Jackson, Noel et al. (2021) International Worm Meeting "Defining a functional role for splicing factors in modulating longevity in C. elegans"

Heintz, Caroline, Howell, Porsha, Dutta, Sneha, Perez Matos, Maria, Jackson, Noel, Mair, William

[International Worm Meeting, 2021]

Aging is the decline in proliferative processes and organismal metabolism that promotes deterioration of cellular and physiological function and eventually leads to mortality. Biological aging can be uncoupled from chronological age and slowed by restricting food intake without malnutrition through dietary restriction (DR) and altering nutrient-sensing pathways, such as the mechanistic target of rapamycin (mTORC) pathway. The Mair lab has identified a conserved splicing factor, SFA-1/SF1, that modulates the longevity phenotype usually attained through dietary restriction (DR) and suppressed-mTORC1 activity in C. elegans. However, the mechanism that links DR and mTORC1 longevity to the regulation of SFA-1/SF1 is unknown. SFA-1 is the C. elegans homolog of mammalian splicing factor SF1, which coordinates with other splicing factors to initiate splicing of pre-mRNA transcripts. SF1 splicing efficiency is altered by phosphorylation events at conserved residues, and we have found that altering SFA-1 by inhibiting phosphorylation events in two distinct residues abolishes the suppressed-mTORC1 longevity phenotype in C. elegans. In future studies, I will characterize the functional role of SFA-1 and its downstream targets and interaction partners to identify their contribution to aging. Uncovering biological processes that are regulated by SFA-1 and drive lifespan extension could define novel RNA homeostatic modulators of longevity that may contribute to age-related diseases.

Perez-Matos, Maria C et al. (2021) International Worm Meeting "RNA splicing regulation of lipid metabolism and longevity."

Lanjuin, Anne, Dutta, Sneha, Piper, Mary, Perez-Matos, Maria C, Mair, William, Jackson, Noel A, Heintz, Caroline

[International Worm Meeting, 2021]

The containment of infectious diseases has catalyzed an increase in life-expectancy and age-related disease. Dietary restriction (DR), a reduced food intake without malnutrition, and reduced TORC1 signaling are highly conserved interventions to promote healthy aging and disease resistance. Our lab defined pre-mRNA splicing as a biomarker of aging and determined it has a causal role in DR and reduced TORC1 lifespan extension through splicing factor 1 (SFA-1). However, the mechanistic link between RNA splicing and longevity remains unknown. We found lipid metabolic pathways are enriched in genes differentially spliced between subpopulations of C. elegans with different life expectancy based on splicing status. Similarly, fat metabolic pathways are enriched among genes with SFA-1 dependent splicing changes. In fact, here we show that SFA-1 modulates fat storage in DR and reduced TORC1 longevity. Upon sfa-1 RNAi, eat-2 and raga-1 mutant C. elegans (genetic models of DR and reduced TORC1 longevity) have increased fat storage, while age-1 mutants (reduced insulin signaling longevity model) do not. Moreover, using Cross Linked Immuno-Precipitation (CLIP) methods in C. elegans and Mouse embryonic fibroblasts (MEFs), we identified that SFA-1 binds pod-2 (mammalian acaca), the rate limiting enzyme in fatty acid synthesis. Very excitingly, we found that pod-2 is a pathway-specific regulator of longevity. pod-2 RNAi suppresses the lifespan extension of eat-2 and raga-1 mutants, but not age-1 mutant worms. Here we provide evidence on the interplay between pre-mRNA splicing and lipid metabolism in DR and TORC1 longevity. This brings us closer to the mechanistic understanding of RNA homeostasis as a novel paradigm of aging and physiology.