Naked mole-rats live nine times as long as similarly sized rodents, and are near immune to cancer. Researchers have for some years investigated the biochemistry of this species, in search of mechanisms that might be applied to improve health and longevity in other mammals, or form the basis for cancer therapies. Teams have looked into many different areas: mitochondrial function; better DNA repair; a greatly attenuated senescence-associated secretory phenotype; more efficient operation of cancer-suppression genes; and a heavier form of hyaluronan. Researchers here show that this heavier form of hyaluronan is protective of cells, and can produce this protective effect in human cells as well as naked mole-rat cells.

The longest-living rodent, the naked mole-rat (NMR) (Heterocephalus glaber), has a maximum lifespan of more than 30 years, which is fivefold greater than predicted by body mass. NMR does not show increase in mortality rates for at least 18 years, and seems to be protected from age-related deterioration such as metabolic decline, diabetes, and osteoporosis. These features indicate that NMR has evolved efficient anti-aging mechanisms. However, although NMR is increasingly appreciated as a model for aging research, how they resist aging processes remains largely unknown.

An important NMR-specific anti-cancer mechanism is early contact inhibition (ECI). Cultured NMR fibroblasts are hypersensitive to contact inhibition and stop proliferating at relatively low cell density in a hyaluronan (HA)-dependent manner. HA plays a role in supporting tissue structure and regulating cellular signaling pathways depending on its polymer length. Dynamic regulation of the amount and polymer length of HA is implicated in diverse biological processes including cell proliferation, cell migration, and inflammation. In healthy tissues, most of HA is of high-molecular-mass (HMM-HA). In pathological circumstances, significant fragmentation of HA occurs, giving rise to low-molecular-mass HA. NMR produces very-high-molecular-mass hyaluronan (vHMM-HA), much longer than HA in other mammalian species. However, it is still not clear whether HA of exceptionally high polymer length is functionally different from regular HMM-HA.

The observations that HA exhibits polymer length-dependent cytoprotective effect and that long-lived NMR produces vHMM-HA lead to a hypothesis that additional polymer length of NMR-HA confers superior cytoprotection that could contribute to the NMR’s longevity. Here, we show that vHMM-HA has superior cytoprotective properties compared to the shorter HMM-HA. It protects not only NMR cells, but also mouse and human cells from stress-induced cell-cycle arrest and cell death in a polymer length-dependent manner.

The cytoprotective effect is dependent on the major HA-receptor, CD44. We find that vHMM-HA suppresses CD44 protein-protein interactions, whereas HMM-HA promotes them. As a result, vHMM-HA and HMM-HA induce opposing effects on the expression of CD44-dependent genes, which are associated with the p53 pathway. Concomitantly, vHMM-HA partially attenuates p53 and protects cells from stress in a p53-dependent manner. Our results implicate vHMM-HA in anti-aging mechanisms and suggest the potential applications of vHMM-HA for enhancing cellular stress resistance.