The Relationship Between Telomere Length and Replicative Senescence is Quite Different in Blind Mole Rats

In mammalian tissues, cells become senescent constantly as a result of reaching the Hayflick limit on cell replication. Telomeres, lengths of repeated DNA sequences at the ends of chromosomes, are reduced in length with each cell division. When too short, or otherwise damaged, cellular senescence or programmed cell death is the outcome. In youth, senescent cells don't tend to last long: they secrete a potent mix of pro-inflammatory signals that attracts the attention of the immune system, and are consequently destroyed by immune cells. With advancing age, this clearance slows down and senescent cells accumulate to cause harm.

Matters are somewhat different in the exceptionally long-lived naked mole-rat and blind mole-rat species, however, both species in which individuals exhibit very little age-related decline until very late in life. Their senescent cells are nowhere near as active and pro-inflammatory as is the case in other mammals, for one thing, and thus senescent cell accumulation has nowhere near the same detrimental contribution to long-term health. Secondly, as noted in today's open access paper, the relationship between telomeres and replicative senescence appears to be quite different, and their version of the Hayflick limit may function in ways that have yet to be explored.

The existence of the Hayflick limit on cell replication is fundamental to multicellular life. We are made up of (a) a tiny number of stem cells are are privileged, maintaining long telomeres via the use of telomerase and capable of continued replication, and (b) a vastly greater number of somatic cells that are limited in their ability to replicate. This arrangement is how the risk of cancer is kept low enough for evolutionary success; most potentially cancerous mutational damage has no lasting impact because it occurs in somatic cells that will soon enough be replaced, and cannot spread the mutation to many descendants.

In this context, it is worth recalling that mole-rats exhibit minimal cancer incidence, for reasons still under investigation, but which certainly include highly efficient cancer suppression mechanisms. It may well be the case that this cancer suppression has allowed evolution to take the use of telomeres and the Hayflick limit in a different direction than is the norm for mammals.

Damage-Free Shortening of Telomeres Is a Potential Strategy Supporting Blind Mole-Rat Longevity

In this study, we examined the average telomere length and telomerase activity, as well as the formation of telomere associated foci (TAFs) and the mRNA expression levels of the shelterin components in cultured primary cells of Spalax, a long-lived, hypoxia-tolerant, and cancer-resistant blind mole-rat species.

We showed that with cell passages, Spalax fibroblasts demonstrated significant shortening in telomere length, similar to rat cells, and in line with the processes observed earlier in tissues. We also demonstrated that the average telomere length in Spalax fibroblasts was significantly higher than the average length in rats, similar to previously reported results in Spalax muscles. Long telomeres are controversially described in the literature by their association with cancer risk, aging, or longevity. Extremely long telomeres in mice were reported to produce beneficial metabolic effects, low cancer risks, and longevity. Whether the long, seemingly guarded telomeres are one of the driving forces in Spalax longevity and healthy aging remains unclear.

It may be speculated that longer telomeres are attributed to telomerase overexpression, which presumably prolongs cell survival; however, we found that Spalax fibroblast telomerase activity was, in fact, lower than that of its counterpart in rats, which further supports our hypothesis that integrity maintenance of the telomeres (such as via shelterin activity), rather than telomere elongation, is characteristic of Spalax cells as a strategy that contributes to its long lifespan and supports its unique mode of cellular senescence.

It was suggested that long-lived animals have adopted a mechanism whereby the pace of telomere attrition and the activity of the telomerase is the same as that in other, short-lived animals. However, since initially, Spalax exhibits longer and potentially safeguarded telomeres, it seems tempting to speculate that the time it takes to reach critical length/damage that ignites the senescence machinery is longer and therefore, may contribute to their profoundly unique mode of replicative senescence lacking the canonical inflammatory response known to accompany the senescent phenotype in all studied species.

In summary, our results support that Spalax have evolved strategies for genome protection that apparently include telomere maintenance machinery, together contributing to its longevity and healthy aging. These strategies include a unique mode of senescence not induced by persistent DNA damage response (DDR) or telomere attrition, but which rather seems to be an independent cell program driven by other types of 'clocks'. The precise mechanisms of telomere maintenance and the apparently 'non-canonical senescence clock' require further investigation in Spalax and other long-lived species as possible requisites for long lifespan and healthy aging.


May issue of Nature Aging " The paper, "Discovering small-molecule senolytics with deep neural networks," authored in collaboration with researchers from the Massachusetts Institute of Technology (MIT) and the Broad Institute of MIT and Harvard, describes the AI-guided screening of more than 800,000 compounds to reveal three drug candidates with comparable efficacy and superior medicinal chemistry properties than those of senolytics currently under investigation."

More information: Felix Wong et al, Discovering small-molecule senolytics with deep neural networks, Nature Aging (2023). DOI: 10.1038/s43587-023-00415-z

Posted by: august33 at May 10th, 2023 9:28 PM
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