β-catenin-promoted cholesterol metabolism protects against cellular senescence in naked mole-rat cells

AbstractThe naked mole-rat (NMR; Heterocephalus glaber) exhibits cancer resistance and an exceptionally long lifespan of approximately 30 years, but the mechanism(s) underlying increased longevity in NMRs remains unclear. In the present study, we report unique mechanisms underlying cholesterol metabolism in NMR cells, which may be responsible for their anti-senescent properties. NMR fibroblasts expressed β-catenin abundantly; this high expression was linked to increased accumulation of cholesterol-enriched lipid droplets. Ablation of β-catenin or inhibition of cholesterol synthesis abolished lipid droplet formation and induced senescence-like phenotypes accompanied by increased oxidative stress. β-catenin ablation downregulated apolipoprotein F and the LXR/RXR pathway, which are involved in cholesterol transport and biogenesis. Apolipoprotein F ablation also suppressed lipid droplet accumulation and promoted cellular senescence, indicating that apolipoprotein F mediates β-catenin signaling in NMR cells. Thus, we suggest that β-catenin in NMRs functions to offset senescence by regulating cholesterol metabolism, which may contribute to increased longevity in NMRs.

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Molecular evolution of the hyaluronan synthase 2 gene in mammals: implications for adaptations to the subterranean niche and cancer resistance

Biology Letters ◽

10.1098/rsbl.2015.0185 ◽

2015 ◽

Vol 11 (5) ◽

pp. 20150185 ◽

Cited By ~ 11

Author(s):

Christopher G. Faulkes ◽

Kalina T. J. Davies ◽

Stephen J. Rossiter ◽

Nigel C. Bennett

Keyword(s):

Purifying Selection ◽

High Molecular Mass ◽

Hyaluronan Synthase ◽

Cancer Resistance ◽

Closely Related Species ◽

Heterocephalus Glaber ◽

Mole Rat ◽

Naked Mole Rat ◽

Subterranean Mammals ◽

Hyaluronan Synthase 2

The naked mole-rat (NMR) Heterocephalus glaber is a unique and fascinating mammal exhibiting many unusual adaptations to a subterranean lifestyle. The recent discovery of their resistance to cancer and exceptional longevity has opened up new and important avenues of research. Part of this resistance to cancer has been attributed to the fact that NMRs produce a modified form of hyaluronan—a key constituent of the extracellular matrix—that is thought to confer increased elasticity of the skin as an adaptation for living in narrow tunnels. This so-called high molecular mass hyaluronan (HMM-HA) stems from two apparently unique substitutions in the hyaluronan synthase 2 enzyme (HAS2). To test whether other subterranean mammals with similar selection pressures also show molecular adaptation in their HAS2 gene, we sequenced the HAS2 gene for 11 subterranean mammals and closely related species, and combined these with data from 57 other mammals. Comparative screening revealed that one of the two putatively important HAS2 substitutions in the NMR predicted to have a significant effect on hyaluronan synthase function was uniquely shared by all African mole-rats. Interestingly, we also identified multiple other amino acid substitutions in key domains of the HAS2 molecule, although the biological consequences of these for hyaluronan synthesis remain to be determined. Despite these results, we found evidence of strong purifying selection acting on the HAS2 gene across all mammals, and the NMR remains unique in its particular HAS2 sequence. Our results indicate that more work is needed to determine whether the apparent cancer resistance seen in NMR is shared by other members of the African mole-rat clade.

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Imiquimod does not elicit inflammatory responses in the skin of the naked mole rat (Heterocephalus glaber)

10.21203/rs.3.rs-41203/v2 ◽

2020 ◽

Author(s):

Mosiany Letura Kisipan ◽

Rodi Omondi Ojoo ◽

Titus I. Kanui ◽

Klas S.P. Abelson

Keyword(s):

Granular Layer ◽

Inflammatory Responses ◽

Cancer Resistance ◽

Skin Reactions ◽

Heterocephalus Glaber ◽

Skin Changes ◽

Mole Rat ◽

Naked Mole Rat ◽

Inflammatory Skin ◽

Skin Conditions

Abstract Objective: Naked mole rat (Heterocephalus glaber) has recently attracted interest in biomedical research due to its exceptional longevity, cancer resistance and tolerance to potentially harmful conditions or stimuli. Given its unique attributes, this study was designed to characterize inflammatory skin reactions of this animal to topical application of imiquimod, a toll-like receptor 7 and 8 agonist that triggers psoriasis-like skin reaction. Results: Imiquimod did not cause the expected psoriasis-like skin changes. There was no epidermal thickening and a straight epidermo-dermal boundary was maintained. There was no parakeratosis and the granular layer of epidermis was well formed. In the dermis, there was no leukocyte infiltration. This points to an exceptional nature of inflammatory/immune responses of this animal, but the mechanism could not be explained by our results. Naked mole rat could be a valuable negative model for studying psoriasis and other inflammatory skin conditions but as a prerequisite, there is need for further investigations to establish the mechanisms behind its lack of response to imiquimod.

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Insights into long noncoding RNAs of naked mole rat (Heterocephalus glaber) and their potential association with cancer resistance

Epigenetics & Chromatin ◽

10.1186/s13072-016-0101-5 ◽

2016 ◽

Vol 9 (1) ◽

Cited By ~ 6

Author(s):

Jian-Jun Jiang ◽

Le-Hua Cheng ◽

Huan Wu ◽

Yong-Han He ◽

Qing-Peng Kong

Keyword(s):

Noncoding Rnas ◽

Long Noncoding Rnas ◽

Cancer Resistance ◽

Heterocephalus Glaber ◽

Mole Rat ◽

Potential Association ◽

Naked Mole Rat

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Imiquimod does not elicit inflammatory responses in the skin of the naked mole rat (Heterocephalus glaber)

10.21203/rs.3.rs-41203/v1 ◽

2020 ◽

Author(s):

Mosiany Letura Kisipan ◽

Rodi Omondi Ojoo ◽

Titus I. Kanui ◽

Klas S.P. Abelson

Keyword(s):

Granular Layer ◽

Inflammatory Responses ◽

Cancer Resistance ◽

Skin Reactions ◽

Heterocephalus Glaber ◽

Skin Changes ◽

Mole Rat ◽

Naked Mole Rat ◽

Inflammatory Skin ◽

Skin Conditions

Abstract Objective Naked mole rat (Heterocephalus glaber) has recently attracted interest in biomedical research due to its exceptional longevity, cancer resistance and tolerance to potentially harmful conditions or stimuli. Given its unique attributes, this study was designed to characterize inflammatory skin reactions of this animal to topical application of imiquimod, a toll-like receptor 7 and 8 agonist that triggers psoriasis-like skin reaction. Results Imiquimod did not cause the expected psoriasis-like skin changes. There was no epidermal thickening and a straight epidermo-dermal boundary was maintained. There was no parakeratosis and the granular layer of epidermis was well formed. In the dermis, there was no leukocyte infiltration. This points to an exceptional nature of inflammatory/immune responses of this animal, but the mechanism could not be explained by our results. Naked mole rat could be a valuable negative model for studying psoriasis and other inflammatory skin conditions but as a prerequisite, there is need for further investigations to establish the mechanisms behind its lack of response to imiquimod.

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