Stress resistance at the cellular level is correlated with longevity at the organismal level, to such an extent that one can screen for longevity mutants by first identifying stress-resistant animals. Conversely, the cells of prematurely aging mutants tend to be hypersensitive to stress. The idea here is that longevity is controlled in part by basal and inducible molecular defenses like antioxidants and chaperones, and that high levels of such factors confer both stress resistance and enhanced longevity.

What’s interesting about this pattern is that it seems to apply to a wide range of multiple stresses, with very different physical bases: oxidation, irradiation, starvation, heavy metal toxicity, and temperature, to name a few. Without a great deal of experimental proof to support it, one can imagine some central homeostatic integrator of cellular well-being, upon which all manner of perturbations might impinge and which might in turn control both the appropriate defensive responses and factors that determine longevity.

It would therefore come as a surprise if a long-lived organism turned out to be unusually sensitive to stress — and in particular, sensitive to particular stresses. In one fell swoop, this would falsify both the general, well-accepted correlative pattern (stress resistance = longevity) and the somewhat more fanciful model of a central homeostatic integrator.

Lo, the naked mole rat, Heterocephalus glaber. A eusocial rodent roughly intermediate in size between a mouse and a rat (depending on where you shop), and slightly less aesthetically pleasing than an overcooked boudin blanc with teeth, the naked mole rat has recently drawn the attention of model-hungry biogerontologists worldwide: Perhaps because of the quirky selection pressures on eusocial animals, H. glaber is unusually long-lived compared to animals of similar size and body plan (like mice and rats). Like, ten times longer-lived. So, compared to mice and rats, mole rats should be much more resistant to all stresses, right?

Well, yes and no. From Salmon et al.:

Fibroblasts From Naked Mole-Rats Are Resistant to Multiple Forms of Cell Injury, But Sensitive to Peroxide, Ultraviolet Light, and Endoplasmic Reticulum Stress 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 H2O2, 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.

Short version: naked mole rats are more resistant than mice and rats some stressors, but not all of them. Heat and starvation, two of the classic and longest-known types of stress known to correlate with longevity, work in the expected direction, with the mole rat more resistant. Beyond that, curiously, it’s hard to find patterns. Mole rats are resistant to some oxidative stressors (paraquat) but not others (peroxide) — and to some DNA-damaging agents (MMS) but not others (UV). So it’s hard to imagine that broad-spectrum defensive measures can explain the longevity of the naked mole rat, and the opposite responses to similar stresses more or less rules out the central integrator idea I floated above.

The authors take special note of the fact that cells from both Snell mice (a dwarf variety that is also long-lived) and mole rats are unusually sensitive to factors that block protein folding in the endoplasmic reticulum (ER). Here we have two different longevity models, both showing increased sensitivity to the same stress. Admittedly, it’s a sample size of 2, but it’s still tempting to speculate: Could some output of the unfolded protein response be involved in governing organismal longevity?