Research Progress of Aging-related MicroRNAs.

Senescence refers to the irreversible state in which cells enter cell cycle arrest due to internal or external stimuli. The accumulation of senescent cells can lead to many age-related diseases, such as neurodegenerative diseases, cardiovascular diseases, and cancers. MicroRNAs are short non-coding RNAs that bind to target mRNA to regulate gene expression after transcription and play an important regulatory role in the aging process. From nematodes to humans, a variety of miRNAs have been confirmed to alter and affect the aging process. Studying the regulatory mechanisms of miRNAs in aging can further deepen our understanding of cell and body aging and provide a new perspective for the diagnosis and treatment of aging-related diseases. In this review, we illustrate the current research status of miRNAs in aging and discuss the possible prospects for clinical applications of targeting miRNAs in senile diseases.

Metformin ameliorates 5-fluorouracil-induced intestinalinjury by inhibiting cellular senescence, inflammation, and oxidative stress.

5-Fluorouracil (5-Fu), which inhibits metabolism, isanessentialpartof the first-line treatment of colorectal cancer but causes severe side effects, including nausea, vomiting, anorexia, and gastrointestinal injury with severe diarrhea, and requires dose reduction or treatment deferral, resulting in a poor prognosis. Metformin has anti-inflammatory effects, but its role in the mechanism of treatment in intestinal injury caused by 5-Fu remains unclear. In our present research, we assessed the impact of metformin on damagetotheintestinefrom5-Fuby inhibiting cellular senescence, intestinalcanal inflammation, and oxidative stress by using HUVECs, HIECs, and male BALB/c mice. It has been found that intestinal damage caused by 5-Fu is associated with the accumulation of senescent cells. Metformin relieved intestinaldamage by suppressing the activity of senescence-ß-galactosidase (SA-ß-gal) and the development of the senescence-associated secretory phenotype (SASP). Furthermore, we observed that the anti-aging effect was closely correlated with mTOR suppression in cell and mouse models. In conclusion, this is the first time that metformin has been able to reduce intestinaldamage related to chemotherapy by inhibiting cellular senescence and oxidative stress.

Belinostat (PXD101) resists UVB irradiation-induced cellular senescence and skin photoaging.

Belinostat (PXD101), a new histone deacetylase inhibitor, has shown good performance in various cancer treatments and has been approved by the FDA for the treatment of recurrent or refractory peripheral T-cell lymphoma (PTCL) in patients with drugs. PXD101 is considered to have certain anti-allergic and anti-inflammatory properties, but its beneficial effects in UVB-induced skin photoaging have not been reported. In a recent study, HacaT cells and C57BL6 mice were used to study the impact of PXD101 on UVB-induced cellular senescence and skin photoaging and to explore their potential mechanisms of action. Studies have shown that PXD101 inhibits UVB-induced HacaT cell senescence, which appears to be achieved by inhibiting activation of the UVB-induced NF-κB/p65 signaling pathway. At the same time, PXD101 inhibits the expression of MMPs. In addition, PXD101 alleviated skin damage on the dorsal skin of mice, reduced skin aging and inflammation, increased collagen fiber synthesis, and restored UVB-induced epidermal thickening. In short, we believe that PXD101 effectively inhibits cellular senescence and skin photoaging caused by UVB exposure, a potential method for developing clinical prevention and treatment of skin aging.

Trifluridine induces HUVECs senescence by inhibiting mTOR-dependent autophagy.

Trifluridine, a key component of trifluridine/tipiracil, is a potential anti-cancer drug that can act effectively on refractory metastatic colorectal cancer. Chemotherapy is important for cancer treatment, but its adverse effects limit its use. Long-term side-effects caused by the drug used during chemotherapy are closely related to the accumulation of cellular senescence. However, the relationship between trifluridine and normal cell aging remains unclear. The purpose of this study is to evaluate whether trifluridine can induce the senescence of human umbilical vein endothelial cells and to explore the possible mechanism. Human umbilical vein endothelial cells were treated with trifluridine, senescence levels were measured via senescence-related acidic ß-galactosidase staining and senescence-associated secretory phenotype levels respectively. Autophagy was assessed by the protein levels of LC3II/LC3I and p62, and LC3 fusion was detected by fluorescence microscopy. Chloroquine diphosphate salt and rapamycin were used to detect the effect of trifluridine on autophagy flux and mTOR signaling pathway. Trifluridine increased the expression of senescence-associated acidic ß-galactosidase and senescence-related secretory phenotype mRNA levels in cells. In addition, also trifluridine induced cellular senescence by inhibiting autophagy and was closely related to the activation of the mTOR signaling pathway, therefore, we believe that trifluridine may be an effective mTOR activator. The findings also provide a new strategy for establishing autophagy or aging models, as well as a new theoretical basis for the use of trifluridine in clinical treatment.