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Insulin-mechanistic target of rapamycin (mTOR) signaling drives anabolic growth during organismal development; its late-life dysregulation contributes to aging and limits lifespans. Age-related regulatory mechanisms and functional consequences of insulin-mTOR remain incompletely understood. Here, we identify LPD-3 as a megaprotein that orchestrates the tempo of insulin-mTOR signaling during C. elegans aging. We find that an agonist insulin, INS-7, is drastically overproduced from early life and shortens lifespan in lpd-3 mutants. LPD-3 forms a bridge-like tunnel megaprotein to facilitate non-vesicular cellular lipid trafficking. Lipidomic profiling reveals increased hexaceramide species in lpd-3 mutants, accompanied by up-regulation of hexaceramide biosynthetic enzymes, including HYL-1. Reducing the abundance of HYL-1, insulin receptor/DAF-2 or mTOR/LET-363, normalizes INS-7 levels and rescues the lifespan of lpd-3 mutants. LPD-3 antagonizes SINH-1, a key mTORC2 component, and decreases expression with age. We propose that LPD-3 acts as a megaprotein brake for organismal aging and that its age-dependent decline restricts lifespan through the sphingolipid-hexaceramide and insulin-mTOR pathways.

Background: Muscle Tension Dysphonia is a relatively new clinical entity that, despite being one of the most frequent causes of functional dysphonia, is little-known by many otorhinolaryngologists. Objective: The objective of the current work is to describe the evolution of Muscle Tension Dysphonia—the concepts and the ways it has been diagnosed and treated—from its first descriptions to our current knowledge. Design: A scoping review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. A search of three bibliographic databases was performed to identify original articles on Muscle Tension Dysphonia. Study selection and characterization was conducted by three independent reviewers and was further reviewed by a fourth individual. In case of relocating any of the studies, it was performed by agreement of two reviewers. We excluded articles not written in English or Spanish, letters to the editor, review articles, studies of the pediatric population, articles related to dysphagia, and other publications that were not relevant. Results: The search identified 1144 articles published from 1983 to December 2022. A total of 581 studies were repeated and another 462 were excluded because they were not written in English or Spanish, were not original articles, or were not relevant to the objective of the study. Finally, 101 articles were included in the review. The articles included in the review were divided into three groups considering the objective and conclusions of each study: 21 articles were classified as "Etiology and Physiopathology", 29 articles as "Diagnosis", and 51 articles were included in the "Treatment" group. Conclusions: The concept of Muscle Tension Dysphonia has been developed during the last forty years. For its diagnosis, endoscopic visualization of the larynx is crucial, but must be combined with the patient's clinical history and other methods can also be useful. This entity should be addressed in a multidisciplinary approach, with the active participation of speech therapists. Most therapeutic options include voice education, vocal hygiene, and rehabilitation of the voice. [ABSTRACT FROM AUTHOR]

Background: Muscle Tension Dysphonia is a relatively new clinical entity that, despite being one of the most frequent causes of functional dysphonia, is little-known by many otorhinolaryngologists. Objective: The objective of the current work is to describe the evolution of Muscle Tension Dysphonia—the concepts and the ways it has been diagnosed and treated—from its first descriptions to our current knowledge. Design: A scoping review was conducted using the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) checklist. A search of three bibliographic databases was performed to identify original articles on Muscle Tension Dysphonia. Study selection and characterization was conducted by three independent reviewers and was further reviewed by a fourth individual. In case of relocating any of the studies, it was performed by agreement of two reviewers. We excluded articles not written in English or Spanish, letters to the editor, review articles, studies of the pediatric population, articles related to dysphagia, and other publications that were not relevant. Results: The search identified 1144 articles published from 1983 to December 2022. A total of 581 studies were repeated and another 462 were excluded because they were not written in English or Spanish, were not original articles, or were not relevant to the objective of the study. Finally, 101 articles were included in the review. The articles included in the review were divided into three groups considering the objective and conclusions of each study: 21 articles were classified as “Etiology and Physiopathology”, 29 articles as “Diagnosis”, and 51 articles were included in the “Treatment” group. Conclusions: The concept of Muscle Tension Dysphonia has been developed during the last forty years. For its diagnosis, endoscopic visualization of the larynx is crucial, but must be combined with the patient’s clinical history and other methods can also be useful. This entity should be addressed in a multidisciplinary approach, with the active participation of speech therapists. Most therapeutic options include voice education, vocal hygiene, and rehabilitation of the voice.

Understanding mechanisms of ageing remains a complex challenge for biogerontologists, but recent adaptations of evolutionary ageing theories offer a compelling lens in which to view both age-related molecular and physiological deterioration. Ageing is commonly associated with progressive declines in biochemical and molecular processes resulting from damage accumulation, yet the role of continued developmental gene activation is less appreciated. Natural selection pressures are at their highest in youthful periods to modify gene expression towards maximising reproductive capacity. After sexual maturation, selective pressure diminishes, subjecting individuals to maladaptive pleiotropic gene functions that were once beneficial for developmental growth but become pathogenic later in life. Due to this selective 'shadowing' in ageing, mechanisms to counter such hyper/hypofunctional genes are unlikely to evolve. Interventions aimed at targeting gene hyper/hypofunction during ageing might, therefore, represent an attractive therapeutic strategy. The nematode Caenorhabditis elegans offers a strong model for post-reproductive mechanistic and therapeutic investigations, yet studies examining the mechanisms of, and countermeasures against, ageing decline largely intervene from larval stages onwards. Importantly, however, lifespan extending conditions frequently impair early-life fitness and fail to correspondingly increase healthspan. Here, we consolidate multiple evolutionary theories of ageing and discuss data supporting hyper/hypofunctional changes at a global molecular and functional level in C. elegans , and how classical lifespan-extension mutations alter these dynamics. The relevance of such mutant models for exploring mechanisms of ageing are discussed, highlighting that post-reproductive gene optimisation represents a more translatable approach for C. elegans research that is not constrained by evolutionary trade-offs. Where some genetic mutations in C. elegans that promote late-life health map accordingly with healthy ageing in humans, other widely used genetic mutations that extend worm lifespan are associated with life-limiting pathologies in people. Lifespan has also become the gold standard for quantifying 'ageing', but we argue that gerospan compression (i.e., 'healthier' ageing) is an appropriate goal for anti-ageing research, the mechanisms of which appear distinct from those regulating lifespan alone. There is, therefore, an evident need to re-evaluate experimental approaches to study the role of hyper/hypofunctional genes in ageing in C. elegans. [Display omitted] • Views that ageing stems from molecular damage has narrowed our view that hyperactive wild-type genes drive physiological decline. • Systems biology will uncover hyperfunctional expression changes in ageing, enabling late-life gene optimisations to improve health. • Healthy phenotypes of long-lived Caenorhabditis elegans mutants are bound within evolutionary constraints. • There is an urgent need to employ pharmaco-genetic interventions commencing in post-reproductive animals to study healthy ageing. [ABSTRACT FROM AUTHOR]

Objective: The objective of the present study was to investigate the effect of fast speaking on pause duration, breath group duration, and fundamental frequency (F O ) in rote speech (counting)., Method: Twenty-eight healthy women (age 18-39) who had no experience of voice training, repeated a counting task in both a habitual and fast speaking rate. Pause duration, breath group duration, and mean fundamental frequency were measured from audio recordings. Differences in the study variables between habitual and fast speaking rates were analyzed and tested for statistical significance., Results: In fast speaking rate, mean pause duration was shorter and mean breath group duration longer as compared with habitual speaking rate, both with statistical significance at the group level. Surprisingly, mean fundamental frequency was significantly lower in the fast-speaking rate condition., Conclusion: The results overall supported the hypothesis that pause duration becomes shorter and breath group duration longer with a fast-speaking rate. This may have clinical relevance for voice therapy and supports the importance of speaking rate for the understanding and treatment of some hyperfunctional voice disorders. Notably, however, our findings indicated that counting as a speech task induces a specific pattern which may not be comparable to other speech tasks, nor representative of spontaneous speech in every-day-life., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)