Investigating aging hallmarks: from identifying accelerated senescence signature using machine learning, to discovering taurine’s lifespan extension mechanisms
Loading...
Date issued
Authors
Editors
Journal Title
Journal ISSN
Volume Title
Publisher
Reuse License
Abstract
Ageing is a complex and multifaceted process that has puzzled scientists for decades
and humanity for ages. Although progress has been made to better understand ageing
and cellular senescence, pieces of this puzzle are still missing. In this study, I advance in
two routes. First, I focus on the identification of key players in the accelerated senescence
(AS) phenotype. Subsequently I unveil the mechanisms underlying lifespan extension
upon taurine supplementation.
I based my work on a previously published study reporting the existence of 200 gene
deletion mutants that senesce rapidly upon telomerase deletion. In order to understand if
there are any commonalities among these mutants that may drive the onset of replicative
senescence, we utilized publicly available mRNA datasets of single KO mutants in
telomerase positive conditions and trained a machine-learning model to identify common
expression patterns that might predispose these cells to senesce rapidly upon telomerase
deletion. Following the identification of a putative mRNA expression signature, said
signature was used in order to predict and identify novel fast senescing mutants, based
on the mRNA expression profile of their non-senescing (telomerase proficient)
counterparts.
In addition to the aforementioned identification of novel accelerated senescence mutants,
it was recently published that in several organisms that taurine supplementation
significantly increases their lifespan. The mechanisms underlying this phenomenon
remain largely unknown, so we decided to dissect the primary hallmarks of ageing using
the powerful genetic model organism, S. cerevisiae, to see which one is affected by
taurine. My work is predominantly focused on the proteostasis hallmark, whereas
members of the team are investigating the rest. Taurine’s lifespan extension results were
not present in the telomere positive budding yeast; hence, we decided to investigate that
in telomerase negative conditions, to better mimic the rest of the organisms in the original
publication. Although there was no difference in the replicative lifespan, I found out that
taurine supplementation leads to in vivo stabilization of various TS (temperature sensitive)
proteins. Similar stabilizing effects can be replicated with other osmolytes, however the
degree of stabilization depends on the protein-osmolyte pair. In short, I suggest that the
reason taurine has such an impact on the lifespan of the models used in the original
publication, is protein stabilization, which is in line with the fact that senescent or older
cells are often characterized by accumulation of missfolding proteins and UPR stress.
The discovery of taurine's role in lifespan extension provides a potential therapeutic target
for improving human life-health span and paves the way to developing anti-ageing
therapies.