The combination of nicotinamide mononucleotide and lycopene prevents cognitive impairment and attenuates oxidative damage in D-galactose induced aging models via Keap1-Nrf2 signaling

Gene. 2022 May 15:822:146348. doi: 10.1016/j.gene.2022.146348. Epub 2022 Feb 17.


Aging is referred to progressive dysfunction of body organs, including the brain. This study aims to explore the anti-aging effect of combing nicotinamide mononucleotide (NMN) and lycopene (Lyco) (NMN + Lyco) on aging rats and senescent PC12 cells. Both in vivo and in vitro aging models were established using D-galactose (D-gal). The combination showed a trend to superiority over monotherapy in preventing aging in vivo and in vitro. Morris water maze test showed that NMN + Lyco effectively improved the ability of spatial location learning and memory of aging model rats. NMN + Lyco mitigated the oxidative stress of rat brains, livers, and PC12 cells by elevating the levels of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), GSH, as well as total antioxidant capacity (T-AOC), and reducing malondialdehyde (MDA) content. CCK-8 assay, senescence-associated β-galactosidase staining, and flow cytometer confirmed the cellular senescence of PC12 cells after exposing D-gal, and indicated the anti-senescence effect of NMN + Lyco in vitro. Moreover, NMN + Lyco effectively down-regulated the expressions of p53, p21, and p16 (senescence-related genes), and activated Keap1-Nrf2 signaling in both in vivo and in vitro aging models. In total, NMN + Lyco protected rats and PC12 cells from cognitive impairment and cellular senescence induced by D-gal, of which effects might be linked to the reduction of oxidative stress and the activation of Keap1-Nrf2 signaling.

Keywords: Aging; Keap1-Nrf2 signaling; Lycopene; Nicotinamide mononucleotide; Oxidative stress.

MeSH terms

  • Aging / drug effects
  • Aging / psychology*
  • Animals
  • Cognitive Dysfunction / etiology
  • Cognitive Dysfunction / prevention & control*
  • Drug Therapy, Combination
  • Galactose / adverse effects*
  • Gene Expression Regulation / drug effects
  • Kelch-Like ECH-Associated Protein 1 / metabolism*
  • Lycopene / administration & dosage*
  • Lycopene / pharmacology
  • Male
  • Morris Water Maze Test
  • NF-E2-Related Factor 2 / metabolism*
  • Nicotinamide Mononucleotide / administration & dosage*
  • Nicotinamide Mononucleotide / pharmacology
  • Oxidative Stress / drug effects
  • PC12 Cells
  • Rats
  • Signal Transduction / drug effects
  • Spatial Learning / drug effects
  • Treatment Outcome


  • KEAP1 protein, rat
  • Kelch-Like ECH-Associated Protein 1
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, rat
  • Nicotinamide Mononucleotide
  • Lycopene
  • Galactose