Senescent cell death as an aging resistance mechanism in naked mole-rat

Abstract

<jats:title>Abstract</jats:title><jats:p>Naked mole-rats (NMRs) are the longest-lived rodents, showing minimal aging phenotypes. An unsolved paradox is that NMRs exhibit low intracellular anti-oxidant defence despite minimal aging. Here, we explained a link between these “contradicting” features by a phenomenon termed “senescent cell death (SCD)”—Senescence induced cell death in NMR cells due to their inherent vulnerability to reactive oxygen species and unique metabolic system. In NMR skin, we observed few senescent cells during aging or after ultraviolet irradiation, suggesting suppression of senescent cell accumulation in NMR tissue. We discovered that senescent NMR-fibroblasts induce SCD through retinoblastoma protein activation accompanied by autophagy dysregulation, increased oxidative damage and accelerated H<jats:sub>2</jats:sub>O<jats:sub>2</jats:sub>-releasing metabolic pathways. During senescence, NMR cells showed resistance to metabolic remodelling unlike mice. Our findings provide mechanistic insights into how extraordinary aging resistance is accomplished in NMR. This will contribute to the development of senolytic drugs to regulate age-related diseases.</jats:p>

Single-cell transcriptomics reveals age-resistant maintenance of cell identities, stem cell compartments and differentiation trajectories in long-lived naked mole-rats skin

“…In addition, a recent study suggests that NMR skin could be immune to senescent cells build-up through a unique mechanism: senescent cell death, an immune-independent apoptosis of senescent cells. This mechanism could reduce the chance of senescent cell accumulation, a hallmark of skin aging [ 54 ].…”

DNA Homeostasis and Senescence: Lessons from the Naked Mole Rat

“…NMR senescent cells transcriptome showed an expected increase in transcription of senescence-associated secretory phenotype (SASP) genes, but downregulation of genes in key pathways relating to SASP production and excretion [106]. NMR translation and ribosomal protein genes all demonstrated reduced transcription rates.…”

“…NMRs exhibit the unique phenotype of senescent cell death (SCD) [106], causing senesced cells to spontaneously die, unlike other species where they must be removed directly by the immune system [17]. Immune-independent apoptosis of senescent cells in NMRs prevents build-up of toxic SASP.…”

“…Immune-independent apoptosis of senescent cells in NMRs prevents build-up of toxic SASP. Upon artificial induction of senescence, NMR cells exhibited dysregulation of autophagy, ROS-sensitisation and spontaneous SCD [106]. Healthy NMR cells have a high autophagic response, antioxidant activity and mitochondria containing a high concentration of antioxidants and detoxifying enzymes [103,107].…”

“…Thus, when stress or DNA damage is sufficiently high, NMR cells are still able to enter senescence [108]. However, reduction in protein production and secretion results in lower production of SASP, protecting NMRs from their effects; NMR SCD phenotype enables effective clearance of senescent cells, abrogating their impact on the cellular microenvironment [106].…”