Ageing as a two-phase process: theoretical framework.

Human ageing, along with the ageing of conventional model organisms, is depicted as a continuous and progressive decline of biological capabilities accompanied by an exponentially increasing mortality risk. However, not all organisms experience ageing identically and our understanding of the phenomenon is coloured by human-centric views. Ageing is multifaceted and influences a diverse range of species in varying ways. Some undergo swift declines post-reproduction, while others exhibit insubstantial changes throughout their existence. This vast array renders defining universally applicable "ageing attributes" a daunting task. It is nonetheless essential to recognize that not all ageing features are organism-specific. These common attributes have paved the way for identifying "hallmarks of ageing," processes that are intertwined with age, amplified during accelerated ageing, and manipulations of which can potentially modulate or even reverse the ageing process. Yet, a glaring observation is that individuals within a single population age at varying rates. To address this, demographers have coined the term 'frailty'. Concurrently, scientific advancements have ushered in the era of molecular clocks. These innovations enable a distinction between an individual's chronological age (time since birth) and biological age (physiological status and mortality risk). In 2011, the "Smurf" phenotype was unveiled in Drosophila, delineating an age-linked escalation in intestinal permeability that presages imminent mortality. It not only acts as a predictor of natural death but identifies individuals exhibiting traits normally described as age-related. Subsequent studies have revealed the phenotype in organisms like nematodes, zebrafish, and mice, invariably acting as a death predictor. Collectively, these findings have steered our conception of ageing towards a framework where ageing is not linear and continuous but marked by two distinct, necessary phases, discernible in vivo, courtesy of the Smurf phenotype. This framework includes a mathematical enunciation of longevity trends based on three experimentally measurable parameters. It facilitates a fresh perspective on the evolution of ageing as a function. In this article, we aim to delineate and explore the foundational principles of this innovative framework, emphasising its potential to reshape our understanding of ageing, challenge its conventional definitions, and recalibrate our comprehension of its evolutionary trajectory.

Smurfness-based two-phase model of ageing helps deconvolve the ageing transcriptional signature.

Ageing is characterised at the molecular level by six transcriptional 'hallmarks of ageing', that are commonly described as progressively affected as time passes. By contrast, the 'Smurf' assay separates high-and-constant-mortality risk individuals from healthy, zero-mortality risk individuals, based on increased intestinal permeability. Performing whole body total RNA sequencing, we found that Smurfness distinguishes transcriptional changes associated with chronological age from those associated with biological age. We show that transcriptional heterogeneity increases with chronological age in non-Smurf individuals preceding the other five hallmarks of ageing that are specifically associated with the Smurf state. Using this approach, we also devise targeted pro-longevity genetic interventions delaying entry in the Smurf state. We anticipate that increased attention to the evolutionary conserved Smurf phenotype will bring about significant advances in our understanding of the mechanisms of ageing.

Transcriptional Characterization of Stage I Epithelial Ovarian Cancer: A Multicentric Study.

Stage I epithelial ovarian cancer (EOC) represents about 10% of all EOCs. It is characterized by a complex histopathological and molecular heterogeneity, and it is composed of five main histological subtypes (mucinous, endometrioid, clear cell and high, and low grade serous), which have peculiar genetic, molecular, and clinical characteristics. As it occurs less frequently than advanced-stage EOC, its molecular features have not been thoroughly investigated. In this study, using in silico approaches and gene expression data, on a multicentric cohort composed of 208 snap-frozen tumor biopsies, we explored the subtype-specific molecular alterations that regulate tumor aggressiveness in stage I EOC. We found that single genes rather than pathways are responsible for histotype specificities and that a cAMP-PKA-CREB1 signaling axis seems to play a central role in histotype differentiation. Moreover, our results indicate that immune response seems to be, at least in part, involved in histotype differences, as a higher immune-reactive behavior of serous and mucinous samples was observed with respect to other histotypes.