Single-cell transcriptomics reveals age-resistant maintenance of cell identities, stem cell compartments and differentiation trajectories in long-lived naked mole-rats skin.

Naked mole-rats (NMR) are subterranean rodents characterized by an unusual longevity coupled with an unexplained resistance to aging. In the present study, we performed extensive in situ analysis and single-cell RNA-sequencing comparing young and older animals. At variance with other species, NMR exhibited a striking stability of skin compartments and cell types, which remained stable over time without aging-associated changes. Remarkably, the number of stem cells was constant throughout aging. We found three classical cellular states defining a unique keratinocyte differentiation trajectory that were not altered after pseudo-temporal reconstruction. Epidermal gene expression did not change with aging either. Langerhans cell clusters were conserved, and only a higher basal stem cell expression of Igfbp3 was found in aged animals. In accordance, NMR skin healing closure was similar in young and older animals. Altogether, these results indicate that NMR skin is characterized by peculiar genetic and cellular features, different from those previously demonstrated for mice and humans. The remarkable stability of the aging NMR skin transcriptome likely reflects unaltered homeostasis and resilience.

DNA methylation clocks as a predictor for ageing and age estimation in naked mole-rats, Heterocephalus glaber.

The naked mole-rat, Heterocephalus glaber (NMR), the longest-lived rodent, is of significance and interest in the study of biomarkers for ageing. Recent breakthroughs in this field have revealed 'epigenetic clocks' that are based on the temporal accumulation of DNA methylation at specific genomic sites. Here, we validate the hypothesis of an epigenetic clock in NMRs based on changes in methylation of targeted CpG sites. We initially analysed 51 CpGs in NMR livers spanning an age range of 39-1,144 weeks and found 23 to be significantly associated with age (p<0.05). We then built a predictor of age using these sites. To test the accuracy of this model, we analysed an additional set of liver samples, and were successfully able to predict their age with a root mean squared error of 166 weeks. We also profiled skin samples with the same age range, finding a striking correlation between their predicted age versus their actual age (R=0.93), but which was lower when compared to the liver, suggesting that skin ages slower than the liver in NMRs. Our model will enable the prediction of age in wild-caught and captive NMRs of unknown age, and will be invaluable for further mechanistic studies of mammalian ageing.

Management of carotid stenosis for primary and secondary prevention of stroke: state-of-the-art 2020: a critical review.

Carotid atherosclerotic plaque is encountered frequently in patients at high cardiovascular risk, especially in the elderly. When plaque reaches 50% of carotid lumen, it induces haemodynamically significant carotid stenosis, for which management is currently at a turning point. Improved control of blood pressure, smoking ban campaigns, and the widespread use of statins have reduced the risk of cerebral infarction to <1% per year. However, about 15% of strokes are still secondary to a carotid stenosis, which can potentially be detected by effective imaging techniques. For symptomatic carotid stenosis, current ESC guidelines put a threshold of 70% for formal indication for revascularization. A revascularization should be discussed for symptomatic stenosis over 50% and for asymptomatic carotid stenosis over 60%. This evaluation should be performed by ultrasound as a first-line examination. As a complement, computed tomography angiography (CTA) and/or magnetic resonance angiography are recommended for evaluating the extent and severity of extracranial carotid stenosis. In perspective, new high-risk markers are currently being developed using markers of plaque neovascularization, plaque inflammation, or plaque tissue stiffness. Medical management of patient with carotid stenosis is always warranted and applied to any patient with atheromatous lesions. Best medical therapy is based on cardiovascular risk factors correction, including lifestyle intervention and a pharmacological treatment. It is based on the tri-therapy strategy with antiplatelet, statins, and ACE inhibitors. The indications for carotid endarterectomy (CEA) and carotid artery stenting (CAS) are similar: for symptomatic patients (recent stroke or transient ischaemic attack ) if stenosis >50%; for asymptomatic patients: tight stenosis (>60%) and a perceived high long-term risk of stroke (determined mainly by imaging criteria). Choice of procedure may be influenced by anatomy (high stenosis, difficult CAS or CEA access, incomplete circle of Willis), prior illness or treatment (radiotherapy, other neck surgery), or patient risk (unable to lie flat, poor AHA assessment). In conclusion, neither systematic nor abandoned, the place of carotid revascularization must necessarily be limited to the plaques at highest risk, leaving a large place for optimized medical treatment as first line management. An evaluation of the value of performing endarterectomy on plaques considered to be at high risk is currently underway in the ACTRIS and CREST 2 studies. These studies, along with the next result of ACST-2 trial, will provide us a more precise strategy in case of carotid stenosis.

The Naked Mole Rat: A Unique Example of Positive Oxidative Stress.

The oxidative stress theory of aging, linking reactive oxygen species (ROS) to aging, has been accepted for more than 60 years, and numerous studies have associated ROS with various age-related diseases. A more precise version of the theory specifies that mitochondrial oxidative stress is a direct cause of aging. The naked mole rat, a unique animal with exceptional longevity (32 years in captivity), appears to be an ideal model to study successful aging and the role of ROS in this process. Several studies in the naked mole rat have shown that these animals exhibit a remarkable resistance to oxidative stress. At low concentrations, ROS serve as second messengers, and these important intracellular signalling functions are crucial for the regulation of cellular processes. In this review, we examine the literature on ROS and their functions as signal transducers. We focus specifically on the longest-lived rodent, the naked mole rat, which is a perfect example of the paradox of living an exceptionally long life with slow aging despite high levels of oxidative damage from a young age.