Friday, May 9, 2025
5/9/2025
Mechanistic tRNA modification affects to aging - Abstract Age-related phenomena are not comprehensively explained by current aging theories. As a main risk factor of degenerative diseases, aging is associated with inflammation, organ failure, oxidative stress, and reduced metabolism. Many diseases with age-related risk factors (cardiovascular disease, diabetes, cancer, etc.) are associated with deviation of protein translation affected by transfer RNA (tRNA) biology. Endogenous enzymatic chemical modifications to tRNA can regulate protein translation by affecting tRNA anticodon-codon recognition, tRNA folding, and tRNA stability. Cellular stress can perturb tRNA modifications and cause cellular dysfunction. Additional tRNA biochemistries can be regulated by changes of tRNA modifications. Cleavage of tRNAs into tRNA-derived fragments (tsRNA) was once believed to be inadvertent, though now is understood to be a controlled process that is important for cellular biological function. Enzymes, such as angiogenin (ANG), are responsible for this predictable cleavage. tRNA modifications, such as 5-methylcytosine, have been shown to affect ANG cleavage, especially under cellular oxidative stress. However, the mechanisms by which tRNA modifications in aged tissue affects ANG cleavage of tRNA have not been identified. We hypothesize that age- induced reprogramming of tRNA methylation leads to biased tRNA cleavage and tRNA levels, which then induces the repression of translation and leads to senescence. Here we propose to examine tRNA and tsRNA modification levels and expression levels in aged and young mice and cell models of senescence to understand how they affect translation and senescence. As we have previously identified differing tRNA modification levels in various healthy murine tissues, we predict there will be tissue-specificity of tRNA modifications in extended aging murine models. In Aim 1 we will examine tRNA and tsRNA modification levels in tissues that commonly manifest age-induced dysfunction, such as heart, lung, skin, and liver. In Aim 2, we will evaluate tRNA and tsRNA modifications with multiple in vitro models of senescence to examine underlying mechanisms. Thus, this proposal seeks to elucidate the mechanisms by which age-associated tRNA modification aberrations affect tRNA cleavage and how that affects senescence. This information will allow us to build molecular models for tRNA modifications associated with aging. Further, tRNA machinery provides unique molecular targets for future therapies of age-related diseases.
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