A common feature of aging is the accumulation of genetic damage throughout life. DNA damage can lead to genomic instability. Many diseases associated with premature aging are a result of increased accumulation of DNA damage. In order to minimize these damages, organisms have evolved a complex network of DNA repair mechanisms, including mismatch repair (MMR). In this review, we detail the effects of MMR on genomic instability and its role in aging emphasizing on the association between MMR and the other hallmarks of aging, serving to drive or amplify these mechanisms. These hallmarks include telomere attrition, epigenetic alterations, mitochondrial dysfunction, altered nutrient sensing and cell senescence. The close relationship between MMR and these markers may provide prevention and treatment strategies, to reduce the incidence of age-related diseases and promote the healthy aging of human beings.
Aging is an inevitable progressive decline in physiological organ function that increases the chance of disease and death. The renin–angiotensin system (RAS) is involved in the regulation of vasoconstriction, fluid homeostasis, cell growth, fibrosis, inflammation, and oxidative stress. In recent years, unprecedented advancement has been made in the RAS study, particularly with the observation that angiotensin II (Ang II), the central product of the RAS, plays a significant role in aging and chronic disease burden with aging. Binding to its receptors (Ang II type 1 receptor – AT1R in particular), Ang II acts as a mediator in the aging process by increasing free radical production and, consequently, mitochondrial dysfunction and telomere attrition. In this review, we examine the physiological function of the RAS and reactive oxygen species (ROS) sources in detail, highlighting how Ang II amplifies or drives mitochondrial dysfunction and telomere attrition underlying each hallmark of aging and contributes to the development of aging and age-linked diseases. Accordingly, the Ang II/AT1R pathway opens a new preventive and therapeutic direction for delaying aging and reducing the incidence of age-related diseases in the future.
Dietary habits contribute to the characteristics of Alzheimer’s disease (AD) and cognitive impairment, which are partly induced by the accumulation of hyperphosphorylated Tau, a microtubule-associated protein. In mice, a fat-rich diet facilitates cognitive dysfunction. However, the mechanism by which dietary fat damages the brain remains unclear. In this study, 13-month-old C57BL/6 mice were fed a normal or high-fat diet (HFD) for 6 months. Neuro-2a cells were incubated with the normal medium or palmitic acid (200 μM). Spatial memory was assessed utilizing a behavioral test. Further, western blotting and immunofluorescence techniques were used to determine the levels of mitophagy-related proteins. The synaptic morphology and phosphorylation of Tau proteins were also evaluated. Administration of HFD decreased the expression of synaptophysin and brain-derived neurotrophic factor expression, leading to significant damage to neurons. Tau protein hyperphosphorylation was detected at different loci both in vivo and in vitro. Significantly impaired learning and memory abilities, accompanied by impaired mitophagy-related processes, were observed in mice fed with HFD as compared to mice fed with normal food. In conclusion, high fatty-acid intake hinders mitophagy and upregulates Tau protein phosphorylation, including age-related synaptic dysfunction, which leads to cognitive decline.
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