Proteasome function is not impaired in healthy aging of the lung

Abstract

Aging is the progressive loss of cellular function which inevitably leads to death. Failure of proteostasis including the decrease in proteasome function is one hallmark of aging. In the lung, proteasome activity was shown to be impaired in age‐related diseases such as chronic obstructive pulmonary disease. However, little is known on proteasome function during healthy aging. Here, we comprehensively analyzed healthy lung aging and proteasome function in wildtype, proteasome reporter and immunoproteasome knockout mice. Wildtype mice spontaneously developed senile lung emphysema while expression and activity of proteasome complexes and turnover of ubiquitinated substrates was not grossly altered in lungs of aged mice. Immunoproteasome subunits were specifically upregulated in the aged lung and the caspase‐like proteasome activity concomitantly decreased. Aged knockout mice for the LMP2 or LMP7 immunoproteasome subunits showed no alteration in proteasome activities but exhibited typical lung aging phenotypes suggesting that immunoproteasome function is dispensable for physiological lung aging in mice.Our results indicate that healthy aging of the lung does not involve impairment of proteasome function. Apparently, the reserve capacity of the proteostasis systems in the lung is sufficient to avoid severe proteostasis imbalance during healthy aging.

The age- and sex-specific decline of the 20s proteasome and the Nrf2/CncC signal transduction pathway in adaption and resistance to oxidative stress in Drosophila melanogaster

“…The proteasome core is crucial to the rapid removal of damaged proteins from cells and tissues. However, loss of protein turnover has been considered to be a hallmark of aging [ 55 , 56 ], accompanied by diminished basal proteolytic capacity of the 20S proteasome [ 57 , 58 ], though this finding is somewhat controversial [ 20 , 53 , 59 - 61 ]. To explore this matter further, tissue lysate (abdomen, head, thorax) from 3 day old and 60 day old females, pretreated with various concentrations of H 2 O 2 [0μM-100μM] were assessed for changes in proteolytic capacity (measured fluorometrically) following the addition of fluorogenic peptides specific for the three proteolytic activities of the 20S proteasome core.…”

“…A key measure of age-related changes in proteolytic function is protein degradation. While, the general consensus is in accord with the amount and activity of the catalytic core declining with age [ 77 ], it is not universal [ 20 , 61 ], and is highly tissue-dependent [ 57 , 78 ]. Moreover, earlier studies indicate an age-associated increase in the basal amounts of the 20S proteasome in rat muscle [ 79 , 80 ], C. elegans [ 53 ], and as presented here, in D. melanogaster .…”

Oncogenic addiction to high 26S proteasome level

“…These findings highlight the notion that the ratio of proteasome complexes in the cell is a regulated and crucial process. Further findings demonstrate the functional alteration of the 26S/20S proteasome complex ratio in the context of cell cycle progression 27 , neuronal function 28 , 29 , metabolic regulation 30 – 33 , and aging 34 – 36 .…”

The proteostasis network and its decline in ageing

“…Indeed, transient inhibition of translation via phosphorylation of translation initiation factor 2α (eIF2α) is an important strategy to protect cells from protein misfolding stress 187 and is prominently associated with the unfolded protein response of the ER and the integrated stress response 31,188 . Reduction of protein synthesis has beneficial effects, including lifespan extension in worms 189-192 . An imbalance between the production of misfolded proteins and available proteasome capacity is implicated in various age-related pathologies 128,193 , and a decline in proteasome function has been observed during ageing in model organisms in various tissues and cell types [194][195][196] . In C. elegans, the abundance of proteasomal subunits was found to increase with age 166 (Fig.…”