Declining NAD+ Induces a Pseudohypoxic State Disrupting Nuclear-Mitochondrial Communication during Aging

In the citing paper

“Notably, NAD+ declines with age in several tissues”

In the citing paper

“Although HIF1α has been shown to increase during aging affecting nuclear–mitochondrial communication”

In the citing paper

“Metformin’s direct activation of SIRT1 may help combat age-related mitochondrial dysfunction which is attributed to a reduction in SIRT1 activity leading to downregulation of a nuclear-encoded mitochondrial transcription factor A (TFAM) and declines in NAD+ levels”

In the citing paper

“NAD+ is a vital redox cofactor for metabolism and ATP production, and a key substrate for at least four families of enzymes involved in healthspan and longevity (Fang et al., 2017; Gomes et al., 2013; Verdin, 2015).”

In the citing paper

“NAD+ is central to mitochondrial homeostasis, including in mitochondrial biogenesis, mitophagy, the mitochondrial unfolded protein response (UPRmt), and nuclear-mitochondrial communication (Fang et al., 2014; Gomes et al., 2013; Mouchiroud et al., 2013).”

In the citing paper

“Furthermore, NAD+ depletion induces a pseudohypoxic state that disrupts PGC-1α/β-independent nuclear-mitochondrial communication, which contributes to the decline in mitochondrial function with age (Gomes et al., 2013).”

In the citing paper

“NMN enhances mitochondrial function in various organs, including skeletal muscle201, kidney202–204, liver203, heart205, eyes206, brain161 and the cardiovascular system207, and can mitigate oxidative stress in the vasculature208, including improvements in neurovascular coupling responses in the aged cortex of the brain209.”

In the citing paper

“These studies also documented that NMN has a significant effect on improving disease conditions and reducing age-related physiological decline [203–206].”

In the citing paper

“causing mitochondrial dysfunction and metabolic abnormalities”

In the citing paper

“Recent studies show that levels of NAD+ and its precursors decline during chronological aging and in progeroid syndromes”

In the citing paper

“many of these phenotypes are regulated by NAD+ availability and the activity of NAD+-dependent enzymes”

In the citing paper

“These data indicate that age-related mitochondrial dysfunction is reversible and contributes to dysfunction in aged tissues.”

In the citing paper

“A recent study reported that reduced levels of NAD+ contribute to the mitochondrial decay associated with skeletal muscle aging and that SIRT1 modulates this process118.”

In the citing paper

“The imbalance between nuclearly and mitochondrially encoded respiratory chain subunits caused by declining nuclear NAD+ was shown to disrupt oxidative phosphorylation in aged mice, whereas raising nuclear NAD+ levels restored mitochondrial function in old mice.”

In the citing paper

“The imbalance between nuclearly and mitochondrially encoded respiratory chain subunits caused by declining nuclear NAD+ was shown to disrupt oxidative phosphorylation in aged mice, whereas raising nuclear NAD+ levels restored mitochondrial function in old mice.”

In the citing paper

“A recent study reported that reduced levels of NAD+ contribute to the mitochondrial decay associated with skeletal muscle aging and that SIRT1 modulates this process118.”

In the citing paper

“In aged mice, loss of SIRT1 activity (via a decline in NAD+ levels) leads to increased activity of the HIF-1α transcription factor that is linked with age-associated mitochondrial dysfunction and changes in oxidative phosphorylation (Gomes et al., 2013).”

In the citing paper

“nuclear-mitochondrial communication is also a key determinant of longevity in animals (Chang et al., 2015; Gomes et al., 2013).”

In the citing paper

“Mitochondrial dysfunction and low nicotinamide adenine dinucleotide (NAD+) levels are hallmarks of skeletal muscle ageing and sarcopenia1–3”

In the citing paper

“In rodents, the age-dependent decline in NAD+ levels decreases SIRT1 activity, ultimately affecting mitochondrial homeostasis48.”

In the citing paper

“In 22-month-old mice, NMN restored NAD+ levels and markers of mitochondrial decline during ageing48, while reducing age-associated body weight gain and increasing energy metabolism and physical activity254.”

In the citing paper

“Reduced NAD+ levels in skeletal muscle of aged or Nampt deficient mice alter mitochondrial bioenergetics and impair muscle mass, strength and endurance49,50,52,53”

In the citing paper

“However, low NAD+ is a causal mechanism for mitochondrial perturbations in age-related pathologies in model organisms49–51.”

In the citing paper

“It is now recognized that one of the major causes of aging and degenerative disease is the depletion of NAD+ in aging cells [87,88,89,90,91,92].”

In the citing paper

“Of note, the expression of Sirt1, Tfam and c-myc was also increased in Parib treated muscles (Figure S3K), which indicates that a recently identified SIRT1-dependent pathway (Gomes et al., 2013) by which NAD+ controls metabolic health might also be at play.”

In the citing paper

“Gomes et al. reported that intraperitoneal injection of 500 mg/kg/day nicotinamide mononucleotide for 7 days could reverse muscle atrophy in aged C57BL/6J mice by decreasing the expression of MAFbx and MuRF1 [69].”