To adapt or not to adapt: Consequences of declining Adaptive Homeostasis and Proteostasis with age

Abstract

Many consequences of ageing can be broadly attributed to the inability to maintain homeostasis. Multiple markers of ageing have been identified, including loss of protein homeostasis, increased inflammation, and declining metabolism. Although much effort has been focused on characterization of the ageing phenotype, much less is understood about the underlying causes of ageing. To address this gap, we outline the age-associated consequences of dysregulation of 'Adaptive Homeostasis' and its proposed contributing role as an accelerator of the ageing phenotype. Adaptive Homeostasis is a phenomenon, shared across cells and tissues of both simple and complex organisms, that enables the transient plastic expansion or contraction of the homeostatic range to modulate stress-protective systems (such as the Proteasome, the Immunoproteasome, and the Lon protease) in response to varying internal and external environments. The age-related rise in the baseline of stress-protective systems and the inability to increase beyond a physiological ceiling is likely a contributor to the reduction and loss of Adaptive Homeostasis. We propose that dysregulation of Adaptive Homeostasis in the final third of lifespan is a significant factor in the ageing process, while successful maintenance of Adaptive Homeostasis below a physiological ceiling results in extended longevity.

Keywords: Aging; Immunoproteasome; Lon protease; Nrf2; Physiological ceiling; Proteasome; Protein aggregates; longevity.

Figure 1. Adaptive Homeostasis is not Hormesis

Hormesis results following the initial exposure of a cell or organism to a damaging, non-lethal toxin, chemical or environmental condition. Exposure leads to cellular damage, which as long as it is not lethal, causes activation of stress-protective pathways, enabling the cell or organism to remove and repair the damage and preparing the organism or cell to better withstand a future, potentially more damaging oxidative insult, increasing the likelihood of survival. Some DNA repair mechanisms appear to be activated by small amounts of DNA damage. In contrast, adaptive homeostasis relies upon exposure to non-damaging amounts of an internal or external signaling molecule or condition, which does not cause damage, but is enough to activate specific signal-transduction pathways (such as Nrf2 and IRF1) that ensure the increased expression of downstream protective and repair enzymes, such as the 20S Proteasome, the Immunoproteasome, and the Lon protease. In turn, the upregulation of such protective enzymes protects cells and organisms against potentially future toxic insults, increasing their likelihood of survival.

Figure 2. Protein Accumulation is Evident only during the Final Third, or End-Stage of Life

According to the Free Radical Theory of Aging [109], protein accumulation goes hand-in-hand with cellular homeostasis. However, work measuring protein oxidation has shown that (in the absence of disease) protein aggregates do not really accrue to any great extent until the final third of life. The ability to appropriately regulate protective systems, however, shows minor evidence of decline as soon as late middle-life. These findings suggest that loss of inducibility of the adaptive homeostatic response may contribute to protein oxidation, aggregation, and cross-linking. Furthermore, measurement of changes in the adaptive homeostatic response may be a better indicator of ageing processes before physiological manifestations of many classical ageing markers occurs.

Figure 3. The Imperfect System: Age-Dependent Protein Aggregation

The cell relies upon the 20S Proteasome to remove damaged proteins from the cytoplasm, nucleus and endoplasmic reticulum. Throughout an organism’s life, the majority of damaged proteins are degraded predominantly by the 20S Proteasome, which recognizes its target substrates through the exposure of (normally internalized) hydrophobic patches. In turn, its role as a protease ensures that the majority of oxidized proteins are cleared away. However, as no system is perfect, a small percentage escapes the 20S Proteasome turnover machinery. With time (including the ageing process), the small percentage of oxidized proteins begin to accumulate, aggregate, and crosslink, making it extremely difficult for removal. However, the 20S Proteasome still tries to remove these protein aggregates by attaching to clumps of them. Unfortunately, these clumps of proteins are no longer the ideal size to progress through the barrel-shaped opening of the Proteasome. This leads to multiple Proteasomes latching onto protein aggregates, in an attempt (though futile) to try and degrade these oxidized masses. Unfortunately, the increased accumulation of 20S Proteasomes further exacerbates the aggregation, rather than staunches it, and accelerates the loss of proteostasis with age.

Figure 4. Age-Dependent Decline in the Nrf2-Mediated Adaptive Homeostatic Response

A. During homeostatic conditions in young organisms, Nrf2 is sequestered by Keap1 in the cytosol, wherein it is ubiquitin-tagged and targeted for degradation by the 26S Proteasome. Upon activation of the adaptive homeostatic response, Nrf2 rapidly dissociates from Keap1 and translocates into the nucleus (typically within minutes), where it binds to antioxidant-response elements (ARE), leading to activation of Nrf2-regulated genes. Simultaneously, the 19S regulatory caps dissociate from the Proteasome, leading an immediate pool of 20S Proteasome and loss of Nrf2 degradation. After time (typically within hours) the adaptive response is turned off. Though much work is still needed in this area, one mechanism that has been explored is that Nrf2 competitors (such as Bach1 and c-Myc) move into the nucleus, wherein they bind to Nrf2-target genes, turning off their activation. Thus the temporal balance between the adaptive response activator (Nrf2) and its inhibitors (potentially c-Myc and Bach1) is crucial in allowing the transient and coordinated response necessary for maintenance of homeostasis. B. With age this temporal response may become dysregulated. Basal amounts of Nrf2 and its transcriptional inhibitors (Bach1 and c-Myc) show an age-dependent rise, along with increased accumulation of protein damage. With age, Nrf2 and Bach1 may have similar rates of nuclear translocation following exposure to signaling molecules or events. This can lead to an abbreviated or truncated Nrf2 response and inadequate Nrf2 signal activation. As a result, dysregulation of adaptive homeostasis leads to greater accumulation of damaged protein aggregates, and loss of cellular proteostasis and homeostasis.

Figure 5. Compression of the Adaptive Homeostatic Response with Age

Young organisms exhibit low basal amounts of multiple protective proteins/enzymes (such as Nrf2, Proteasome, Immunoproteasome, and Lon protease). Exposure to a non-damaging signaling level of agents, such as oxidants, leads to rapid transcription and translation of protective and repair enzymes, and transient increases in their overall cellular levels. With age, however, basal levels of protective/repair enzymes increase (although activity may be compromised) but adaptive increases (induction) no longer occurs. This results in an age-dependent physiological ceiling to adaptive homeostasis.