Fight Aging!

Polyadenylation occurs during the creation of messenger RNA (mRNA). It is one part of the complex processes of transcription of the DNA sequence for a gene and assembly of the resulting RNA molecule. In the polyadenylation process, a tail of repeated adenine bases - called the poly(A) tail - is appended to the mRNA molecule. This protects the mRNA from degradation once it has left the nucleus, and also helps in other ways with the process of translation, in which the mRNA molecule is used as a blueprint by a ribosome to assemble protein molecules from amino acids. Changes in the length of the mRNA tail will affect levels of protein production, and thus the behavior of cells.

In today's open access paper, researchers report on their efforts to discover novel age-related changes in the nematode worm species Caenorhabditis elegans via extensive single cell sequencing of the transcriptome. This led them to uncover differences in the polyadenylation process (a) over the course of aging, and (b) between short-lived and long-lived nematode lineages. This age-related change in polyadenylation acts to reduce the pace of production of many proteins, which likely has many complex downstream effects, while longer-lived nematodes are somewhat resistant to this change in polyadenylation. Can this be dysfunction be rescued by a comparatively simple set of changes? Perhaps, as polyadenylation is regulated by a proteins that might be upregulated or downregulated, but it is likely a lengthy road from here to that sort of intervention.

Aging atlas reveals cell-type-specific effects of pro-longevity strategies

Although multiple pro-longevity strategies have been discovered in multicellular organisms ranging from Caenorhabditis elegans to mice, whether and how these strategies slow aging of different tissues in distinct manners are yet to be determined. In recent years, single-cell and single-nucleus RNA sequencing (scRNA-seq and snRNA-seq) have proven to be effective ways to systemically profile transcriptomes at single-cell resolution and have facilitated the discovery of cell-type-specific transcriptomic signatures in different tissues.

In this study, we used snRNA-seq transcriptomic profiling of different somatic cell and germ cell types to build an adult cell atlas. Using snRNA-seq data from wild-type (WT) adults at different ages, we generated tissue-specific transcriptomic aging clocks as well as germ cell differentiation trajectory maps to assess how aging affects the function of different cell types. We also revealed age-associated, tissue-specific transcriptomic changes associated with three different pro-longevity mechanisms. Furthermore, we profiled pre-mRNA alternative polyadenylation (APA) at the genome level in different cell types at different ages and systemically discovered APA events with tissue-specific patterns and how age-associated APA changes in different tissues are attenuated by those pro-longevity mechanisms.

APA plays a crucial role in the control of mRNA metabolism, gene regulation and protein diversification51. Our study provides, to our knowledge, the first systematic profiling of APA changes at the whole transcriptome level. Interestingly, APA events exhibit tissue-specific distribution, undergo significant changes during aging and can be differentially regulated by different pro-longevity mechanisms. We discovered that, during aging, all cell types shift their APA preference toward the distal site, and this shifted preference is suppressed in the long-lived strains. Previous studies revealed that the usage of the distal APA site is inversely correlated with the level of core polyadenylation factors.

Additionally, the increased usage of distal APA sites may lead to longer 3′ UTRs, which are associated with mRNA instability. Based on our findings, we speculate that, with aging, the level of core polyadenylation factors may decrease and the length of 3′ UTRs may increase, potentially resulting in declines in translational efficiency. Thus, suppressing the distal APA usage in the long-lived strains may help improve protein outputs, contributing to their longevity effects.