NAD+ International Scientist-training

Project Information

NADIS

Grant agreement ID: 101073251

DOI

10.3030/101073251

EC signature date 6 July 2022

Start date 1 November 2022

End date 31 October 2026

Funded under

• Marie Skłodowska-Curie Actions (MSCA)

Total cost

No data

EU contribution

€ 2 530 832,34

Coordinated by

STICHTING AMSTERDAM UMC
Netherlands

Periodic Reporting for period 1 - NADIS (NAD+ International Scientist-training)

Reporting period: 2022-11-01 to 2024-10-31

Summary of the context and overall objectives of the project

Nicotinamide adenine dinucleotide (NAD+) is a molecule that plays a vital role in the body’s energy production and many other functions. When cells run low on NAD+, it can lead to various diseases, including diabetes mellitus, neurodegenerative disorders, and infertility. On the flip side, increasing NAD+ levels might help prevent or treat these conditions. Research has uncovered important links between NAD+ and diseases like diabetes, Alzheimer’s, and even how long we live. Scientists are also looking at how lifestyle choices, nutrition, and medications can affect NAD+ levels to improve health and aging. However, there is still much we do not know, such as how NAD+ levels change throughout life, how their imbalance leads to disease, and which methods for boosting NAD+ are best for treating different conditions. The NADIS research group aims to fill these gaps by training new scientists to use advanced tools to study NAD+ and its role in health and disease. The potential scientific and societal impact of advancing our understanding of NAD+ is significant. By uncovering how NAD+ affects metabolism and disease, we expect to pave the way for new treatments for a wide range of age-related diseases. This could not only improve the quality of life for millions of people but also reduce healthcare costs associated with chronic and age-related diseases. Furthermore, developing NAD+-based therapies could promote healthier aging and extend lifespans, benefiting society as a whole by enhancing well-being in older populations and potentially transforming public health strategies. Finally, the knowledge gained through this research could also drive innovation in nutrition, pharmaceuticals, and lifestyle interventions, creating new opportunities for economic growth.

Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far

In Work Package 1, a template for Personal Career Development Plans was introduced to help Doctoral Candidates (DCs) align their PhD projects with long-term and short-term training goals. Training activities included a mix of in-person and online events to build both scientific and transferable skills. Additionally, DCs participated in secondments at partner institutions, fostering collaboration and learning new techniques. Regular meetings and journal clubs were held to discuss project progress and developments in the field.

Work Package 2-5 focused on scientific advancements. In Work Package 2, the AMC group developed a precise method for quantifying NAD+ in small blood volumes, emphasizing the importance of sample preservation. The EPFL group evaluated NAD+ precursors and found that some showed limited effectiveness compared to other precursors. The UNIGE group studied TRPM2 and CD38’s roles in adipose tissue and is investigating their potential for addressing obesity and metabolic diseases. The UCPH group examined extracellular PARylation, uncovering insights into its role in cellular communication and stress responses, particularly during DNA damage.

Work Package 3 included projects on NAD metabolism in contexts like ovarian health and obesity. The AMC group pursues efforts related to research on oocyte metabolism. The UOULU group optimized methods to measure NAD+ in adipocyte models, identifying metabolic differences linked to obesity and weight loss strategies. Meanwhile, the Khondrion group studied NAD+ precursors in mitochondrial disease models, finding mixed results regarding their ability to prevent cell death.

Work Package 4 focused on Alzheimer’s and Parkinson’s diseases. The UiO team demonstrated that NAD+ precursors and mitophagy inducers could mitigate tau pathology in Alzheimer’s models, while also reducing Aβ aggregates in mouse models. The IMAGINE group successfully developed midbrain and intestinal organoid models, replicating key aspects of Parkinson’s disease and revealing vulnerabilities in specific neuron populations.

Work Package 5 explores NAD in aging, focusing on its loss due to DNA damage and the effects of supplementation. UCPH investigates NAD's role in aging and lifespan using models like Cockayne syndrome fish and Alzheimer’s 5XFAD mice, alongside cell studies on DNA damage responses. EPFL examines tissue-specific NAD+ dynamics during early life, revealing differential NAD+ precursor use. AMC screens over 150 plants for NAD+ precursors, optimizing extraction methods, and using the methods developed in WP2 to identify changes in blood NAD+ metabolism in human cohorts.

Overall, this highlights significant progress in research, training, and collaboration within the NADIS project.

Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far)

The NADIS project offers several advancements that push beyond the current state of the art. The AMC group’s method for NAD+ quantification in small blood volumes represents a significant improvement for diagnostic applications, offering precision and reliability through enhanced preservation protocols, with the ultimate potential of monitoring healthy aging in people. The EPFL group’s work highlights the nuanced roles and limited efficacy of certain NAD+ precursors, and emphasizes the therapeutic potential of reduced precursors. The UNIGE group’s findings on TRPM2 and its role in lipid metabolism introduce promising therapeutic targets for combating obesity and metabolic diseases through white adipose tissue browning. Meanwhile, the UCPH group’s discovery of extracellular PARylation as a mechanism for cellular communication and stress response provides novel insights into DNA damage repair processes and can offer new directions to treat age-related diseases. UiO’s work on NAD+-related therapies for Alzheimer’s disease offer a transformative approach to neurodegeneration. UCPH provides state-of-the-art advancements by linking NAD+ loss to DNA damage and demonstrating its replenishment can mitigate defects in Cockayne syndrome fish and Alzheimer’s mice. AMC's innovative screening of over 150 plants for NAD+ precursors and optimization of metabolite quantification methods enhances natural NAD+ source identification. IMAGINE’s development of midbrain and intestinal organoids brings unprecedented models for Parkinson’s disease research, enabling better replication of disease mechanisms. Combined with its innovative public engagement strategies, the project is setting new standards in both science and outreach.