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NADH-cytochrome b5 reductase 3 (EC (B5R) (Cytochrome b5 reductase) (Diaphorase-1) [Contains: NADH-cytochrome b5 reductase 3 membrane-bound form; NADH-cytochrome b5 reductase 3 soluble form] [DIA1]


Overexpression of CYB5R3 and NQO1, two NAD -producing enzymes, mimics aspects of caloric restriction.

Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD /sirtuin pathway. The results highlight the importance of these NAD producers for the promotion of health and extended lifespan.

MeSH Terms

  • Animals
  • Caloric Restriction
  • Cytochrome-B(5) Reductase
  • Energy Metabolism
  • Gene Expression Regulation, Enzymologic
  • Longevity
  • Male
  • Mice
  • Mice, Transgenic
  • NAD(P)H Dehydrogenase (Quinone)
  • Rats


  • CYB5R3
  • NQO1
  • aging
  • calorie restriction
  • metabolic homeostasis

CYB5R3: a key player in aerobic metabolism and aging?

Aging results from a complex and not completely understood chain of processes that are associated with various negative metabolic consequences and ultimately leads to senescence and death. The intracellular ratio of pyridine nucleotides (NAD( )/NADH), has been proposed to be at the center stage of age-related biochemical changes in organisms, and may help to explain the observed influence of calorie restriction and energy-sensitive proteins on lifespan in model organisms. Indeed, the NAD( )/NADH ratios affect the activity of a number of proteins, including sirtuins, which have gained prominence in the aging field as potential mediators of the beneficial effects of calorie restriction and mediating lifespan. Here we review the activities of a redox enzyme (NQR1 in yeast and CYB5R3 in mammals) that also influences the NAD( )/NADH ratio and may play a regulatory role that connects aerobic metabolism with aging.

MeSH Terms

  • Aging
  • Animals
  • Cytochrome-B(5) Reductase
  • Energy Metabolism
  • Humans
  • NAD
  • Sirtuins


  • /NADH
  • NAD
  • NQR1
  • cytochrome b
  • lifespan
  • reductase
  • respiration