Fibroblasts From Naked Mole-Rats Are Resistant to Multiple Forms of Cell Injury, But Sensitive to Peroxide, Ultraviolet Light, and Endoplasmic Reticulum Stress

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Abstract

Fibroblasts from long-lived mutant mice are resistant to many forms of lethal injury as well as to the metabolic effects of rotenone and low-glucose medium. Here we evaluated fibroblasts from young adult naked mole-rats (NMR; Heterocephalus glaber), a rodent species in which maximal longevity exceeds 28 years. Compared to mouse cells, NMR cells were resistant to cadmium, methyl methanesulfonate, paraquat, heat, and low-glucose medium, consistent with the idea that cellular resistance to stress may contribute to disease resistance and longevity. Surprisingly, NMR cells were more sensitive than mouse cells to H(2)O(2), ultraviolet (UV) light, and rotenone. NMR cells, like cells from Snell dwarf mice, were more sensitive to tunicamycin and thapsigargin, which interfere with the function of the endoplasmic reticulum (ER stress). The sensitivity of both Snell dwarf and NMR cells to ER stress suggests that alterations in the unfolded protein response might modulate cell survival and aging rate.

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When protein folding in the endoplasmic reticulum (ER) is disrupted by alterations in homeostasis in the ER lumen, eucaryotic cells activate a series of signal transduction cascades that are collectively termed the unfolded protein response (UPR). Here we summarize our current understanding of how the UPR functions upon acute and severe stress. We discuss the mechanism of UPR receptor activation, UPR signal transduction to translational and transcriptional responses, UPR termination, and UPR signals that activate upon irreversible damage. Further, we review recent studies that have revealed that UPR provides a wide spectrum of physiological roles. Each individual UPR subpathway provides a unique and specialized role in diverse developmental and metabolic processes. This is especially observed for professional secretory cells, such as plasma cells, pancreatic beta cells, hepatocytes, and osteoblasts, where high-level secretory protein synthesis requires a highly evolved mechanism to properly fold, process, and secrete proteins. There is a growing body of data that suggest that different subpathways of the UPR are required throughout the entire life of eucaryotic organisms, from regulation of differentiation to induction of apoptosis.

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The naked mole-rat: a new long-living model for human aging research.

R Buffenstein (2005)

Tremendous variation in maximum life span among species overshadows modest increases in longevity resulting from experimental manipulation. Few aging studies focus on long-lived mammals even though these species may expose mechanisms involved in resisting aging. Naked mole-rats (NMRs approximately 35 grams) are the longest-living (>28.3 years) rodents known. This review describes their biology and potential use in aging research. Lifestyle features concur with most evolutionary theories with the exception of the disposable soma theory. Indeed, maximum life span is similar in breeders and nonbreeders, and these highly fecund animals reproduce until they die. Shared characteristics with calorie-restricted, methionine-restricted, and dwarf mice models of extended longevity include reduced body temperature; reduced thyroid, and blood glucose concentrations; and low glycated hemoglobin; in addition to reduced incidence of cancer. Young naked mole-rats surprisingly have high levels of accrued oxidative damage. With their similar longevity quotient to humans, these rodents may provide a novel opportunity to examine mechanisms modulating aging.