The role of declining adaptive homeostasis in ageing

Abstract

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.

Keywords: Lon protease; Nrf2-Keap1; caloric restriction; cold shock; emotional stress; exercise-induced adaptation; heat shock; hypoxia; immune response; mechanical stress; osmotic stress; oxidative stress; proteasome; stress response.

Figure 1. Activation and deactivation of the adaptive homeostasis pathway

During periods of homeostasis, the physiological range enables cells, tissues, and organisms to cope with minor changes in redox status. However, external or internal perturbations, that exceed the homeostatic range, trigger the transient activation of adaptive responses. Adaptive homeostasis is activated following exposure to sub‐lethal, non‐damaging amounts of a signalling event – such as exposure to nanomolar levels of hydrogen peroxide (H₂O₂). Although toxic amounts of a stressor can also induce adaptive responses, it is actually not the damage but rather the initial signalling that is important; this distinguishes adaptive homeostasis from hormesis (Davies, 2016). Initial exposure to low amounts of signalling agent or conditions triggers transcriptional activation, within minutes. One of the most notable pathways for adaptive homeostasis is the nuclear recruitment and binding of Nrf2 to antioxidant response elements (AREs), also called electrophile response elements (EPREs), located in the upstream activation sites of key stress protective genes. Following transcription, translational activation occurs over a period of hours, resulting in the upregulation of stress responsive enzymes, including the 20S Proteasome and the mitochondrial Lon protease. In turn, elevation in the levels of such protective enzymes better prepare cells, tissues, or organisms, to cope with future, potentially more harmful, stresses. Lastly, as the adaptive response is transient, adaptive homeostasis will gradually contract back to the basal homeostatic range.

Figure 2. Loss of adaptive homeostasis with age

Young organisms show a wide basal homeostatic range (dashed green), that upon transient activation, results in the robust increase (continuous green) of the adaptive homeostatic response. For convenience, only positive adaptive homeostatic responses (expanding the homeostatic range) are shown. With age, however, the inducibility of the response declines, becoming evident beginning in middle age (continuous brown). As cells, tissues, and organisms age towards senescence (continuous red) adaptive homeostasis can decline so much that it may no longer be effective at all. Additionally, aged organisms are further compromised by compression of the basal homeostatic range (dashed red), limiting the ability to cope with even day‐to‐day small variations that are no challenge to their young counterparts.

Figure 3. Increased transcription of stress‐protective genes by the Keap1‐Nrf2 signal transduction pathway

During normal periods of homeostasis (‘no stress’), Nrf2 is kept in the cytoplasm by Keap1 which prevents Nrf2 from moving into the nucleus and binding to antioxidant response elements (AREs or EpREs) of stress‐responsive genes. Nrf2 levels are kept low (despite high rates of synthesis) by first being poly‐ubiquitinylated and then targeted for degradation by the 26S Proteasome. In this process, the Cul3 ubiquitin ligase component of the Keap1‐Cul3 complex is responsible for poly‐ubiquitinylation of Nrf2. During periods of stress, the 26S Proteasome undergoes disassembly by Ecm29 and HSP70 (generating free 20S Proteasomes) and Nrf2 can no longer be degraded. Nrf2 then disassociates from Keap1 and undergoes phosphorylation, enabling it to translocate into the nucleus and bind to ARE/EpRE elements in the upstream regions of target (protective) genes. These processes are the steps that cause activation of the adaptive homeostatic response, leading to the upregulation of stress‐protective enzymes an overall, but transient, increase in stress resistance.

Figure 4. Age‐dependent loss of adaptive homeostasis appears to be a common biological phenomenon, as it is evident in multiple organisms

Detailed studies in cultured mammalian cells, nematode worms (C. elegans), fruit flies (D. melanogaster), mice, and limited studies in humans show a consistent age‐dependent decline in the inducibility of the stress‐responsive circuitry; in other words, the capacity for adaptive homeostasis is lost with age. Studies from our lab and others have uniformly shown that young organisms can rapidly activate Nrf2 and increase the expression of multiple stress‐responsive enzymes, including the 20S Proteasome and the mitochondrial Lon protease (as well as their various regulators). With age, however, despite a significant increase in the basal steady‐state levels of these protective enzymes, no additional stress‐protective adaptive response is seen. Interestingly, the basal levels of protective enzymes, such as Proteasome and Lon, in older organisms approximate the inducible levels of these same enzymes in young organisms. These findings potentially demonstrate an upper limit or ‘ceiling‐effect’ for the inducibility of stress‐protective systems, and may also indicate that older organisms are in something of a state of constant or chronic stress.