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Natural lung aging is characterized by molecular and cellular changes in multiple lung cell populations. These changes include shorter telomeres, increased expression of cellular senescence markers, increased DNA damage, oxidative stress, apoptosis, and stem cell exhaustion. Aging, combined with the loss of protective repair processes, correlates with the development and incidence of chronic respiratory diseases, including idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease. Ultimately, it is the interplay of age-related changes in biology and the subsequent responses to environmental exposures that largely define the physiology and clinical course of the aging lung., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Female smokers have a faster decline in lung function with increasing age and overall develop a greater loss of lung function than male smokers. This raises the question of whether estrogen status in women affects susceptibility to cigarette smoke (CS)-induced lung disease. Mouse models suggest that female mice are more susceptible than males to CS-induced lung disease. Moreover, young CS-exposed female mice develop emphysema earlier than male mice. The purpose of this study was to characterize the relationship of estrogen status on the pattern and severity of CS-induced lung disease. In this study, 15-month-old female C57BL/6J mice were ovariectomized and administered either placebo (pla) or 17β-estradiol (E 2 , 0.025 mg) 2 weeks after ovariectomy. They were further divided into those that were exposed to CS and no-smoke controls (NSC). Mice were exposed to CS in stainless steel inhalation chambers 3 hours a day, 5 days a week for 6 months, and sacrificed after 24 weeks of CS exposure. Blood and urine were collected at sacrifice to measure estrogen and cotinine levels, a metabolite of nicotine. Uterine weight was recorded as an indicator of estrogen status. Results showed that CS in the absence of E 2 induced a decrease in hydroxyproline content, macrophage number, and respiratory chain complex-1 protein. CS without E 2 also resulted in an increase in matrix metalloproteinase-2 activity and apoptosis and a change in the ratio of estrogen receptor subtype. These findings were abrogated with administration of E 2, suggesting that estrogen deficiency increases susceptibility to CS-induced lung disease., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Age-related increases in oxidant stress (OS) play a role in regulation of estrogen receptor (ER) expression in the kidneys. In this study, we establish that in vivo 17β-estradiol (E2) replacement can no longer upregulate glomerular ER expression by 21 months of age in female mice (anestrous). We hypothesized that advanced glycation end product (AGE) accumulation, an important source of oxidant stress, contributes to these glomerular ER expression alterations. We treated 19-month old ovariectomized female mice with pyridoxamine (Pyr), a potent AGE inhibitor, in the presence or absence of E2 replacement. Glomerular ERα mRNA expression was upregulated in mice treated with both Pyr and E2 replacement and TGFβ mRNA expression decreased compared to controls. Histological sections of kidneys demonstrated decreased type IV collagen deposition in mice receiving Pyr and E2 compared to placebo control mice. In addition, anti-AGE defenses Sirtuin1 (SIRT1) and advanced glycation receptor 1 (AGER1) were also upregulated in glomeruli following treatment with Pyr and E2. Mesangial cells isolated from all groups of mice demonstrated similar ERα, SIRT1, and AGER1 expression changes to those of whole glomeruli. To demonstrate that AGE accumulation contributes to the observed age-related changes in the glomeruli of aged female mice, we treated mesangial cells from young female mice with AGE-BSA and found similar downregulation of ERα, SIRT1, and AGER1 expression. These results suggest that inhibition of intracellular AGE accumulation with pyridoxamine may protect glomeruli against age-related oxidant stress by preventing an increase of TGFβ production and by regulation of the estrogen receptor.