<aside> đź’µ 2000 USDC | VitaDAO Longevity Fellowship 5000 DAI | Longevity Prize 2nd Place
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Sugar Byproducts and How They May Influence Aging
Methylglyoxal Affects Translation Fidelity
Accurate conversion of genetic information into protein tertiary structure is one of the pillars of proper cellular function, and disruption of protein homeostasis (proteostasis), which leads to intracellular accumulation of misfolded proteins, is a hallmark of aging and a contributor to age-related pathologies (1, 2).
The mechanisms of the aforementioned conversion are somewhat “noisy” – for transcription, the error rate is $10^{-5}$-$10^{-4}$ (1/100,000 ribonucleotides are mismatched with the transcribed DNA template); for translation, the rate is $10^{-4}$-$10^{-3}$ (1/10,000 mRNA codons are paired with a wrong amino acid) (3). In addition, erroneous tRNA aminoacylation (when tRNA is coupled with an amino acid that does not match the anticodon) presents an extra source of mistakes in the flow of information from DNA to protein (4, 5).
Any deviation from the background error rate affects the aging dynamics. It has been shown that certain long-lived organisms inherently benefit from a relatively more faithful translation (6–8), whereas experimental elevation of translation error rate in animal models shortens lifespan (9) and elicits age-related alterations (10, 11). It is therefore important to deconstruct the mechanisms that alter the fidelity of protein synthesis in order to devise strategies and interventions for extending healthy life.
Methylglyoxal (MGO) is a byproduct of glycolysis with reactivity towards biological amines – arginine guanidino groups, lysine amino groups, and exposed protein N-termini (12, 13). Non-enzymatic modification of amino acid residues by MGO leads to the formation of various chemical adducts and crosslinks (collectively known as advanced glycation end products (AGEs)) that may affect the susceptible proteins’ three-dimensional conformations (in other words, how they are spatially folded) and their proper functioning (14). Numerous reports implicate MGO production in diabetic complications – cardiomyopathy, nephropathy, peripheral neuropathy, retinopathy, etc. – and age-related organ decline (15–17).
Unfolded protein response (UPR) is a mechanism to circumvent the accumulation of misfolded proteins either in the lumen of the endoplasmic reticulum (ER stress) or in the cytosol (cytosolic UPR). It has been shown that cells grown in the presence of high glucose display ER stress mediated by MGO (18, 19). The authors conclude that the UPR is brought about by non-enzymatic post-translational modification of existing proteins by MGO (18). Here, I propose an additional hypothetical mechanism: MGO-mediated glycation of ribosomes – i.e. ribosomal proteins, rRNAs – increases the error rate at the level of translation, resulting in enhanced synthesis of polypeptides prone to misfolding.
Extracellular matrix (ECM) is a heterogeneous but highly organized matter located in-between cells that provides structural support to tissues (20, 21). Cells and their environment, represented by the ECM, communicate reciprocally to drive organogenesis during development and remodeling in response to insult (22, 23). ECM composition and ensuing mechanical properties greatly affect cellular behavior (24). For example, mesenchymal stem cells commit to specific lineages depending on substrate elasticity: soft matrices that mimic the brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic (25). Moreover, the accumulation of crosslinks (including but not limited to MGO-derived crosslinks) in matrix collagen has been shown to increase ECM stiffness and contribute to cardiovascular pathology (26) and cancer (27, 28).
Cells continuously monitor the state of their environment, including its mechanical properties, via cell-surface receptors. Transduction of mechanical cues (mechanotransduction) is mediated by integrin receptors that probe the ECM elasticity and initiate a cascade of intracellular responses to fine-tune cellular behavior to the surrounding mechanical context (29, 30). Increased ECM rigidity (stiffness) leads to translocation of the transcription coactivator YAP/TAZ from the cytoplasm into the nucleus where it binds to the transcription factor TEAD, driving expression of genes involved in tumorigenesis: those promoting growth, proliferation, survival, glucose uptake, glycolysis, epithelial-to-mesenchymal transition, apoptosis inhibition (31–33). Concurrently, I propose that enhanced glycolysis (and subsequent MGO generation) in response to the stiffened ECM leads to the loss of proteostasis at least partially due to ribosome glycation and an ensuant increase in mistranslation rate.
The proposed mechanism of proteostasis disruption may have even broader implications for the ECM organization. For instance, the substitution of key amino acid residues in tropoelastin has been shown to impede monomer coacervation and lead to aberrant elastic fiber formation (34).
The project proposes to investigate the effect of ribosome glycation on translation fidelity. In other words, to determine whether post-translational non-enzymatic modification of ribosomal proteins and rRNAs by the glycolysis-derived metabolite methylglyoxal affects the accuracy of protein synthesis at the level of mRNA decoding.
The hypothetical mechanism of ribosomal dysfunction has not yet been described in the literature. Shedding light on novel aspects of translation fidelity, especially in relation to metabolism, will draw a link between the tightly regulated proteostasis maintenance machinery and the stochastic nature of glycation, possibly paving the way to a new class of life-extending interventions.
Connecting metabolic dysregulation, extracellular matrix stiffening, and loss of proteostasis, the project integrates several established hallmarks of aging into a unified framework. Elucidation of the outlined hypothetical mechanisms will shed light on hitherto unexplored aspects of cellular physiology and will contribute to a better understanding of the aging process.