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Aging is a universal biological process characterized by a progressive, cumulative decline in homeostatic capabilities and physiological functions, which inevitably increases vulnerability to diseases. A number of molecular pathomechanisms and hallmarks of aging have been recognized, yet we miss a thorough understanding of their complex interconnectedness. This review explores the molecular and cellular mechanisms underlying human aging, with a focus on the multiple roles of high mobility group Box 1 protein (HMGB1), the archetypal damage-associated molecular pattern (DAMP) molecule. In the nucleus, this non-histone chromatin-associated protein functions as a DNA chaperone and regulator of gene transcription, influencing DNA structure and gene expression. Moreover, this versatile protein can translocate to the cytoplasm to orchestrate other processes, such as autophagy, or be unconventionally secreted into the extracellular environment, where it acts as a DAMP, combining inflammatory and regenerative properties. Notably, lower expression of HMGB1 within the cell and its heightened extracellular release have been associated with diverse age-associated traits, making it a suitable candidate as a universal biomarker of aging. In this review, we outline the evidence implicating HMGB1 in aging, also in light of an evolutionary perspective on its functional pleiotropy, and propose critical issues that need to be addressed to gauge the value of HMGB1 as a potential biomarker across age-related diseases and therapeutic target to promote healthy longevity., Competing Interests: Declaration of Competing Interest The authors have nothing to declare., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Genital involvement in atopic dermatitis(AD) can have a significant impact on the patient's quality of life. However, inspection of genital areas is not usually conducted during routine examination and patients may be reluctant to inform the clinician or show this area., Objective: to evaluate the efficacy of tralokinumab in AD patients with genital involvement., Methods: Adult patients with moderate/severe AD and genital involvement receiving tralokinumab have been analyzed. Primary endpoints were EASI, DLQI, PP-NRS, genital-IGA (g-IGA) and genital itching (GI) at week 16., Results: out of 48 patients with moderate/severe AD under treatment with tralokinumab, 12 patients (25%) showed a genital involvement. Seven patients reported itching in the genital area (58%), while none reported a positive history of genital infections. Median scores at T0 were EASI 17.5, PP-NRS 8 and DLQI 14. After 16 weeks of treatment, we observed a median EASI of 3, a median PP-NRS of 1 and a median DLQI of 1. Finally, concerning the genital response, after 16 weeks of treatment, we observed a statistically significant decrease in mean GI and g-IGA scores., Conclusion: despite the small size of our sample, tralokinumab can be considered as a valid treatment option for AD with genital involvement.

Autophagy is a fundamental multi-tasking adaptive cellular degradation and recycling strategy. Following its causal implication in age-related decline, autophagy is currently among the most broadly studied and challenged mechanisms within aging research. Thanks to these efforts, new cellular nodes interconnected with this phylogenetically ancestral pathway and unexpected roles of autophagy-associated genetic products are unveiled daily, yet the history of functional adaptations of autophagy along its evolutive trail is poorly understood and documented. Autophagy is traditionally studied in canonical and research-wise convenient model organisms such as yeast and mice. However, unconventional animal models endowed with extended longevity and exemption from age-related diseases offer a privileged perspective to inquire into the role of autophagy in the evolution of longevity. In this mini review we retrace the appearance and functions evolved by autophagy in eukaryotic cells and its protective contribution in the pathophysiology of aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Locatelli and Cenci.)

Background: Since the beginning of the coronavirus disease 2019 (COVID-19) pandemic, an increasing number of chilblain-like lesions (ChLL) have been increasingly reported worldwide. To date, the causal link between ChLL and SARS-CoV-2 infection has not been unequivocally established., Methods: In this case series, we present demographic, clinical, laboratory, and histopathological information regarding 27 young patients with a clinical diagnosis of ChLL who referred to the Dermatology Unit of Papa Giovanni XXIII Hospital, Bergamo, Italy, from 1 April 2020 to 1 June 2020., Results: The mean age was 14.2 years, and 21 patients (78%) experienced mild systemic symptoms a median of 28 days before the onset of cutaneous lesions. ChLL mostly involved the feet (20 patients - 74%). Among acral lesions, we identified three different clinical patterns: (i) chilblains in 20 patients (74%); (ii) fixed erythematous macules in 4 children (15%); (iii) erythrocyanosis in 3 female patients (11%). Blood examinations and viral serologies, including parvovirus B19, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and coxsackievirus were normal in all. Three patients (11%) underwent nasopharyngeal swab for RT-PCR for SARS-CoV-2 showing only 1 positive. Histopathological examinations of 7 skin biopsies confirmed the clinical diagnosis of chilblains; vessel thrombi were observed only in 1 case. Our findings failed to demonstrate the direct presence of SARS-CoV-2 RNA in skin biopsies, both with real-time polymerase chain reaction (RT-PCR) and RNAscope in situ hybridization (ISH)., Limitations: Limited number of cases, unavailability of laboratory confirmation of COVID-19 in all patients, potential methodological weakness, and latency of skin biopsies in comparison to cutaneous lesions onset., Conclusions: These observations may support the hypothesis of an inflammatory pathogenesis rather than the presence of peripheral viral particles. Although, we could not exclude an early phase of viral endothelial damage followed by an IFN-I or complement-mediated inflammatory phase. Further observations on a large number of patients are needed to confirm this hypothesis., (© 2022 Wiley Periodicals LLC.)

Autophagy maintains cellular homeostasis and its dysfunction has been implicated in aging. Bats are the longest-lived mammals for their size, but the molecular mechanisms underlying their extended healthspan are not well understood. Here, drawing on >8 years of mark-recapture field studies, we report the first longitudinal analysis of autophagy regulation in bats. Mining of published population level aging blood transcriptomes ( M. myotis , mouse and human) highlighted a unique increase of autophagy related transcripts with age in bats, but not in other mammals. This bat-specific increase in autophagy transcripts was recapitulated by the western blot determination of the autophagy marker, LC3II/I ratio, in skin primary fibroblasts ( Myotis myotis, Pipistrellus kuhlii , mouse), that also showed an increase with age in both bat species. Further phylogenomic selection pressure analyses across eutherian mammals (n=70 taxa; 274 genes) uncovered 10 autophagy-associated genes under selective pressure in bat lineages. These molecular adaptations potentially mediate the exceptional age-related increase of autophagy signalling in bats, which may contribute to their longer healthspans.

Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols 1 to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our 'Tool to infer Orthologs from Genome Alignments' (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease 1 .

The Kuhl's pipistrelle ( Pipistrellus kuhlii ) is a small, vespertilionid bat species, with a large range extending from the Iberian Peninsula into the Near East and the Arabian Peninsula. In this study, we determine for the first time the complete mitogenome of this species. The P. kuhlii mitogenome is 16,991 base pairs long with 37 genes and 1 control region, showing conserved gene content and order with other vertebrate mitogenomes. The length of the 22 tRNA genes ranges between 60 bp (tRNA-Ser) and 75 bp (tRNA-Leu). The D-loop region is 1553 bp long with low CG content (39.8%)., Competing Interests: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper., (© 2016 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)