Queen asked in their song of the same title “Who Wants to Live Forever?” Humanity has always struggled with its mortality. Everything ages from machinery to homes to organisms and people. However, Sinclair and LaPlante wrote, “There is no law of biology that says we must age at the rate at which we do now.” Different organisms age at different rates; for example, giant tortoises have been estimated to live 250 years, Bowhead whales 200 years, and Bristlecone pine trees 5000 plus years with no signs of aging. What makes humans so susceptible to the march of time? Research has delved into that exact question as we look for what Juan Ponce de León searched for, so many years, the Fountain of Youth.
Aging is a cellular process with numerous checks and balances as cells divide and move temporally. Numerous academic endeavors have uncovered the molecular pathogenesis of aging and, in their search, have uncovered many pathways that regulate our aging processes. Processes such as the production of reactive oxygen/nitrogen species, shortening of chromosomal telomeres, epigenetic modifications, and decreased functionality of DNA repair mechanisms all lead to an accumulation of cellular oxidation and damage that promotes aging.
Ongoing research has investigated other molecular processes that contribute to cellular aging. Recently, Judith Frydman’s lab at Stanford University uncovered a new mechanism involving the ribosome and looked at the loss of optimal protein function and the errors in protein folding during aging.
The processes that cause protein misfolding and aggregation that accompany aging remain unclear. However, they found a decrease in cellular proteostasis that underlies many age-related protein folding diseases. Their hypothesis that altered ribosomal translational efficiency during aging could be responsible for proteostasis collapse is the cornerstone of the ongoing research. Using Caenorhabditis elegans (nematode) and Saccharomyces cerevisiae (yeast) as aging models they were able to show alterations within the translocation elongation kinetics during aging. They found that ribosomal pausing increased ribosomal collisions triggering ribosome-associated quality control (RQC). Within aged yeast cells, it was observed that decreased clearance and increased aggregation of RQC substrates overwhelmed the RQC pathway indicating that aging plays a significant role in the dysregulation of proteostasis. Interestingly long-lived yeast cells reduced age-dependent ribosomal pausing via a greater flux through the RQC pathway.
Their research has helped uncover a new mechanism that happens at a cellular level through ribosomal pausing leading to RQC overload, thus causing protein aggregation and a significant decline in and eventual failure of proteostasis, which may be the underlying cause of many age-dependent protein folding diseases. This research gives valuable insight and potential new drug targets that can potentially cure disease and bring an age of immortality.
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