Senescent Cells in Blind Mole Rats do not Exhibit the Senescence-Associated Secretory Phenotype

Naked mole-rats live as much as nine times longer than similarly sized rodent species. A short summary of what is known of their biochemistry is that they exhibit many of the molecular signs of aging found in other mammals, such as oxidative damage, presence of senescent cells, and so forth, but few to none of the consequences found in other mammals. Naked mole rats stay fit and healthy and physiologically youthful right up until very late life. The near relative species of blind mole-rat has many of the same characteristics, although it is less well studied than naked mole-rats at the present time.

The accumulation of senescent cells is an important contribution to the aging process, as shown by the ability of senolytic drugs to significantly reverse many aspects of aging and age-related disease via clearance of lingering senescent cells in aged tissues. So it was something of a mystery as to how naked mole-rats and blind mole-rats could simply ignore the presence of senescent cells and carry on regardless. Here, scientists determine that this is because blind mole-rat senescent cells do not secrete the potent mix of inflammatory and damaging molecules known as the senescence-associated secretory phenotype (SASP). It is this process that causes all the harms resulting from cellular senescence in mice and other mammals.

This raises interesting questions as to how senescent cells in naked mole-rats and blind mole-rats carry out their normal, transient, beneficial functions in cancer suppression and wound healing. Perhaps they simply do not participate in the same way. Certainly these species have a whole array of other extraordinarily efficient means of suppressing cancer. One of the reasons why naked mole-rats are so well studied is their near immunity to cancer; whether researchers can find mechanisms that can be turned into human cancer suppression therapies remains to be seen, however.

Downregulation of the inflammatory network in senescent fibroblasts and aging tissues of the long-lived and cancer-resistant subterranean wild rodent, Spalax

The blind mole rat (Spalax) is a wild, long-lived rodent that has evolved mechanisms to tolerate hypoxia and resist cancer. Previously, we demonstrated high DNA repair capacity and low DNA damage in Spalax fibroblasts following genotoxic stress compared with rats. Since the acquisition of senescence-associated secretory phenotype (SASP) is a consequence of persistent DNA damage, we investigated whether cellular senescence in Spalax is accompanied by an inflammatory response.

Spalax fibroblasts undergo replicative senescence and etoposide-induced senescence, evidenced by an increased activity of senescence-associated beta-galactosidase (SA-β-Gal), growth arrest, and overexpression of p21, p16, and p53 mRNAs. Yet, unlike mouse and human fibroblasts, senescent Spalax cells showed undetectable or decreased expression of the well-known SASP factors: interleukin-6 (IL6), IL8, IL1α, growth-related oncogene alpha (GROα), SerpinB2, and intercellular adhesion molecule (ICAM-1). Apparently, due to the efficient DNA repair in Spalax, senescent cells did not accumulate the DNA damage necessary for SASP activation.

Conversely, Spalax can maintain DNA integrity during replicative or moderate genotoxic stress and limit pro-inflammatory secretion. However, exposure to the conditioned medium of breast cancer cells MDA-MB-231 resulted in an increase in DNA damage, activation of the nuclear factor κB (NF-κB) through nuclear translocation, and expression of inflammatory mediators in RS Spalax cells. Evaluation of SASP in aging Spalax brain and intestine confirmed downregulation of inflammatory-related genes. These findings suggest a natural mechanism for alleviating the inflammatory response during cellular senescence and aging in Spalax, which can prevent age-related chronic inflammation supporting healthy aging and longevity.

Comments

Unless I overlooked it, the paper does not refer to the fact that naked mole rats' hyaluronan is high molecular weight. A web search on the string --
"high molecular weight hyaluronan" inflammation
-- produces papers revealing that this type of hyaluronan suppresses inflammation.

BTW, dietary fisetin may increase high molecular weight hyaluronan --
https://www.ncbi.nlm.nih.gov/pubmed/27335141

Posted by: L Pagnucco at November 3rd, 2019 1:28 AM

Fascinating! Scientists need to investigate the hell out of death-resistant Naked and Blind Mole-Rats. And despite seeming not to need it, they should treat them with senolytics anyway. Maybe such treatment would make them immortal!

Posted by: Zan at November 3rd, 2019 6:25 AM

This should be read as an indication of what can be done by suppressing the harm of senescent cells without removing them, i.e. by rapamycin or other anti-inflammatories.

Posted by: Mark at November 4th, 2019 4:40 AM

It seems to me living in a hypoxic environment is a commonality in long lived species. possibly hypoxia in some way modulates SASP expression. I wonder if naked/blind mole rats have been raised in non hypoxic environments.

Posted by: JohnD at November 4th, 2019 1:33 PM

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