image: Figure 1. WRN is essential in maintaining metabolic, mitochondrial, and other longevity-related pathways as well as in inhibiting senescence in mesenchymal stem cells. (A, B) Gene-set-enrichment analysis demonstrates upregulated and downregulated signaling pathways (KEGG pathways) in WT and WRN−/− MSCs with/without 1 mM NR treatment for 24 h. The KEGG terms were ranked on the basis of enrichment scores. The upregulated KEGG pathways and downregulated KEGG pathways are summarised separately. (C) Heat map data showing fpkm changes of significantly up- or down-regulated genes (DEGs) related to NAD+ metabolism in the comparisons shown (list of target genes is found in Supplementary Table 1; full list of fpkm values is found in Supplementary File 1). WRN−/− (Veh) clusters alone, whereas WRN−/− (NR) and WT (Veh) cluster together. (D) Correlation matrix of fpkm values showing the correlation between expression of NAD+ related DEGs and proliferation/senescence related markers. (E–G) Senescence evaluation by senescence associated β-Galactosidase (SA-β-Gal) staining of MSCs derived from control (WT) and WS patients (WS). SA-β-Gal positive cells decreased with 11–18 days of 1 mM NR treatment in WRN−/− MSCs (Student’s t-test, p-values = 0.0097 and 0.0156, respectively) (F, G), but not in WT MSCs (Student’s t-test, p-value = 0.2029) (E). SA-β-Gal positive MSCs relative to total number of cells were quantified from two biological experiments per cell line. (H) SA-β-Gal staining of primary fibroblasts from healthy control donors (WT) and WS patients (WS). SA-β-Gal staining was increased in WS patient derived fibroblasts compared to healthy controls (WT) (Two-way ANOVA, Tukey’s multiple comparisons test, p-value = 0.0036). SA-β-Gal staining decreased with 10 days 1 mM NR treatment in WS patient derived primary fibroblasts (Two-way ANOVA, Tukey’s multiple comparisons test, p-value = 0.0115) (F, G), but not in WT MSCs (Two-way ANOVA, Tukey’s multiple comparisons test, p-value = 0.9930) (Senescence evaluation by Spider β-Gal (Dojindo) staining of primary fibroblasts from healthy donors (WT) or WS patients (WS) without or with 1 mM NR for 10 days prior to staining are found in Supplementary Figure 1). (I) Staining of HMGB1 in primary fibroblasts from healthy donors (WT) or WS patients (WS) without or with 1 mM NR treatment for 10 days prior to staining. The number of cells with nuclear HMGB1 only relative to the total number of cells is shown in the figure from three biological repeats from two WT cell lines and two WS cell line. The percentage of cells with nuclear HMGB1 was decreased in WS-derived primary fibroblasts compared to WT (Two-way ANOVA, Tukey’s multiple comparisons test, p-value < 0.0001). Supporting the SA-β-Gal staining, 10 days 1 mM NR treatment increased the proportion of WS-derived fibroblasts with nuclear HMGB1 staining compared to vehicle treated cells significantly (Two-way ANOVA, Tukey’s multiple comparisons test, p-value = 0.0006), indicating decreased senescence with NR treatment.
Credit: Copyright: © 2025 Lautrup et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
“Our results indicated compromised NAD+ metabolism in WS while NAD+ augmentation decreased senescence in both WS mesenchymal stem cells (MSCs) and primary fibroblasts, shedding light on potential therapeutics.”
BUFFALO, NY — May 1, 2025 — A new research paper was published in Aging (Aging-US) on April 2, 2025, as the cover of Volume 17, Issue 4, titled “Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation.”
In this study, the team led by first author Sofie Lautrup and corresponding author Evandro F. Fang, from the University of Oslo and Akershus University Hospital in Norway, discovered that cells from people with Werner syndrome (WS)—a rare genetic disorder that causes premature aging—have low levels of a molecule called NAD+ in their mitochondria. This molecule is essential for energy production, cellular metabolism, and maintaining cell health. The researchers also found a potential way to improve cell function in WS patients, pointing to new directions for treating age-related decline and other premature aging disorders.
Werner syndrome leads to signs of aging much earlier than normal, including problems such as cataracts, hair loss, and atherosclerosis by age 20 to 30. The team found that when the WRN gene is missing or damaged, cells cannot maintain healthy NAD+ levels in their mitochondria. As a result, the cells age more quickly and stop growing properly. When the researchers boosted NAD+ levels using nicotinamide riboside (a vitamin B3 compound) the affected stem cells and skin cells from patients showed less aging and improved mitochondrial activity.
“Interestingly, only 24 h treatment with 1 mM nicotinamide riboside (NR), an NAD+ precursor, rescued multiple pathways in the WRN−/− cells, including increased expression of genes driving mitochondrial and metabolism-related pathways, as well as proliferation-related pathways.”
The study also found that the WRN gene helps regulate other important genes that control how NAD+ is made in the body. Without WRN, this system becomes unbalanced, which affects how cells function, grow, and respond to stress. Although adding more NAD+ helped some cells look healthier, it could not completely fix the growth problems in other types of lab-grown cells. This suggests that while NAD+ supplementation is beneficial, it cannot fully replace the essential functions of the WRN gene.
These findings offer new insights into the biological mechanisms of aging and reinforce the therapeutic potential of targeting NAD+ metabolism in age-related and genetic diseases. Future studies will aim to better understand how subcellular NAD+ regulation interacts with mutations like those seen in WS. Finally, this research supports ongoing efforts to develop NAD+-based treatments that could slow cellular aging and improve quality of life for patients with premature aging conditions.
Read the full paper: DOI: https://doi.org/10.18632/aging.206236
Corresponding author: Evandro F. Fang – e.f.fang@medisin.uio.no
Keywords: aging, Werner syndrome, premature aging, NAD+, mitochondria, proliferation
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Journal
Aging-US
Method of Research
News article
Subject of Research
Cells
Article Title
Decreased mitochondrial NAD+ in WRN deficient cells links to dysfunctional proliferation
Article Publication Date
2-Apr-2025
COI Statement
EFF is a co-owner of Fang-S Consultation AS (Organization number 931 410 717) and NO-Age AS (Organization number 933 219 127); he has an MTA with LMITO Therapeutics Inc (South Korea), a CRADA arrangement with ChromaDex (USA), a commercialization agreement with Molecule AG/VITADAO, and MTAs with GeneHarbor (Hong Kong) Biotechnologies Limited and Hong Kong Longevity Science Laboratory (Hong Kong); he is a consultant to MindRank AI (China), NYO3 (Norway), AgeLab (Vitality Nordic AS, Norway), and Hong Kong Longevity Science Laboratory (Hong Kong). HLN has a CRADA arrangement with ChromaDex (USA).