Cellular senescence is a biological process by which cells lose their capacity to proliferate yet remain metabolically active. Although originally considered a protective mechanism to limit the formation of cancer, it is now appreciated that cellular senescence also contributes to the development of disease, including common respiratory ailments such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. While many factors have been linked to the development of cellular senescence, mitochondrial dysfunction has emerged as an important causative factor. In this study, we uncovered that the mitochondrial biogenesis pathway driven by the mammalian target of rapamycin/peroxisome proliferator-activated receptor-γ complex 1α/β (mTOR/PGC-1α/β) axis is markedly upregulated in senescent lung epithelial cells. Using two different models, we show that activation of this pathway is associated with other features characteristic of enhanced mitochondrial biogenesis, including elevated number of mitochondrion per cell, increased oxidative phosphorylation, and augmented mitochondrial reactive oxygen species (ROS) production. Furthermore, we found that pharmacological inhibition of the mTORC1 complex with rapamycin not only restored mitochondrial homeostasis but also reduced cellular senescence to bleomycin in lung epithelial cells. Likewise, mitochondrial-specific antioxidant therapy also effectively inhibited mTORC1 activation in these cells while concomitantly reducing mitochondrial biogenesis and cellular senescence. In summary, this study provides a mechanistic link between mitochondrial biogenesis and cellular senescence in lung epithelium and suggests that strategies aimed at blocking the mTORC1/PGC-1α/β axis or reducing ROS-induced molecular damage could be effective in the treatment of senescence-associated lung diseases.

Background Adipose tissue accumulation in specific body compartments has been associated with diabetes, hypertension and dyslipidemia. Perirenal fat (PRF) may lead to have direct lipotoxic effects on renal function and intrarenal hydrostatic pressure. This study was undertaken to explore the association of PRF with cardiovascular risk factors and different stages of chronic kidney disease (CKD). Methods We studied 103 patients with CKD of different stages (1 to 5). PRF was measured by B-mode renal ultrasonography in the distal third between the cortex and the hepatic border and/or spleen. Results The PRF thickness was greater in CKD patients with impaired fasting glucose than in those with normal glucose levels (1.10 ± 0.40 cm vs. 0.85 ± 0.39 cm, P < 0.01). Patients in CKD stages 4 and 5 (glomerular filtration rate [GFR] < 30 mL/min/1.73 m 2 ) had the highest PRF thickness. Serum triglyceride levels correlated positively with the PRF thickness; the PRF thickness was greater in patients with triglyceride levels ≥ 150 mg/dL (1.09 ± 0.40 cm vs. 0.86 ± 0.36 cm, P < 0.01). In patients with a GFR < 60 mL/min/1.73 m 2 , uric acid levels correlated positively with the PRF thickness ( P < 0.05). Conclusion In CKD patients, the PRF thickness correlated significantly with metabolic risk factors that could affect kidney function.

Idiopathic pulmonary fibrosis (IPF) is age-related interstitial lung disease of unknown etiology. About 100,000 people in the U.S have IPF, with a 3-year median life expectancy post-diagnosis. The development of an effective treatment for pulmonary fibrosis will require an improved understanding of its molecular pathogenesis and the “normal” and “pathological’ hallmarks of the aging lung. An important characteristic of the aging organism is its lowered capacity to adapt quickly to, and counteract, disturbances. While it is likely that DNA damage, chronic endoplasmic reticulum (ER) stress, and accumulation of heat shock proteins are capable of initiating tissue repair, recent studies point to a pathogenic role for mitochondrial dysfunction in the development of pulmonary fibrosis. These studies suggest that damage to the mitochondria induces fibrotic remodeling through a variety of mechanisms including the activation of apoptotic and inflammatory pathways. Mitochondrial quality control (MQC) has been demonstrated to play an important role in the maintenance of mitochondrial homeostasis. Different factors can induce MQC, including mitochondrial DNA damage, proteostasis dysfunction, and mitochondrial protein translational inhibition. MQC constitutes a complex signaling response that affects mitochondrial biogenesis, mitophagy, fusion/fission and the mitochondrial unfolded protein response (UPRmt) that, together, can produce new mitochondria, degrade the components of the oxidative complex or clearance the entire organelle. In pulmonary fibrosis, defects in mitophagy and mitochondrial biogenesis have been implicated in both cellular apoptosis and senescence during tissue repair. MQC has also been found to have a role in the regulation of other protein activity, inflammatory mediators, latent growth factors, and anti-fibrotic growth factors. In this review, we delineated the role of MQC in the pathogenesis of age-related pulmonary fibrosis.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic and progressive lung disease of unknown etiology with limited treatment options. It is characterized by repetitive injury to alveolar epithelial cells and aberrant activation of numerous signaling pathways. Recent evidence suggests that metabolic reprogramming, metabolic dysregulation, and mitochondria dysfunction are distinctive features of the IPF lungs. Through numerous mechanisms, metabolomic abnormalities in alveolar epithelial cells, myofibroblast, macrophages, and fibroblasts contribute to the abnormal collagen synthesis and dysregulated airway remodeling described in lung fibrosis. This review summarizes the metabolomic changes in amino acids, lipids, glucose, and heme seen in IPF lungs. Simultaneously, we provide new insights into potential therapeutic strategies by targeting a variety of metabolites.

Background The utility of convalescent COVID-19 plasma (CCP) in the current pandemic is not well defined. We sought to evaluate safety and efficacy of CCP in severely or life threateningly ill COVID-19 patients when matched with a contemporaneous cohort. Methods Patients with severe or life threatening COVID-19 were treated with CCP according to FDA criteria, prioritization by an interdisciplinary team and based on CCP availability. Individual-level matched controls (1:1) were identified from patients admitted during the prior month when no CCP was available. Safety outcome was freedom from adverse transfusion reaction and efficacy outcome a composite of death or worsening O2 support. Demographic, clinical and laboratory data were analyzed by univariate and multivariable regression analyses accounting for matched design. Results Study patients (N=94, 47 matched pairs) were 62% male with mean age of 58 and 98% (90/94) were minority (53% Hispanic, 45% Black, non-Hispanic) in our inner-city population. Seven-day composite and mortality outcomes suggested a non-significant benefit in CCP treated patients (adjusted hazard ratio (aHR), 0.70; 95% confidence interval (CI), 0.23 to 2.12; P=0.52; aHR, 0.23; 95% CI, 0.04 to 1.51; P=0.13, respectively). Stratification by pre-transfusion mechanical ventilation status showed no differences between groups. No serious transfusion reactions occurred. Conclusion In this short-term matched cohort study, transfusion with CCP was safe and showed a non-significant association with study outcomes. Randomized and larger trials to identify appropriate timing and dosing of CCP in COVID-19 is warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT04420988