Aging and SKN-1-dependent Loss of 20S Proteasome Adaptation to Oxidative Stress inC. elegans

Abstract

Aging is marked by a collapse of protein homeostasis and deterioration of adaptive stress responses that often lead to disease. During aging, the induction of stress responses decline along with protein quality control. Here, we have shown that the ability to mount an adaptive response by pretreatment with minor oxidative stress is abrogated in aged Caenorhabditis elegans We have identified a defect in SKN-1 signaling sensitivity during aging and have also found an aging-related increase in basal proteasome expression and in vitro activity, however, adaptation of the 20S proteasome in response to stress is lost in old animals. Interestingly, increased activation of SKN-1 promotes stress resistance, but is unable to rescue declining adaptation during aging. Our data demonstrate that the aging-dependent decline in SKN-1 signaling negatively impacts adaptation of the 20S proteasome in response to acute oxidative stress.

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

“…Indeed, early studies suggested that increased proteasome expression resulted in decreased accumulation of damaged proteins [63]. As well, prior studies in cell culture demonstrated increased protein removal in cells pretreated with an adaptive dose prior to being subjected to a challenge dose of an oxidant [53, 64, 65]. …”

“…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 . These findings substantiate prior studies that suggested a similar trend in the dysregulation of proteasome expression and activity with age.…”

Oxidative DNA damage & repair: An introduction

“…Adaptive homeostasis involves transient expansion of the physiological, or homeostatic, range of stress resistance that is typically reversed within hours. Major pathways for adaptive homeostasis include the Nrf2 signal transduction pathway in mammals (31), its CncC orthologue in flies (32), and its SKN-1 orthologue in worms (33). …”

“…More recently it has become clear that inducible systems for transient adaptation, such as hormesis and adaptive homeostasis, also decline with age (31–33). Indeed, mounting evidence now suggests that diminished ability to modulate homeostasis in response to varying levels of environmental and metabolic stressors, may be a significant contributor to age-related degeneration.…”

Oxidised protein metabolism: recent insights

“…Aggregated, oxidised proteins are recognised as a hallmark of ageing (Höhn et al, 2013). Recently deficiencies in the ability of the 20S proteasome to respond to oxidative stress have been observed in aged Caenorhabitis elegans due to a defect in the Nrf2 homolog SKN-1 (Raynes et al, 2017). An emerging area of research is the autophagic degradation of damaged proteasomes and the material they contain, dubbed proteaphagy (Hoeller and Dikic, 2016).…”