CD38 Dictates Age-Related NAD Decline and Mitochondrial Dysfunction through an SIRT3-Dependent Mechanism.
Nicotinamide adenine dinucleotide (NAD) levels decrease during aging and are involved in age-related metabolic decline. To date, the mechanism responsible for the age-related reduction in NAD has not been elucidated. Here we demonstrate that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of SIRT3 activity. We also identified CD38 as the main enzyme involved in the degradation of the NAD precursor nicotinamide mononucleotide (NMN) in vivo, indicating that CD38 has a key role in the modulation of NAD-replacement therapy for aging and metabolic diseases.
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil.
Juliana
J
Camacho-Pereira
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Mariana G
MG
Tarragó
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Claudia C S
CCS
Chini
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Veronica
V
Nin
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Carlos
C
Escande
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Gina M
GM
Warner
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Amrutesh S
AS
Puranik
Oncology Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Renee A
RA
Schoon
Oncology Research, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Joel M
JM
Reid
Instituto de Bioquímica Médica, Centro de Ciências da Saúde, Universidade Federal do Rio de Janeiro, Cidade Universitária, Ilha do Fundão, Rio de Janeiro, RJ 21941-590, Brazil.
Antonio
A
Galina
Signal Transduction Laboratory, Kogod Aging Center, Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: chini.eduardo@mayo.edu.
Eduardo N
EN
Chini
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism*; D000375:Aging / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat; D008322:Mammals / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000378:metabolism* / Q000648:ultrastructure; D009243:NAD / Q000378:metabolism*; D009244:NAD+ Nucleosidase / Q000235:genetics / Q000378:metabolism; D009536:Niacinamide / Q000031:analogs & derivatives / Q000378:metabolism; D009928:Organ Specificity; D011726:Pyridinium Compounds; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D056566:Sirtuin 3 / Q000378:metabolism*
D011726:Pyridinium Compounds; D012333:RNA, Messenger; C018613:nicotinamide-beta-riboside; D009243:NAD; D009536:Niacinamide; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1; D056566:Sirtuin 3
CD38; NAD(+); aging; glucose intolerance; mitochondrial function