Naked Mole-Rat Senescent Cells are Unusually Vulnerable to Oxidative Stress

This open access paper expands on earlier work on cellular senescence in long-lived naked mole-rats. Individuals of this species can live as much as nine times longer than equivalently sized rodents, and are near immune to cancer. In other mammals, senescent cells accumulate with age and disrupt tissue function via their inflammatory signaling. Evidence suggests that this is an important cause of degenerative aging, given that selective destruction of these errant cells produces rejuvenation and extended life span in mice.

In naked mole-rats, senescent cells exhibit very little of the harmful signaling that occurs in other mammals. These cells also also self-destruct more readily when stressed. That naked mole-rat senescent cells are more prone to self-destruction following oxidative stress is not just a benefit when it comes to getting rid of these harmful cells, but it also prevents damage to molecules caused by oxidative reactions - another important mechanism of aging - from causing further harm to tissues.

Naked mole-rats (NMRs) are the longest-lived rodents, showing minimal aging phenotypes. An unsolved paradox is that NMRs exhibit low intracellular anti-oxidant defence despite minimal aging. Here, we explained a link between these "contradicting" features by a phenomenon termed "senescent cell death" - senescence induced cell death in NMR cells due to their inherent vulnerability to reactive oxygen species and unique metabolic system.

Generally, the "free radical theory of aging", later modified to "mitochondrial free radical theory", is the well-known theory of aging mechanism. Intracellular reactive oxygen species (ROS), deriving especially from mitochondria, damages macromolecules such as lipids, DNA, and proteins, and the accumulated damages in tissues are assumed to contribute aging process. Indeed, the mitochondrial ROS production rate is negatively correlated with the maximal lifespan of animal species.

However, previous insights on responses of long-lived NMRs to ROS are puzzling: 1) Several reports suggested that NMRs have stronger anti-oxidant mechanisms. 2) However, many other reports suggested that NMRs exhibit low anti-oxidant defence. From young ages, NMR suffers greater oxidative damages in tissue DNA, protein, and lipids than mice. Nevertheless, the level of oxidative damage does not increase further and remains constant for more than 20 years. Thus, at least in part, NMR exhibits low intracellular anti-oxidant defence despite their delayed aging. These complex but interesting observations raise a possibility that NMR may have developed a unique system to remove damaged cellular components or the cells that suffered the oxidative damage during aging.

In mammalian cells, one of the typical "damaged" cellular status along with elevated oxidative damage is cellular senescence. Cellular senescence is an irreversible cell proliferation arrest induced in response to stresses such as DNA damage, oncogene activation, and telomere shortening. Cellular senescence contributes to avoidance of cancer formation by stopping proliferation of damaged cells. In addition, cellular senescence has important roles in tissue homeostasis, embryonic development, and wound healing. On the other hand, accumulation of senescent cells promotes age-related physiological deterioration and disorders, by secreting a bioactive "secretome" called senescence-associated secretory phenotype (SASP).

In NMR skin, we observed few senescent cells during aging or after ultraviolet irradiation, suggesting suppression of senescent cell accumulation in NMR tissue. We discovered that senescent NMR fibroblasts induce senescent cell death through retinoblastoma protein activation accompanied by autophagy dysregulation, increased oxidative damage, and accelerated H2O2-releasing metabolic pathways.

Link: https://doi.org/10.1101/2020.07.02.155903

Comments

Another example of the malleability of aging. The organism allows damage to occur at a certain rate to control its aging/lifespan (i.e., your aging body is actively trying to kill you, with NMRs taking longer to do it compared to other rodents). We are free to adjust the corresponding aging levers to extend lifespan, although it's more complex than, for example, consuming more anti-oxidants.

Posted by: dtkamp at July 29th, 2020 9:21 AM

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