Rodent frailty models provide novel and effective tools for frailty research.
Furthermore, exercise, diet, and medication interventions, in addition to their combinations, could improve frailty status in rodents. Such models were developed for use in investigating frailty-related physiological changes at the gene, cellular, molecular, and system levels, including the organ system level. Rodent frailty models can be classified broadly into the genetic modification and non-genetic modification models, the latter of which include frailty assessment models (based on the Fried frailty phenotype and frailty index methods) and induced frailty models. As rodents share homology with humans, they are used extensively as animal models to study human diseases. Although numerous studies have been conducted on frailty, the underlying mechanisms and management strategies remain unclear. These findings highlight the intriguing hypothesis about the capacity of the naked mole-rat proteome to delay aging through its proteomic intrinsic architecture.įrailty is a clinical geriatric syndrome characterized by decreased multisystem function and increased vulnerability to adverse outcomes. Among them, we identified proteins known to be associated with neurodegenerative and age-related diseases. On the other hand, proteins with lower aggregation propensity in naked mole-rat have a significantly higher mutation tolerance compared to the rest of the proteins. We found an enrichment of proteins with higher aggregation propensity in naked mole-rat, and these are functionally involved in the inflammasome complex and nucleic acid binding. Our analysis showed no proteome-wide differential effects in aggregation propensity and mutation tolerance between these species, but several subsets of proteins with a significant difference in aggregation propensity. To identify the general principles behind their protein homeostasis robustness, we compared the aggregation propensity and mutation tolerance of naked mole-rat and mouse orthologous proteins. Their resistance toward oxidative stress has been proposed as one hallmark of their healthy aging, suggesting their ability to maintain cell homeostasis, specifically their protein homeostasis. Notably, naked mole-rats, the longest-lived rodent, present attenuated aging phenotypes compared to mice. However, long-lived species may provide insights into successful strategies for healthy aging, potentially opening the door for novel therapeutic interventions in age-related diseases. The molecular mechanisms of aging and life expectancy have been studied in model organisms with short lifespans. Taken together, we revealed an epigenetic-metabolism axis contributing to aging and illustrate the power of an AI-based approach in structure-function studies. Furthermore, restoration of mitochondrial activity can rescue age-related macular degeneration (AMD) phenotypes induced by Elovl2 deficiency in human retinal pigmental epithelial (RPE) cells this indicates a conservative mechanism in both human and mouse. Impaired Elovl2 function disturbs lipid synthesis with increased endoplasmic reticulum stress and mitochondrial dysfunction, leading to key aging phenotypes at both cellular and physiological level. We applied artificial intelligence to predict the protein structure of ELOVL2 and the interaction with its substrate. Here we show ELOVL fatty acid elongase 2 (Elovl2), a gene whose epigenetic alterations are most highly correlated with age prediction, contributes to aging by regulating lipid metabolism. However, the mechanism of how their interaction regulates aging, particularly in mammals, remains largely unknown. Epigenetic alterations and metabolic dysfunction are two hallmarks of aging.
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