Aging attenuates redox adaptive homeostasis and proteostasis in female mice exposed to traffic-derived nanoparticles (‘vehicular smog’)

Abstract

Environmental toxicants are catalysts for protein damage, aggregation, and the aging process. Fortunately, evolution selected adaptive homeostasis as a system to mitigate such damage by expanding the normal capacity to cope with toxic stresses. Little is known about the subcellular degradative responses to proteins oxidatively damaged by air pollution. To better understand the impact of environmental toxicants upon the adaptive homeostatic response, female C57BL/6 mice were exposed for 10 weeks to filtered air or reaerosolized vehicular-derived nano-scale particulate matter (nPM), at which point tissues from young (6 month) and middle-aged (21 month) mice were studied. We found significant increases of proteolytic capacity in lung, liver, and heart. Up to two-fold increases were seen in the 20S Proteasome, the Immunoproteasome, the mitochondrial Lon protease, and NF-E2-related factor 2 (Nrf2), a major transcriptional factor for these and other stress-responsive genes. The responses were equivalent in all organs, despite the indirect input of inhaled particles to heart and liver which are downstream of lung. To our knowledge, this is the first exploration of proteostatic responses to oxidative damage by air pollution. Although, middle-aged mice had higher basal levels, their Nrf2-responsive-genes exhibited no response to nanoparticulate exposure. We also found a parallel age-associated rise in the Nrf2 transcriptional inhibitors, Bach1 and c-Myc which appear to attenuate adaptive responses in older mammals, possibly explaining the 'age-ceiling effect.' This report extends prior findings in male mice by demonstrating the involvement of proteolytic responses to traffic-related air pollution in lung, liver, and heart of female mice, with an age-dependent loss of adaptive homeostasis.

Does Bach1 & c-Myc dependent redox dysregulation of Nrf2 & adaptive homeostasis decrease cancer risk in ageing?

“…Interestingly, the basal expression of all four Nrf2 regulated genes, was increased in the middle-aged male mice. The same pattern of changes in baseline and inducibility in GCLC and GCLM as well as subunits of the proteasome were observed in female mice exposed to the same protocol [54]. In primary human bronchial epithelial cells, we found a similar pattern of increased basal expression of Nrf2-regulated genes along with a decline in inducibility by sulforaphane in cells from older donors [55].…”

Female vulnerability to the effects of smoking on health outcomes in older people

“…Further studies of sex differences in response to cigarette smoke should consider physiologically distinct stages of the lifespan: development (0-18), young adulthood (18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), middleage including post-menopause , and older ages when chronic diseases increase exponentially (60+). For example, a mouse model of air pollution toxicity had attenuated responses of lung and brain by middle-age (18 months) [46,47]. We should also consider potential middle-aged survivor bias in older age cohorts such as HRS, which combines individuals in latemiddle age and older ages.…”

Bach1: Function, Regulation, and Involvement in Disease

“…In addition, Bach1 is also associated with an age-dependent loss of adaptive homeostasis. Bach1 was increased in all tissues (heart, liver, and lung) of aging mice [ 35 ] and was higher in human bronchial epithelial cells from older adults than from young adult donors [ 36 ]. Thus, Bach1 appears to attenuate redox adaptive homeostasis in aging mice and old people.…”

Isomeric O-methyl cannabidiolquinones with dual BACH1/NRF2 activity

“…This is a very attractive profile for drugs against oxidative stress and/or inflammatory associated conditions, such as most neurodegenerative disorders, and our data on a HD cell model provide a solid rationale for future studies in vivo using NDs models. It is noteworthy that with aging, NRF2 signaling is impaired [ [54] , [55] , [56] ]. A comparison of NRF2 activation by sulforaphane in bronchial epithelial cells isolated from young human subjects (21–29 years) and older (60–69 years) individuals, non-smokers, has shown that the inducibility of the NRF2-mediated cytoprotective responses is diminished in cells from older adults [ 57 ].…”

The proteostatic effects of traffic-derived air pollution on Alzheimer's disease risk

“…Specifically, when young mice were exposed to nano-sized particulate air pollution, the animals responded with increased levels of proteasome, immunoproteasome and lon protease subunits. Interestingly, the response in older animals was less robust [ 7 ], suggesting that a decline in proteostasis during ageing may render older individuals especially susceptible to air pollution-mediated oxidative damage. This is consistent with our initial hypothesis that protein damage during ageing, compounded with environmental exposure, tips the proteostasis balance toward disease ( figure 1 c ).…”