Ana P. Gomes, et al., Declining NAD⁺ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging, Cell 155, 2013
We show that, during aging, there is a specific loss of mitochondrial, but not nuclear, encoded OXPHOS subunits. We trace the cause to an alternate PGC-1 α/β-independent pathway of nuclear-mitochondrial communication that is induced by a decline in nuclear NAD⁺ and the accumulation of HIF-1 α under normoxic conditions, with parallels to Warburg reprogramming. Deleting SIRT1 accelerates this process, whereas raising NAD⁺ levels in old mice in a SIRT1-dependent manner.
The original idea of Harman, that reactive oxygen species (ROS) from mitochondria are a primary cause of aging, has been challenged by recent studies of long-lived species and genetically altered animals.
Mammalian sirtuins (SIRT1-7) are a conserved family of NAD⁺- dependent lysine-modifying amylases that physiological responses to diet and exercise. The expression of SIRT1, and NAD⁺-dependent deacetylase, is elevated in a number of tissues following calorie restriction (CR), an intervention that extends lifespan in diverse species. Overexertion or pharmacological activation of SIRT1 reproduces many of the health benefits of CR, including protection from metabolic decline, cardiovascular disease, cancer, and neurodegeneration.
An aging mechanism that disrupts OXPHOS prior to the accumulation of significant tDNA damage.
Treatment of 22-month-old mice for 1 week with NMN, a precursor to NAD⁺ that increases NAD⁺ levels in vivo, reversed that decline in VHL and accumulation of HIF-1α; reduced lactate levels; and increased ATP, COX activity, and mitochondrially encoded OXPHOS transcripts.
All of the main players in the nuclear NAD⁺-SIRT1-HIF-1α-OXPHOS pathway are present in lower eukaryotes, indicating that the pathway evolved early in life’s history. This pathway may have evolved to coordinate nuclear-mitochondrial synchrony in response to charges in energy supplies and oxygen levels, and its decline may be a conserved cause of aging.