Deletion of Nrip1 delays skin aging by reducing adipose-derived mesenchymal stem cells (ADMSCs) senescence, and maintaining ADMSCs quiescence

Abstract

Our previous studies found that deletion of nuclear receptor interacting protein 1 (Nrip1) extended longevity in female mice and delayed cell senescence. The current study investigates the role of NRIP1 in regulating functions of adipose-derived mesenchymal stem cells (ADMSCs) and explores the mechanisms of NRIP1 in skin aging. We first verified the skin aging phenotypes in young (6 months) and old (20 months) C57BL/6J (B6) mice and found deletion of Nrip1 can delay skin aging phenotypes, including reduced thickness of dermis and subcutaneous white adipose tissue (sWAT), as well as the accumulation of senescent cells in sWAT. In ADMSCs isolated from sWAT, we found that deletion of Nrip1 could decrease cell proliferation, prevent cell apoptosis, and suppress adipogenesis. Interestingly, deletion of Nrip1 also reduced cell senescence and maintain cell quiescence of ADMSCs. Moreover, the expressions of genes associated with senescence (p21, and p53), inflammation (p65, IL6, and IL1a), and growth factor (mTOR, Igf1) were reduced in Nrip1 knockout ADMSCs, as well as in siNrip1-treated ADMSCs. Suppression of Nrip1 by siNrip1 also decreased the expressions of mTOR, p-mTOR, p65, and p-p65 in ADMSCs. Reduced expressions of p65 and p-p65 were also confirmed in the skin of Nrip1 knockout mice. These findings suggest that NRIP1 plays an important role in delaying skin aging by reducing ADMSCs senescence and maintaining ADMSCs quiescence.

Whole-body adipose tissue multi-omic analyses in sheep reveal molecular mechanisms underlying local adaptation to extreme environments

“…Selective sweeps tests detected a set of genes involved in adipocyte hyperplasia, which have been identified as candidate genes for the fat tail phenotype of involvement in the sheep in previous studies, such as BMP2 5,19,20 , PDGFD 18,23,50,51 , GLIS1 16 , and VEGFA 52 . In addition, selective sweep tests detected a few candidate genes involved in terminal adipogenic differentiation such as IGFBP-3 (Interference with PPARγ) 53 , INSIG2 (Involvement in human adipocyte metabolism and body weight regulation) 54 , JAK2 (The JAK2/STAT3 pathway regulates C/EBPβ transcription) 55 , ALG3 (Being involved in the biosynthesis of the N glycan precursor) 56 and Nrip1 (Deletion of Nrip1 could decrease cell proliferation, prevent cell apoptosis, and suppress adipogenesis) 57 . These genes are involved in adipocyte hyperplasia and terminal adipogenic differentiation in the early stages of adipogenesis, resulting in a large difference in the adipocyte numbers in tail fat between fat-tailed sheep and thin-tailed sheep (Fig.…”

Mechanism of action and therapeutic effects of oxidative stress and stem cell-based materials in skin aging: Current evidence and future perspectives

“…Meanwhile, the forced maintenance of COL17A1 showed anti-aging potential ( Liu et al, 2019 ). Besides, the crucial role of nuclear receptor interacting protein 1 (Nrip1) in aging was proposed by Hu et al Skin aging was indicated to be delayed with the reduced expression of senescence-associated (p21 and p53), inflammation-associated (p65, IL6, and IL-1α), and growth factor-associated (mTOR, Igf1) genes under Nrip1 knockout in ADMSCs ( Hu et al, 2021 ). The disruption of circadian clock activity through BMAL1 depletion is linked to the increased differentiation of interfollicular epidermal stem cells (IFESCs) in arrhythmic, prematurely aging mice ( Welz et al, 2019 ).…”

Cellular senescence in skin‐related research: Targeted signaling pathways and naturally occurring therapeutic agents

“…Recently, the role of p53, which regulates cell cycle arrest, DNA repair, and apoptosis, has been linked to inducing cellular senescence secondary to loss of p53 function and chromosomal instability (Mijit et al, 2020 ). Moreover, Hu et al ( 2021 ) demonstrated that genes associated with cellular senescence such as p21 and p53 were reduced in vitro and in vivo models. Interesting is the role of Forkhead box O (FOXO), which modulates the cell cycle, apoptosis, and metabolism, and its misregulation is linked to numerous diseases, including melanoma.…”