Crasta, K. | Search bioRxiv

bioRxiv2023

Therapeutic effect of dietary interventions on senescence in animals and humans: A systematic review

BackgroundCellular senescence is a permanent state of cell cycle arrest and has been regarded as a therapeutic target for ageing and age-related diseases. Several senotherapeutic agents have been proposed, including compounds derived from natural products which hold the translational potential to promote healthy ageing. It is largely unclear whether cellular senescence could be targeted by dietary interventions. This systematic review examined diets and dietary ingredients and their association with cellular senescence load in animal models and humans, with an intent to identify dietary interventions with senotherapeutic potential. MethodsThe databases PubMed and Embase were systematically searched for key terms related to cellular senescence, senescence markers, diets, nutrients and bioactive compounds. Intervention and observational studies on human and animal models investigating the effects of diets or dietary ingredients via oral administration on cellular senescence load were included. The studies were screened using the Covidence systematic review software. Study design, methods and results were extracted. Biomaterials used for senescence detection were categorized into physiological systems. The SYRCLEs risk of bias tool and Cochrane risk of bias tool v2.0 were used to assess the risk of bias for animal and human studies respectively. ResultsOut of 5707 identified articles, 82 articles consisting of 78 animal studies and 4 human studies aimed to reduce cellular senescence load using dietary interventions. In animal studies, the most-frequently used senescence model was normal ageing (26 studies), followed by D- galactose-induced models (17 studies). Resveratrol (8 studies), vitamin E (4 studies) and soy protein isolate (3 studies) showed positive effects on reducing the level of senescence markers such as p53, p21, p16 and senescence-associated {beta}-galactosidase in various tissues of physiological systems. In three out of four human studies, ginsenoside Rg1 had no positive effect on reducing senescence in muscle tissues after exercise. The risk of bias for both animal and human studies was largely unclear. ConclusionResveratrol, vitamin E and soy protein isolate are promising senotherapeutics studied in animal models. Studies testing dietary interventions with senotherapeutic potential in humans are limited and translation is highly warranted.

cell biology↗

bioRxiv2021

PLK1 inhibition selectively kills ARID1A deficient cells through uncoupling of oxygen consumption from ATP production

Inhibitors of the mitotic kinase PLK1 yield objective responses in a subset of refractory cancers. However, PLK1 overexpression in cancer does not correlate with drug sensitivity, and the clinical development of PLK1 inhibitors has been hampered by the lack of patient selection marker. Using a high-throughput chemical screen, we discovered that cells deficient for the tumor suppressor ARID1A are highly sensitive to PLK1 inhibition. Interestingly this sensitivity was unrelated to canonical functions of PLK1 in mediating G2-M cell cycle transition. Instead, a whole-genome CRISPR screen revealed PLK1 inhibitor sensitivity in ARID1A deficient cells to be dependent on the mitochondrial translation machinery. We find that ARID1A knocked-out (KO) cells have an unusual mitochondrial phenotype with aberrant biogenesis, increased oxygen consumption/ expression of oxidative phosphorylation genes, but without increased ATP production. Using expansion microscopy and biochemical fractionation, we see that a subset of PLK1 localizes to the mitochondria in interphase cells. Inhibition of PLK1 in ARID1A KO cells further uncouples oxygen consumption from ATP production, with subsequent membrane depolarization and apoptosis. Knockdown of a key subunit of the mitochondrial ribosome reverses PLK1-inhibitor induced apoptosis in ARID1A deficient cells, confirming specificity of the phenotype. Together, these findings highlight a novel interphase role for PLK1 in maintaining mitochondrial fitness under metabolic stress, and a strategy for therapeutic use of PLK1 inhibitors. To translate these findings, we describe a quantitative microscopy assay for assessment of ARID1A protein loss, which could offer a novel patient selection strategy for the clinical development of PLK1 inhibitors in cancer. Statement of significanceCurrently, no predictive biomarkers have been identified for PLK1 inhibitors in cancer treatment. We show that ARID1A loss sensitizes cells to PLK1 inhibitors through a previously unrecognized vulnerability in mitochondrial oxygen metabolism.

cancer biology↗