Ageing drop by drop: Disturbance of the membrane-less organelle biogenesis as an aging hallmark

Despite extensive research, the features associated with the aging phenotype are not all-inclusive and need to be updated on a regular basis to incorporate new findings. We propose to include the dysfunction of membrane-less organelle (MLO) as a new aging hallmark. Special scaffold proteins with a high degree of intrinsic disorder drive the formation of MLOs via the liquid-liquid phase separation (LLPS) process. Aberrant behavior of MLOs was shown to be associated with the pathogenesis of many neurodegenerative diseases. In this work, we challenge the aging through bidirectional bioinformatics analysis of human proteins found in Granulome consisting of 7264 protein and Ageome containing 1624 aging-related proteins. The analysis indicates the interconnectivity of MLOs and aging. Approximately 67 % of the Ageome are presented in Granulome thereby constituting the Intersectome that include 1084 proteins showing an enrichment significantly higher than for the random datasets of the same size. Furthermore, for proteins in 10 representative MLOs, we analyzed in detail molecular functions, association with the already known aging hallmarks, and the roles in MLO formation (scaffold, client, or regulator). Cumulatively, our results strengthen the hypothesis that the dysfunction of MLOs can serve as a potent new aging hallmark. •Aging is accompanied by aberrant behavior of membrane-less organelle (MLO).•Intrinsically disordered scaffold proteins drive MLO formation via LLPS.•Significant overlap between the granulome and ageome indicated the interconnectivity of MLOs and aging.•Regulation and organization of MLOs is strongly intersected with the aging.•Dysfunction of MLOs can serve as a potent new aging hallmark.