Naked Mole Rats Employ Cholesterol Metabolism to Enable Cells to Resist the Senescent State

Naked mole-rats exhibit an unusually longevity, with a life span something like nine times as long as that of equivalently sized mammals. They are also highly resistant to cancer. This makes them an attractive subject for research into ways to treat aging and age-related disease. No one mechanism will be the exclusive source of these traits in the naked mole-rat, but it is interesting to look at the way in which cellular senescence is different in this species.

Senescent cell accumulation takes place in tissues throughout the body with advancing age, and in other mammals those senescent cells cause harm via their senescence-associated secretory phenotype (SASP), signals that provoke chronic inflammation and tissue dysfunction. Senescent cells in naked mole-rats - and in the related blind mole-rat species - on the other hand exhibit a minimal SASP.

That is not the only difference in the mechanisms of cellular senescence, as noted here. Naked-mole rat cells employ cholesterol metabolism in ways yet to be fully explored in order to make cells resistant to cellular senescence, thus reducing the number of cells that enter a senescent state. Absent this mechanism, the researchers argue that naked-mole rat cells are, if anything, even more prone to becoming senescent than those of other mammals. This is all quite interesting. In the broader context, applying treatments that reduce the pace at which cells become senescent has been shown to produce benefits to health and life span. That is achieved more slowly than clearing out senescent cells via short-term senolyic therapies, but the effect sizes may turn out to be similar at the end of the day.

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

Naked mole-rats (NMRs; Heterocephalus glaber) are known for their exceptional longevity and remarkable resistance to cancer; indeed, only two cases of cancer reported in captive NMRs were reported after multi-year observation of large colonies. In addition, NMRs are strictly subterranean mammals that live in low-oxygen environments; therefore, they exhibit marked resistance to hypoxia. Interestingly, NMRs can survive in oxygen-deprived (anoxia) conditions for 18 min without noticeable injury. Despite accumulating considerable levels of oxidative damage and protein carbonylation under anoxic conditions, NMRs appear to be resilient to oxidative stress and mitochondrial injury, which is strikingly accompanied by a slower aging rate and increased longevity. In addition, NMRs display negligible senescence accompanied by high fecundity, and most importantly, remain healthy and are resistant to age-related diseases.

These attributes mean that the NMR has been utilized increasingly as an animal model for human aging and cancer research. Several cancer-resistant models have been described in this species. For example, NMR fibroblasts exhibit extreme sensitivity to contact inhibition in tissue culture, which is a potential anticancer mechanism regulated by INK4. An additional study demonstrated that hyaluronan, a high molecular mass polysaccharide of the extracellular matrix, triggers early contact inhibition. Furthermore, treatment with a combination of oncoproteins that trigger tumor formation in mouse cells does not cause malignant transformation of NMR cells, corroborating evidence suggesting that the NMR is resistant to both spontaneous cancer development and experimentally-induced tumorigenesis. Furthermore, it was reported that NMR-derived induced pluripotent stem cells are also tumor resistant.

To identify the mechanisms of longevity and cancer resistance in NMRs, we conducted comparative analyses of oncogenic signaling between NMR skin/lung fibroblasts (NSFs/NLFs), mouse skin fibroblasts (MSFs), and NIH 3T3 cells. We found that NMR cells showed altered Wnt/β-catenin signaling. Basal β-catenin expression was significantly higher in NMR cells than in mouse cells. In addition, β-catenin knockdown in NSFs induced senescence-like phenotypic changes. Meanwhile, we observed abundant lipid droplets with high levels of cholesterol in NMR cells. Because both β-catenin knockdown and cholesterol synthesis inhibition abolished lipid droplet formation and promoted senescence-like phenotypes, we investigated the functional link between β-catenin signaling, cholesterol metabolism, and cellular senescence.

These findings confirmed that NMR cells are intrinsically susceptible to cellular senescence, potentially due to their low rate of basal metabolism, which could be beneficial for longevity and cancer resistance. Hence, upregulation of the unique β-catenin pathway in NMR cells could counterbalance its strong senescence potential, thereby promoting longevity and survival under harsh conditions at the whole-organism level. Further analyses of the molecular mechanisms underlying the anti-senescence functions of cholesterol may reveal unique approaches to treating aging-related conditions.

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