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O P E N A C C E S S S O U R C E (.PDF) : BioXirv
Abstract
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 H2O2-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.
To determine whether senescent cells accumulate in NMR skin tissues during aging, we collected skin biopsy specimens from 13–15 year-old NMRs (middle-aged, the oldest available animals) and one year-old NMRs (young) (Fig. 1a). As controls, we also collected skin biopsies from one year-old mice (middle-aged) and four week-old young mice (young). In middle-aged NMR skin (13–15 year-old), we found almost no cells positive for senescence-associated beta galactosidase (SA-b-Gal) activity, which is associated with cellular senescence. On the other hand, middle-aged mouse skins (one year-old) showed a significant increase in SA-b-Gal-positive cells. (Fig. 1b, c).
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Edited by Engadin, 07 July 2020 - 09:53 AM.
