C. elegans DAF-12, Nuclear Hormone Receptors and human longevity and disease at old age.
In Caenorhabditis elegans, DAF-12 appears to be a decisive checkpoint for many life history traits including longevity. The daf-12 gene encodes a Nuclear Hormone Receptor (NHR) and is member of a superfamily that is abundantly represented throughout the animal kingdom, including humans. It is, however, unclear which of the human receptor representatives are most similar to DAF-12, and what their role is in determining human longevity and disease at old age. Using a sequence similarity search, we identified human NHRs similar to C. elegans DAF-12 and found that, based on sequence similarity, Liver X Receptor A and B are most similar to C. elegans DAF-12, followed by the Pregnane X Receptor, Vitamin D Receptor, Constitutive Andosteron Receptor and the Farnesoid X Receptor. Their biological functions include, amongst others, detoxification and immunomodulation. Both are processes that are involved in protecting the body from harmful environmental influences. Furthermore, the DAF-12 signalling systems seem to be functionally conserved and all six human NHRs have cholesterol derived compounds as their ligands. We conclude that the DAF-12 signalling system seems to be evolutionary conserved and that NHRs in man are critical for body homeostasis and survival. Genomic variations in these NHRs or their target genes are prime candidates for the regulation of human lifespan and disease at old age.
Mooijaart
S P
SP
Department of Gerontology and Geriatrics, C-2-R, Leiden University Medical Center, P.O. Box 9600, 2300 RC, Leiden, The Netherlands. s.p.mooijaart@lumc.nl
Brandt
B W
BW
Baldal
E A
EA
Pijpe
J
J
Kuningas
M
M
Beekman
M
M
Zwaan
B J
BJ
Slagboom
P E
PE
Westendorp
R G J
RG
van Heemst
D
D
D000375:Aging / Q000235:genetics / Q000502:physiology*; D000818:Animals; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D000090702:Constitutive Androstane Receptor; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D019143:Evolution, Molecular; D005786:Gene Expression Regulation; D006801:Humans; D000071518:Liver X Receptors; D008136:Longevity / Q000235:genetics; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol / Q000235:genetics / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000145:classification / Q000235:genetics / Q000502:physiology*; D011987:Receptors, Steroid / Q000235:genetics / Q000502:physiology*; D016415:Sequence Alignment; D017385:Sequence Homology; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology
D029742:Caenorhabditis elegans Proteins; D000090702:Constitutive Androstane Receptor; C410905:DAF-12 protein, C elegans; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D000077297:Pregnane X Receptor; D018167:Receptors, Calcitriol; D018160:Receptors, Cytoplasmic and Nuclear; D011987:Receptors, Steroid; D014157:Transcription Factors; D002784:Cholesterol