The NAD+-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications

Abstract

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.

Keywords: Age-related diseases; Ageing; Alzheimer’s disease; Artificial intelligence; Mitophagy; NAD(+).

Fig. 1.. Schematic representation of NAD⁺ mediated coupling of mitophagy and mitochondrial biogenesis for maintenance of homeostasis and longevity.

Cellular levels of NAD⁺ decline in an age-dependent manner. NAD⁺ is a cofactor for sirtuins (i.e. SIRT1) as well as other NAD⁺ consuming enzymes including: PARPs, CD38, and CD157. The NAD⁺/sirtuins pathways regulate both mitochondrial biogenesis and induction of mitophagy through designated pathways as detailed in the text. E.g., mitochondrial biogenesis can be triggered by SIRT1 mediated deacetylation and thus activates peroxisome proliferator-activated receptorgamma coactivator 1-alpha (PGC-1α), which in turn translocates to nucleus and interacts with AMP-activated protein kinase (AMPK) to trigger the expression of nuclear factor-erythroid 2-related factor 2 (NRF-2) that in turn orchestrates numerous mitochondrial, stress resistance and longevity genes. Induction of mitophagy is triggered by the NAD⁺/SIRT1 pathway via multiple pathways, including AMPK-dependent phosphorylation of ULK1, and NIX upregulation. A synergy between mitochondrial biogenesis and mitophagy, as well as the involvement of other known and unknown mechanisms, maintains mitochondrial homeostasis, stress resistance, and finally results in healthy longevity in animals. To note, there may be many other NAD⁺-dependent but sirtuin-independent pathways that contribute to longevity, mitochondrial homeostasis and stress resistance. Abbreviations: Mito., mitochondrial; trans., transfer.