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Last month, researchers at Johan Auwerx’s lab at the Ecole Polytechnique Fédérale de Lausanne (EPFL) had looked at the connections between RNA-binding proteins and aging. RNA binding proteins (RBPs) play an important part in post-transcriptional control by binding to mRNA. After binding, RBPs can aid in the processing of pre-mRNA as well as mRNA stability, transport and translation [1].

Mitochondria

Upon screening aged animals for RBPs, researchers at the EPFL noticed increased activity of Pumilio2 (PUM2), which can lower the production of some proteins. It does this by binding to specific mRNAs (based on recognition sites) so that it can repress the translation of those mRNAs into proteins.

The researchers showed that PUM2 can bind to the mRNA coding for mitochondrial fission factor (MFF). This protein helps regulate mitochondrial fission, which is the breaking up of mitochondria into smaller pieces and is important in mitophagy, the process in which damaged or dysfunctional mitochondria are removed from the cell. In essence, the increase of PUM2 binding serves to inhibit the translation of MFF.

By disrupting mitophagy, PUM2 binding might contribute to an increase of dysfunctional mitochondria, which is one of the hallmarks of aging. The researchers, therefore, tried to alter this process in vivo. When PUM2 was knocked out using CRISPR-Cas9, mitophagy increased and mitochondrial function improved in aged mice.

Senescence

RBPs might play an important role in cellular senescence, another hallmark of aging [1]. In an earlier study, RBP expression was examined across different age groups. In general, regardless of a person’s age, the same RBPs tended to be expressed. The main exception involved senescent cells, in which the normal RBPs were in decline. This indicated that at least some RBPs were playing a role in normal cells that were not present in senescent cells. Moreover, other research supported that RBPs might play a part in controlling the progression of cancer.

This correlates with the control of senescence, because it’s generally theorized that senescence is a biological safeguard to stop cells that could become cancerous from growing. Because RBPs might affect cancer traits, this implicates them as a potential modulator of senescence in aging. Two notable examples are TTP and CPEB1. Both of these RBPs appear to suppress cancer and promote senescence by affecting the stability and translation of mRNAs that regulate senescence and serve as tumor suppressors.

Further effects

Other RBPs play a role in other aging pathologies [1]. One example is sarcopenia, the loss of muscle mass and strength that causes frailty in the aged. The worsening of liver function is connected with an RBP called CUGBP1. Even in the more infamous pathologies, such as Alzheimer’s, RBPs appear to play a role. Some RBPs affect the production of amyloid beta peptides found in Alzheimer’s patients. This has inspired some researchers to explore the potential of targeting these RBPs as a treatment.

Conclusion

RBPs help modulate several age-related pathologies as well as two notable hallmarks of aging: mitochondrial dysfunction and cellular senescence. These proteins do this by controlling whether or not the mRNAs they bind to get translated into their final protein forms.

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Literature

[1] Gorospe, M. (2012). RNA-binding proteins: Post-transcriptional control of aging traits. Ageing research reviews, 4(11), 421-422.

About the author
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Ariah Mackie

Ariah received a bachelor's in Biomolecular Engineering from the University of California in Santa Cruz in 2016. Her career interests are in regenerative medicine for aging, teaching,computational biology, genomics, and bioinformatics
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