Biology subjects

Alic, N.

Publications and source records attributed to Alic, N..

4 recordsLinked to original sources

bioRxiv2026

Transcriptome-wide association study and fly experiments uncover the role of CoA synthase in ageing across species.

While significant progress has been made in understanding the genetic architecture of ageing in model organisms, our understanding of human ageing remains limited. We performed a multi-tissue Transcriptome-wide association study (TWAS) on human lifespan, integrating GWAS data from >1 million parental lifespans with gene expression prediction models derived from reference transcriptomic datasets; followed by replication using healthspan and longevity phenotypes as additional readouts of ageing. The TWAS uncovered 563 significant gene associations, of which 139 replicated. TOMM40, encoding a component of the mitochondrial outer membrane translocase that is fundamental for mitochondrial function, had the strongest association with parental lifespan and longevity and was fine-mapped as a putatively causal lifespan gene at the APOE-TOMM40 region. Uniquely in our study, we identified fly orthologues of replicating genes and examined if modulating their expression impacts Drosophila longevity. The nine novel associations with all three ageing outcomes included COASY, encoding Coenzyme A synthase. Knocking down its fly orthologue, Ppat-dpck, resulted in significant lifespan extension in flies. Hence, in addition to discovering new genes associated with human ageing, by combining human TWAS with experimental Drosophila work, we provide evidence for the role of COASY (Ppat-dpck) in ageing across species. Significance statementExtensive research on ageing has been conducted in Drosophila and C.elegans due to their short lifespan and experimental tractability. However, in human genetic research, only a few loci have been consistently replicated. To bridge this gap, we conducted a transcriptome-wide association study (TWAS) followed by experimental validation in Drosophila. TWAS revealed 139 significant and replicating gene associations, including COASY. Knockdown of its fly orthologue (Ppat-dpck) significantly extended fly lifespan, validating its roles in ageing across species. Thus, integrating multiple ageing outcomes through TWAS in human genetic research can uncover robust associations and highlight genes involved in fundamental ageing mechanisms.

genetics↗

bioRxiv2024

Aging-associated long non-coding RNA boosts longevity and reduces the ribosome content of non-dividing fission yeast cells

Genomes produce widespread long non-coding RNAs (lncRNAs) of largely unknown functions. We characterize aal1 (aging-associated lncRNA) which is induced in quiescent cells of fission yeast. Deletion of aal1 shortens the chronological lifespan of non-dividing cells, while ectopic overexpression of aal1 prolongs their lifespan, indicating that this lncRNA acts in trans. The overexpression of aal1 leads to the repression of ribosomal protein genes and inhibition of cell growth, and aal1 genetically interacts with coding genes functioning in protein translation. The aal1 RNA localizes to the cytoplasm and associates with ribosomes. Notably, aal1 deletion or overexpression is sufficient to increase or decrease the cellular ribosome content. The rpl1901 mRNA, encoding a ribosomal protein, is a binding target of aal1. The levels of rpl1901 are reduced [~]2-fold by aal1, which is critical and sufficient to extend the lifespan. Remarkably, the expression of aal1 lncRNA in Drosophila triggers an extension of fly lifespan. We propose that aal1 reduces the ribosome content by decreasing the levels of Rpl1901, thus attenuating protein translation and promoting longevity. Although the aal1 lncRNA itself is not conserved, its effect in flies raises the possibility that animals feature related mechanisms that modulate aging, based on the conserved translational machinery.

genetics↗

bioRxiv2022

Timing of TORC1 inhibition dictates Pol III involvement in longevity in Caenorhabditis elegans

Organismal growth and lifespan are inextricably linked. Target of Rapamycin (TOR) signalling regulates protein production for growth and development, but if reduced extends lifespan across species. Reduction of the enzyme RNA polymerase III, which transcribes tRNAs and 5S rRNA, also extends longevity. Here, we identify a temporal genetic relationship between TOR and Pol III in C. elegans, showing that they collaborate to regulate progeny production and lifespan. Interestingly, the lifespan interaction between Pol III and TOR is only revealed when TOR signaling is reduced specifically in adulthood demonstrating the importance of timing to control TOR regulated developmental vs adult programs. Additionally, we show that Pol III acts in C. elegans muscle to promote both longevity and healthspan and that reducing Pol III even in late adulthood is sufficient to extend lifespan. This demonstrates the importance of Pol III for lifespan and age-related health in adult C. elegans.

genetics↗

bioRxiv2018

A family of transcription factors that limit lifespan: ETS factors have conserved roles in longevity

Increasing average population age, and the accompanying burden of ill health, is one of the public health crises of our time. Understanding the basic biology of the ageing process may help ameliorate the pathologies that characterise old age. Ageing can be modulated, often through changes in gene expression where regulation of transcription plays a pivotal role. Activities of Forkhead transcription factors (TFs) are known to extend lifespan, but detailed knowledge of the broader transcriptional networks that promote longevity is lacking. This study focuses on the E twenty-six (ETS) family of TFs. This family of TFs is large, conserved across metazoa, and known to play roles in development and cancer, but the role of its members in ageing has not been studied extensively. In Drosophila, an ETS transcriptional repressor, Aop, and an ETS transcriptional activator, Pnt, are known to genetically interact with Foxo and activating Aop is sufficient to extend lifespan. Here, it is shown that Aop and Foxo effect a related gene-expression programme. Additionally, Aop can modulate Foxos transcriptional output to moderate or synergise with Foxo activity depending on promoter context, both in vitro and in vivo. In vivo genome-wide mRNA expression analysis in response to Aop, Pnt or Foxo indicated, and further experiments confirmed, that combinatorial activities of the three TFs dictate metabolic status, and that direct reduction of Pnt activity is sufficient to promote longevity. The role of ETS factors in longevity was not limited to Pnt and Aop. Knockdown of Ets21c or Eip74EF in distinct cell types also extended lifespan, revealing that lifespan is limited by transcription from the ETS binding site in multiple cellular contexts. Reducing the activity of the C. elegans ETS TF Lin-1 also extended lifespan, a finding that corroborates established evidence of roles of this TF family in ageing. Altogether, these results reveal the ETS family of TFs as pervasive and evolutionarily conserved brokers of longevity.

genetics↗