Fig. 2: NAD⁺ decline causes mitochondrial dysfunction and global epigenetic changes.

Systemic NAD⁺ decline, triggered by the phenomenon called “inflammaging”, induces two critical events: (1) Reduction in the NAD⁺/NADH redox state in the mitochondria, leading to mitochondrial dysfunction, and (2) global epigenetic changes in the nucleus, leading to age-associated transcriptomic changes and functional decline. These two events are not mutually exclusive, and a specific nuclear-mitochondrial communication might contribute to age-associated mitochondrial dysfunction. This signal is triggered by nuclear NAD⁺ decline, which is also caused by DNA damage, and also mediated by sirtuin family members, such as SIRT1 and SIRT6. These two events causally induce a variety of aging phenotypes in a tissue-specific manner.