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.

Limitations to adaptive homeostasis in an hyperoxia-induced model of accelerated ageing

“…However, under hyperoxic growth conditions, both Bach1 and c-Myc exhibited elevated basal cytosolic and nuclear levels. This is important as it suggests temporal dysregulation, wherein the ‘off switch’ is activated too early [94]. It would appear that Nrf2 tries to compete with Bach1 and c-Myc in order to further elevate de novo synthesis of stress protective enzymes but that ultimately, with age or chronic hyperoxia, it fails.…”

“…Synthesis of stress protective enzymes may be blocked. Dysregulation of Nrf2 signaling may underlie the age dependent decline in proteostasis that occurs despite a basal rise in stress protective enzymes [14,15,17,21,94,95]. Because activation of proteolytic responses is hindered, transient increases in protein damage may not be dealt with and oxidized proteins that would normally be degraded are allowed to accumulate.…”

Major depression and enhanced molecular senescence abnormalities in young and middle-aged adults

“…The enhanced secretion of SASP signaling proteins after a deleterious stimuli have been previously associated with the development of canonical hallmarks of cellular aging (e.g., telomere attrition, higher expression of p16 ink4 ); likewise, cellular senescence changes can drive the cellular secretome towards an enhanced SASP profile 20–23 . Under non-pathological circumstances, protective cellular responses are rapidly activated to restore the cellular homeostasis 24 . Nonetheless, the persistence of deleterious stimuli can lead to the chronic activation of senescence response, leading to a positive feed-forward loop with enhanced SASP and other pro-senescence cellular changes.…”

Dietary patterns and the neoplastic‐prone tissue landscape of old age

“…12 On the other hand, aging entails a generalized decrease in the efficiency of mechanisms overlooking maintenance of cell fitness, possibly including cell competition, and this can increase persistence of altered cells. 48,49 Mutations in somatic cells increase with age fueling a feedback loop that leads to the age-associated exponential functional decline. 48 This in turn causes a decreased competitive fitness of normal cells, thus (a) increasing the risk for the unopposed emergence of clones with altered phenotype, including preneoplastic ones and/or (b) positively selecting for specific genetic alterations under new environmental conditions (eg, pro-inflammatory, growth-constrained, etc) that favor their phenotype.…”