Ageing as a Two-Phase Process: Development of a new Theoretical Framework

Human ageing, along with the ageing of conventional model organisms, is frequently depicted as a continuous and progressive decline of biological capabilities. Additionally, it is assumed that the risk of mortality increases exponentially during this process. However, it is pivotal to acknowledge that not all organisms experience ageing identically and that our understanding of the phenomenon is coloured by human-centric views. Ageing is multifaceted and influences a diverse range of species in varying ways. For instance, certain organisms undergo swift declines post-reproduction, while others exhibit almost insubstantial changes throughout their existence. This vast array renders the classification of universally applicable "ageing attributes" a daunting task. It is nonetheless essential to also recognize that not all ageing features are organism-specific. The existence of these common attributes has paved the way for identifying the "hallmarks of ageing". These hallmarks are 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 variation, 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 corresponding mortality risk). Rera and colleagues, in 2011, unveiled the "Smurf" phenotype in Drosophila, delineating an age-linked escalation in intestinal permeability that presages imminent mortality. This phenotype not only acts as a predictor of natural death but also identifies individuals exhibiting heightened inflammation, energy-store depletion, and compromised motility, among other age-induced traits. Subsequent studies have revealed the Smurf phenotype's presence in organisms like nematodes, zebrafish, and mice, invariably acting as a death precursor. A compelling study by Zane et al. demonstrated that the transcriptional hallmarks of ageing predominantly impact Smurf individuals, with time primarily influencing transcriptional irregularities. Collectively, these findings have steered our conception of ageing towards a framework where ageing is not a linear and continuous progression. Instead, a lifespan is marked by tw