ear (black) fungus or black wood ear fungus Auricularia auricula–judae, reishi mushroom or Lingzhi Ganoderma lucidum, Ganoderma sinense, maitake mushroom or sheep’s head mushroom Grifola frondosa, lion’s mane mushroom or monkey head mushroom Hericium erinaceum, brown beech mushroom Hypsizigus marmoreus, sulfur polypore mushroom Laetiporus sulphureus, Lentinula edodes (shiitake mushroom), Phellinus linteus (Japanese “meshimakobu,” Chinese “song gen,” Korean “sanghwang,” American “black hoof mushroom”), abalone mushroom Pleurotus abalonus, king oyster mushroom Pleurotus eryngii, oyster mushroom Pleurotus ostreatus, tuckahoe or Fu Ling Poria cocos, and split gill mushroom Schizophyllum commune. Antineoplastic effectiveness in human clinical trials and mechanism of anticancer action have been reported for Antrodia camphorata, Cordyceps sinensis, Coriolus versicolor, Ganoderma lucidum, Grifola frondosa, and Lentinula edodes.

• Hu, Shaoping; Gao, Yuan; Niu, Zhangming; Jiang, Yinghui; Li, Lao & Xiao, Xianglu [Show all 12 contributors for this article] (2020). Weakly supervised deep learning for COVID-19 infection detection and classification from CT images. IEEE Access. 8, p. 118869–118883. doi: 10.1109/ACCESS.2020.3005510. Full text in Research Archive
• Okur, MN; Fang, Fei; Fivenson, EM; Tiwari, V; Croteau, DL & Bohr, Vilhelm A. (2020). Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD+ signaling. Aging Cell. ISSN 1474-9718. 19(12), p. e13268–e13268. doi: 10.1111/acel.13268. Full text in Research Archive
• Zheng, S; Rao, J; Song, Y; Zhang, J; Xiao, X & Fang, Fei [Show all 8 contributors for this article] (2020). PharmKG: a dedicated knowledge graph benchmark for bomedical data mining. Briefings in Bioinformatics. ISSN 1467-5463. 22(4), p. bbaa344–bbaa344. doi: 10.1093/bib/bbaa344. Full text in Research Archive
• Zhou, X; Ye, Q; Jiang, Y; Wang, M; Niu, Z & Menpes-Smith, W [Show all 10 contributors for this article] (2020). Systematic and Comprehensive Automated Ventricle Segmentation on Ventricle Images of the Elderly Patients: A Retrospective Study. Frontiers in Aging Neuroscience. 12, p. 618538–618538. doi: 10.3389/fnagi.2020.618538. Full text in Research Archive
• Aman, Yahyah; Cao, Shuqin & Fang, Fei (2020). Iron out, mitophagy in! A way to slow down hepatocellular carcinoma. EMBO Reports. ISSN 1469-221X. 21(11), p. e51652–e51652. doi: 10.15252/embr.202051652. Full text in Research Archive

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• Fang, Fei; Bergersen, Linda Hildegard & Gilmour, Brian Christopher (2023). Molecular, Cellular, and Metabolic Fundamentals of Human Aging. Academic Press. ISBN 9780323916172. 246 p. Full text in Research Archive

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• Ai, Ruixue & Fang-Stavem, Fei (2025). NAD+ restores proteostasis through splicing-dependent autophagy. Autophagy. ISSN 1554-8627. 22(2), p. 436–438. doi: 10.1080/15548627.2025.2596679. Full text in Research Archive Show summary

  Autophagy preserves neuronal integrity by clearing damaged proteins and organelles, but its efficiency declines with aging and neurodegeneration. Depletion of the oxidized form of nicotinamide adenine dinucleotide (NAD+) is a hallmark of this decline, yet how metabolic restoration enhances autophagic control has remained obscure. Meanwhile, alternative RNA splicing errors accumulate in aging brains, compromising proteostasis. Here, we identify a metabolic – transcriptional mechanism linking NAD+ metabolism to autophagic proteostasis through the NAD+ -EVA1C axis. Cross-species analyses in C. elegans, mice, and human samples reveal that NAD+ supplementation corrects hundreds of age- or Alzheimer-associated splicing errors, notably restoring balanced expression of EVA1C isoforms. Loss of EVA1C impairs the memory and proteostatic benefits of NAD+, underscoring its essential role in neuronal resilience. Mechanistically, NAD+ rebalances EVA1C isoforms that interact with chaperones BAG1 and HSPA/HSP70, reinforcing their network to facilitate chaperone-assisted selective macroautophagy and proteasomal degradation of misfolded proteins such as MAPT/tau. Thus, NAD+ restoration coordinates RNA splicing fidelity with downstream proteostatic systems, establishing a metabolic – transcriptional checkpoint for neuronal quality control. This finding expands the paradigm of autophagy regulation, positioning metabolic splice-switching as a crucial mechanism to maintain proteostasis and suggesting new strategies to combat aging-related neurodegenerative diseases.

• Li, Ang; Cao, Shuqin; Fang-Stavem, Fei & Su, Huanxing (2025). Pharmacological activation of mitophagy antagonizes motor neuron degeneration in a cross-species platform of amyotrophic lateral sclerosis. Autophagy. ISSN 1554-8627. doi: 10.1080/15548627.2025.2610450. Full text in Research Archive
• Berg, Ole Kristian; Fang-Stavem, Fei; Helgerud, Jan & Rødahl, Jenny Mina (2025). Treffsikker formel: så gammel blir du. [Journal]. Dagbladet. Full text in Research Archive
• 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.

• Wang, Heling & Fang, Fei (2024). PFASs May Risk Alzheimer’s Disease. The journals of gerontology. Series A, Biological sciences and medical sciences. ISSN 1079-5006. 79(3). doi: 10.1093/gerona/glad277. Full text in Research Archive
• Zhang, Jianying; Wang, Heling; Veverová, Kateřina; Vyhnálek, Martin & Fang, Fei (2024). Identification and potential clinical applications of novel autophagy/mitophagy proteins in the biofluids of Alzheimer's disease patients. Ageing Research Reviews. ISSN 1568-1637. 99. doi: 10.1016/j.arr.2024.102378. Full text in Research Archive Show summary

  Highlights Elevated PINK1 and reduced TFEB in CSF and serum samples of AD patients. Correlations were found between levels of PINK1, TFEB, and clinical indicators of AD. Changes of the fluid protein levels of mitophagy/autophagy proteins could be developed into markers in assisting diagnsosi and prognosis.

• Aittokallio, Tero Antero & Fang, Fei (2024). Editorial overview–Artificial intelligence methodologies in structural biology: Bridging the gap to medical applications. Current Opinion in Structural Biology. ISSN 0959-440X. 87. doi: 10.1016/j.sbi.2024.102862. Full text in Research Archive
• Cao, Shuqin; Wang, Heling; Palikaras, Konstantinos; Tavernarakis, Nektarios & Fang, Fei (2023). Chemotaxis assay for evaluation of memory-like behavior in wild-type and Alzheimer's-disease-like C. elegans models. STAR Protocols. 4(2). doi: 10.1016/j.xpro.2023.102250. Full text in Research Archive
• Fang, Fei & Anisimov, Aleksander (2023). Turning up the NAD+-mitophagy axis to treat Alzheimer's disease. Neural Regeneration Research. ISSN 1673-5374. 18(2), p. 319–319. doi: 10.4103/1673-5374.346472. Full text in Research Archive Show summary

  The increase in the prevalence of individuals with Alzheimer’s disease (AD) combined with the lack of a cure calls for the development of novel therapies against AD (Canter et al., 2016). The key disease-defining pathological features of AD are the accumulation of extracellular amyloid-beta (Aβ) plaques (accompanied by increasing intracellular Aβ1–42) and higher intracellular neurofibrillary tangles, comprised mostly of hyperphosphorylated tau protein/pTau (Goedert, 2015; Hardy, 2017). It is evident that the elderly are more predisposed to develop AD, and thus aging is considered to be the primary risk factor for AD. By extrapolation, strategies that delay aging may also slow down (if not stop) AD.

• Fang, Fei; Tavernarakis, Nektarios & Palikaras, Konstantinos (2023). Editorial: Mitophagy in health and disease, volume II. Frontiers in Cell and Developmental Biology. 11. doi: 10.3389/fcell.2023.1242664. Full text in Research Archive
• 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
• 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. Full text in Research Archive Show summary

  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.

• Ai, Ruixue; Xu-Xu, Zhuang; Anisimov, Aleksander; Lu, Jia-Hong & Fang, Fei (2022). A synergized machine learning plus cross-species wet-lab validation approach identifies neuronal mitophagy inducers inhibiting Alzheimer disease. Autophagy. ISSN 1554-8627. 18(4), p. 939–941. doi: 10.1080/15548627.2022.2031382. Full text in Research Archive
• Zhang, Can; Fang, Fei & Wang, Changning (2022). Editorial: Progress of Translational Medicine in Alzheimer's Disease. Frontiers in Aging Neuroscience. 14. doi: 10.3389/fnagi.2022.970044. Full text in Research Archive
• Wei, Ziyu; Ma, Heng; Fang, Fei & Chen, Hou-Zao (2022). Editorial: Cellular Senescence and Cellular Communications Within Tissue Microenvironments During Aging. Frontiers in Physiology. 13. doi: 10.3389/fphys.2022.890577. Full text in Research Archive
• Xie, Chenlong; Aman, Yahyah; Frank, Johannes; Donate-Lagartos, Maria Jose; Gudmundsrud, Ruben & Čechová, Kateřina [Show all 9 contributors for this article] (2021). Autophagic processes in early- and late-onset Alzheimer's disease. In Rothermel, Beverly A. & Diwan, Abhinav (Ed.), Autophagy in Health and Disease. Academic Press. ISSN 9780128220030. p. 287–299. doi: 10.1016/B978-0-12-822003-0.00012-7. Full text in Research Archive
• Palikaras, Konstantinos; Fang, Fei & Tavernarakis, Nektarios (2021). Editorial: Mitophagy in Health and Disease. Frontiers in Cell and Developmental Biology. 9. doi: 10.3389/fcell.2021.647036. Full text in Research Archive

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