Ageing is a common feature of living organisms, showing shared molecular features called hallmarks of ageing. Usually they are quantified in groups of individuals as a function of their chronological age (time passed since birth) and display continuous and progressive changes. Such approaches are based on the assumption that individuals taken at a given chronological age are biological replicates. However, even in genetically homogeneous and synchronised populations individuals do die at different chronological ages. This highlights the difference between chronological age and biological age, the latter being defined by the actual mortality risk of the organism, reflecting its physiology. The Smurf assay, previously described by Rera and colleagues, allows the identification of individuals at higher risk of death from natural causes amongst a population of a given chronological age. We found that the categorization of individuals as Smurf or non-Smurf, permits to distinguish transcriptional changes associated with either chronological or biological age. We show that transcriptional heterogeneity increases with chronological age, while four out of the six currently defined transcriptional hallmarks of ageing are associated with the biological age of individuals, i.e. their Smurf state. In conclusion, we demonstrate that studying properties of ageing by applying the Smurf classification allows us to differentiate the effect of time from the effect of a physiological response triggering an end-of-life switch (i.e. Smurf phase). More specifically, we show that the ability to isolate a pre-death phase of life in vivo enables us not only to study late life mechanisms preceding death, but also investigate early physiological changes triggering such phase. This allowed the identification of novel pro-longevity genetic interventions. We anticipate that the use of the evolutionary conserved Smurf phenotype in ageing studies will allow significant advances in our comprehension of the underlying mechanisms of ageing.
Germ line specification is essential in sexually reproducing organisms. Despite their critical role, the evolutionary history of the genes that specify animal germ cells is heterogeneous and dynamic. In many insects, the gene oskar is required for the specification of the germ line. However, the germ line role of oskar is thought to be a derived role resulting from co-option from an ancestral somatic role. To address how evolutionary changes in protein sequence could have led to changes in the function of Oskar protein that enabled it to regulate germ line specification, we searched for oskar orthologs in 1565 publicly available insect genomic and transcriptomic datasets. The earliest-diverging lineage in which we identified an oskar ortholog was the order Zygentoma (silverfish and firebrats), suggesting that oskar originated before the origin of winged insects. We noted some order-specific trends in oskar sequence evolution, including whole gene duplications, clade-specific losses, and rapid divergence. An alignment of all known 379 Oskar sequences revealed new highly conserved residues as candidates that promote dimerization of the LOTUS domain. Moreover, we identified regions of the OSK domain with conserved predicted RNA binding potential. Furthermore, we show that despite a low overall amino acid conservation, the LOTUS domain shows higher conservation of predicted secondary structure than the OSK domain. Finally, we suggest new key amino acids in the LOTUS domain that may be involved in the previously reported Oskar-Vasa physical interaction that is required for its germ line role.
The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. However, long-lived species may provide insights into successful strategies of healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes in comparison to mice. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, and specifically their protein homeostasis. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat involved the inflammasome complex, and in nucleic acid binding. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared to the rest of the proteins. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.
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