Comparing the Effects of Melatonin with Caloric Restriction in the Hippocampus of Aging Mice: Involvement of Sirtuin1 and the FOXOs Pathway

  • Anorut Jenwitheesuk
  • Seongjoon Park
  • Prapimpun Wongchitrat
  • Jiraporn Tocharus
  • Sujira Mukda
  • Isao Shimokawa
  • Piyarat Govitrapong
Original Paper

Abstract

It has been suggested that age-related neurodegeneration might be associated with neuropeptide Y (NPY); sirtuin1 (SIRT1) and forkhead box transcription factors O subfamily (FOXOs) pathways. Melatonin, a hormone mainly secreted by the pineal gland, is another anti-aging agent associated with the SIRT1-FOXOs pathway. This study aimed to compare the effects of melatonin (Mel) and caloric restriction (CR) on the expression of Sirt1, FoxO1, FoxO3a and FOXOs target genes in the aging mouse hippocampus. Neuropeptide Y-knockout (NpyKO) and wild-type (WT) male mice aged 19 months were previously treated either with food ad libitum or CR for 16 months. WT old animals were divided into four groups: control, CR, Mel and CR+Mel treated groups. The Mel and CR+Mel were treated with melatonin 10 mg/kg, daily, subcutaneously for 7 consecutive days. Mel treatment upregulated the mRNA expression of Sirt1, FOXOs (FoxO1 and FoxO3a) target genes that regulated the cell cycle [e.g., cyclin-dependent kinase inhibitor 1B (p27)], Wingless and INT-1 (Wnt1) and inducible signaling pathway protein 1 (Wisp1) in the aged mouse hippocampus. CR treatment also showed the similar actions. However, the mRNA expression of Sirt1, FoxO1, FoxO3a, p27 or Wisp1 did not alter in the CR+Mel group when compared with CR or Mel group. Melatonin could not produce any additive effect on the CR treatment group, suggesting that both treatments mimicked the effect, possibly via the same pathway. NPY which mediates physiological adaptations to energy deficits is an essential link between CR and longevity in mice. In order to focus on the role of Npy in mediating the effects of melatonin, the gene expression between NpyKO and WT male mice were compared. Our data showed that, in the absence of Npy, melatonin could not mediate effects on those gene expressions, suggesting that Npy was required for melatonin to mediate the effect, possibly, on life extension.

Keywords

Caloric restriction Melatonin Sirtuin1 FoxO1 Neuropeptide Y Aging 

Abbreviations

ADAM10

A disintegrin and metalloprotease domain 10

AgRP

Agouti-related peptide

AMPK

Adenosine monophosphate-activated protein kinase

CART

Cocaine and amphetamine regulated transcript

CBP

CREB-binding protein

CR

Caloric restriction

DKK1

Wnt inhibitor Dickkopf WNT signaling pathway inhibitor 1

FOXOs

Forkhead box transcription factors and the O subfamily

GAPDH

Glyceraldehyde 3-phosphate dehydrogenase

IGF-1

Insulin-like growth factor-1

Mel

Melatonin

NAD

Nicotinamide adenine dinucleotide

NAMPT

Nicotinamide phosphoribosyltransferase

NF-κB

Nuclear factor-κB

NMNAT

Nicotinamide/nicotinic acid mononucleotide adenylyltransferase

NPY

Neuropeptide Y

Nrf2

Nuclear factor (erythroid-derived 2)-like 2

POMC

Anorexigenic proopiomelanocortin

p27

Cyclin-dependent kinase inhibitor 1B

p300

E1A binding protein p300

p53

Tumor suppressor protein 53

PGC-1α

Peroxisome proliferator-activated receptor gamma coactivator 1-alpha

PI3K

Phosphoinositide-3-kinase

POMC

Proopiomelanocortin

PPAR-γ

Peroxisome proliferator-activated receptor gamma

SAMP8

Senescence-accelerated mouse prone 8

SAMR1

Senescence-accelerated-resistant mouse

SIRT

Sirtuin

Wisp1

Wn1 inducible pathway protein1

WNT

Wingless-type

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Anorut Jenwitheesuk
    • 1
  • Seongjoon Park
    • 2
  • Prapimpun Wongchitrat
    • 3
  • Jiraporn Tocharus
    • 4
  • Sujira Mukda
    • 1
  • Isao Shimokawa
    • 2
  • Piyarat Govitrapong
    • 1
    • 5
    • 6
  1. 1.Research Center for Neuroscience, Institute of Molecular BiosciencesMahidol UniversitySalayaThailand
  2. 2.Department of PathologyNagasaki University School of Medicine and Graduate School of Biomedical SciencesNagasakiJapan
  3. 3.Center for Research and Innovation, Faculty of Medical TechnologyMahidol UniversitySalayaThailand
  4. 4.Department of Physiology, Faculty of MedicineChiang Mai UniversityChiang MaiThailand
  5. 5.Center for Neuroscience and Department of Pharmacology, Faculty of ScienceMahidol UniversitySalayaThailand
  6. 6.Chulabhorn Graduate InstituteChulabhorn Royal AcademyBangkokThailand

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