Summary Multiple human diseases involving chronic oxidative stress show a significant sex bias, including neurodegenerative diseases, cancer, immune dysfunction, diabetes, and cardiovascular disease. However a possible molecular mechanism for the sex-bias in physiological adaptation to oxidative stress remains unclear. Here we report that Drosophila melanogaster females but not males adapt to hydrogen peroxide stress, whereas males but not females adapt to paraquat (superoxide) stress. Stress adaptation in each sex required the conserved mitochondrial Lon protease and was associated with sex-specific expression of Lon protein isoforms and proteolytic activity. Adaptation to oxidative stress was lost with age in both sexes. Transgenic expression of transformer gene during development transformed chromosomal males into pseudo-females, and conferred the female-specific pattern of Lon isoform expression, Lon proteolytic activity induction and H2O2 stress adaptation; these effects were also observed using adult-specific transformation. Conversely, knockdown of transformer in chromosomal females eliminated the female-specific Lon isoform expression, Lon proteolytic activity induction and H2O2 stress adaptation, and produced the male-specific paraquat (superoxide) stress adaptation. Sex-specific expression of alternative Lon isoforms was also observed in mouse tissues. The results develop Drosophila melanogaster as a model for sex-specific stress adaptation regulated by the Lon protease, with potential implications for understanding sexual-dimorphism in human disease.

The proteasome is a ubiquitous and highly plastic multi-subunit protease with multi-catalytic activity that is conserved in all eukaryotes. The most widely known function of the proteasome is protein degradation through the 26S ubiquitin-proteasome system, responsible for the vast majority of protein degradation during homeostasis. However, the proteasome also plays an important role in adaptive immune responses and adaptation to oxidative stress. The unbound 20S proteasome, the core common to all proteasome conformations, is the main protease responsible for degrading oxidized proteins. During periods of acute stress, the 19S regulatory cap of the 26S proteasome disassociates from the proteolytic core, allowing for immediate ATP/ubiquitin-independent protein degradation by the 20S proteasome. Despite the abundance of unbound 20S proteasome compared to other proteasomal conformations, many publications fail to distinguish between the two proteolytic systems and often regard the 26S proteasome as the dominant protease. Further confounding the issue are the differential roles these two proteolytic systems have in adaptation and aging. In this review, we will summarize the increasing evidence that the 20S core proteasome constitutes the major conformation of the proteasome system and that it is far from a latent protease requiring activation by binding regulators.

Adaptive homeostasis is "the transient expansion or contraction of the homeostatic range for any given physiological parameter in response to exposure to sub-toxic, non-damaging, signalling molecules or events, or the removal or cessation of such molecules or events" (Davies, 2016). Adaptive homeostasis enables biological systems to make continuous short-term adjustments for optimal functioning despite ever-changing internal and external environments. Initiation of adaptation in response to an appropriate signal allows organisms to successfully cope with much greater, normally toxic, stresses. These short-term responses are initiated following effective signals, including hypoxia, cold shock, heat shock, oxidative stress, exercise-induced adaptation, caloric restriction, osmotic stress, mechanical stress, immune response, and even emotional stress. There is now substantial literature detailing a decline in adaptive homeostasis that, unfortunately, appears to manifest with ageing, especially in the last third of the lifespan. In this review, we present the hypothesis that one hallmark of the ageing process is a significant decline in adaptive homeostasis capacity. We discuss the mechanistic importance of diminished capacity for short-term (reversible) adaptive responses (both biochemical and signal transduction/gene expression-based) to changing internal and external conditions, for short-term survival and for lifespan and healthspan. Studies of cultured mammalian cells, worms, flies, rodents, simians, apes, and even humans, all indicate declining adaptive homeostasis as a potential contributor to age-dependent senescence, increased risk of disease, and even mortality. Emerging work points to Nrf2-Keap1 signal transduction pathway inhibitors, including Bach1 and c-Myc, both of whose tissue concentrations increase with age, as possible major causes for age-dependent loss of adaptive homeostasis.

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The Free Radical Theory of Ageing, was first proposed by Denham Harman in the mid-1950's, based largely on work conducted by Rebeca Gerschman and Daniel Gilbert. At its core, the Free Radical Theory of Ageing posits that free radical and related oxidants, from the environment and internal metabolism, cause damage to cellular constituents that, over time, result in an accumulation of structural and functional problems. Several variations on the original concept have been advanced over the past six decades, including the suggestion of a central role for mitochondria-derived reactive species, and the proposal of an age-related decline in the effectiveness of protein, lipid, and DNA repair systems. Such innovations have helped the Free Radical Theory of Aging to achieve widespread popularity. Nevertheless, an ever-growing number of apparent 'exceptions' to the Theory have seriously undermined its acceptance. In part, we suggest, this has resulted from a rather simplistic experimental approach of knocking-out, knocking-down, knocking-in, or overexpressing antioxidant-related genes to determine effects on lifespan. In some cases such experiments have yielded results that appear to support the Free Radical Theory of Aging, but there are just as many published papers that appear to contradict the Theory. We suggest that free radicals and related oxidants are but one subset of stressors with which all life forms must cope over their lifespans. Adaptive Homeostasis is the mechanism by which organisms dynamically expand or contract the homeostatic range of stress defense and repair systems, employing a veritable armory of signal transduction pathways (such as the Keap1-Nrf2 system) to generate a complex profile of inducible and enzymatic protection that best fits the particular need. Viewed as a component of Adaptive Homeostasis, the Free Radical Theory of Aging appears both viable and robust.

The elimination of oxidatively modified proteins is a crucial process in maintaining cellular homeostasis, especially during stress. Mitochondria are protein-dense, high traffic compartments, whose polypeptides are constantly exposed to superoxide, hydrogen peroxide, and other reactive species, generated by ‘electron leakage’ from the respiratory chain. The level of oxidative stress to mitochondrial proteins is not constant, but instead varies greatly with numerous metabolic and environmental factors. Oxidized mitochondrial proteins must be removed rapidly (by proteolytic degradation) or they will aggregate, cross-link, and cause toxicity. The Lon Protease is a key enzyme in the degradation of oxidized proteins within the mitochondrial matrix. Under conditions of acute stress Lon is highly inducible, possibly with the oxidant acting as the signal inducer, thereby providing increased protection. It seems that under chronic stress conditions, however, Lon levels actually decline. Lon levels also decline with age and with senescence, and senescent cells even lose the ability to induce Lon during acute stress. We propose that the regulation of Lon is biphasic, in that it is up-regulated during transient stress and down-regulated during chronic stress and aging, and we suggest that the loss of Lon responsiveness may be a significant factor in aging, and in age-related diseases.

The Immunoproteasome has traditionally been viewed primarily for its role in peptide production for antigen presentation by the Major Histocompatibility Complex (MHC), which is critical for immunity. However, recent research has shown that the Immunoproteasome is also very important for the clearance of oxidatively damaged proteins in homeostasis, and especially during stress and disease. The importance of the Immunoproteasome in protein degradation has become more evident as diseases characterized by protein aggregates have also been linked to deficiencies of the Immunoproteasome. Additionally, there are now diseases defined by mutations or polymorphisms within Immunoproteasome-specific subunit genes, further suggesting its crucial role in cytokine signaling and protein homeostasis (or ‘proteostasis’). The purpose of this review is to highlight our growing understanding of the importance of the Immunoproteasome in the management of protein quality control, and the detrimental impact of its dysregulation during disease and aging.

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.