A bstract. Nicotinamide adenine dinucleotide (NAD) is an essential regulator of cellular metabolism and redox processes. NAD levels and the dynamics of NAD metabolism change with increasing age but can be modulated via the diet or medication. Because NAD metabolism is complex and its regulation still insufficiently understood, achieving specific outcomes without perturbing delicate balances through targeted pharmacological interventions remains challenging. NAD metabolism is also highly sensitive to environmental conditions and can be influenced behaviorally, e.g., by exercise. Changes in oxygen availability directly and indirectly affect NAD levels and may result from exposure to ambient hypoxia, increased oxygen demand during exercise, ageing or disease. Cellular responses to hypoxic stress involve rapid alterations in NAD metabolism and depend on many factors, including age, glucose status, the dose of the hypoxic stress and occurrence of reoxygenation phases, and exhibit complex time-courses. Here we summarize the known determinants of NAD-regulation by hypoxia and evaluate the role of NAD in hypoxic stress. We define the specific NAD responses to hypoxia and identify a great potential of the modulation of NAD metabolism regarding hypoxic injuries.
In conclusion, NAD metabolism and cellular hypoxia responses are strongly intertwined and together mediate protective processes against hypoxic insults. Their interactions likely contribute to age-related changes and vulnerabilities. Targeting NAD homeostasis presents a promising avenue to prevent/treat hypoxic insults and – conversely – controlled hypoxia is a potential tool to regulate NAD homeostasis.
Nicotinamide adenine dinucleotide (NAD) regulates cellular metabolism and redox homeostasis and plays an important role in senescence and ageing (Covarrubias et al., 2021, Xiao et al., 2018). The hydrogen transfer capacity of NAD (Warburg et al., 1935) is enabled by its redox site, depends on the balance between oxidized (NAD+) and reduced (NADH) NAD and is crucial for cellular health. About 10 % of the cellular NAD pool is phosphorylated to NADP+ and NADPH, which exert cellular functions distinct from NAD. They play important roles in fatty acid, cholesterol and steroid synthesis, as well as in antioxidant and immune functions (Liu et al., 2018, Ying, 2008). Ageing is associated with decreasing NAD+ availability in skeletal muscle and many other tissues, including brain, heart, liver, adipose tissue, lungs, spleen and pancreas (Chubanava and Treebak, 2023, Gomes et al., 2013, Migliavacca et al., 2019, Yaku et al., 2018). These declines are of particular relevance in the context of age-related diseases, such as sarcopenia (Chubanava and Treebak, 2023). The age-related decline of NAD and disturbance in NAD-metabolism is thought to be a result of changes in the balance of NAD synthesis and consumption/degradation. How these effects influence aging processes and contribute to age-related diseases has been reviewed in numerous excellent reviews (Chini et al., 2017, Verdin, 2015, Yaku et al., 2018). Since the decreasing cellular NAD+ levels are considered a hallmark for senescence (Cantó et al., 2015, Covarrubias et al., 2021), the assumption that increasing NAD+ levels improves various chronic diseases and promotes healthy ageing has recently spurred renewed scientific and economic interest (Canto, 2022, Cantó et al., 2015). Increasing NAD+ availability prolongs the lifespan of yeast (Belenky et al., 2007) and worms (Mouchiroud et al., 2013) and improves metabolic dysfunction, glucose intolerance and lipid profiles in old mice (Gomes et al., 2013, Yoshino et al., 2011). However, elevating NAD concentration alone may not be sufficient to treat human diseases. The complex dynamics of NAD-metabolism, including consuming reactions, need to be considered, too (Opitz and Heiland, 2015).
