Naked mole rats are the longest-living rodents, with recorded life spans of over 30 years in captivity. They are native to East Africa, where they live in large colonies in underground burrows. Maximum species lifespan is usually correlated with body size but, like us, naked mole rats are outliers, with longevity quotients far exceeding those expected for animals their size (approximately 35g).

We did it with hygiene, vaccines, and other modern public health measures. How do these rodents do it? A new study adds to the confused picture of how these animals maintain their health.

Senescence vs. cancer

A hallmark of cancer cells is their immortality. Cancer and aging are like opposite poles of a cellular seesaw; molecular mechanisms that protect against one tend to have the unfortunate side effect of promoting the other. But naked mole rats seem to have avoided the pitfalls of both. They almost never get cancer, but they don’t appear aged until the very end of their lives and they are capable of breeding the whole time.

Cellular senescence, in which cells permanently stop dividing, is one way that cells avoid cancer. But it's also a hallmark of aging and its associated pathologies and tissue deterioration. Eliminating senescent cells from mice extends their healthy lifespan.

Rather than being a single process, however, there are different types of senescence, each induced by a different kind of biological stress.

One of these is called "replicative senescence," in which cells no longer make a new copy of their DNA, an essential prelude to cell division. This typically occurs when the ends of a cell's chromosomes, which help protect the gene-rich regions, get too short, which happens with age. Cancer cells typically active an enzyme that expands the chromosome ends, getting around this limit.

Naked mole rat cells make a lot of the same enzyme but still do not become cancerous. Possibly as a result, they do not enter replicative senescence.

It’s in the details

Dr. Vera Gorbunova, who uses naked mole rats to study aging, wondered if their cells went through any other type of senescence. She found that they did. The cells shut down in response to DNA-damaging agents like gamma radiation, or when a cancer-inducing gene was inserted. They also undergo senescence in specific cell populations during embryonic development, including their hair follicles. She suggests that perhaps this is why they are naked.

Their senescent cells were different from those in other mammals, though. First of all, they required twice the gamma radiation that mice need to induce senescence. Some mouse cells underwent programmed cell death in response to the radiation, but the naked mole rat cells did not.

Senescence was different in other ways, too. In mice, senescence disturbed that activity of more genes, and in a wider variety of pathways. The genes it disturbed in the naked mole rat cells were clustered in well-defined metabolic pathways. The mole rat cells shut down genes that help them make proteins, while genes involved in metabolism and clearing out damaged proteins were activated. Overall, the pattern indicated an inhibition of cellular metabolism; coupled with the higher dose of radiation they could weather and their lack of cell death suggests that naked mole rat cells can better tolerate DNA damage.

Senescent cells are usually associated with age-related pathologies, like atherosclerosis and osteoarthritis. Naked mole rats have senescent cells but somehow avoid these traumas of aging. We still don’t know how they live so long cancer-free—only now we know that it's not by eliminating cellular senescence.

PNAS, 2018. DOI: 10.1073.pnas.1721160115 (About DOIs).