Aging and sleep deprivation induce the unfolded protein response in the pancreas: implications for metabolism

Abstract

Sleep disruption has detrimental effects on glucose metabolism through pathways that remain poorly defined. Although numerous studies have examined the consequences of sleep deprivation (SD) in the brain, few have directly tested its effects on peripheral organs. We examined several tissues in mice for induction of the unfolded protein response (UPR) following acute SD. In young animals we found a robust induction of BiP in the pancreas, indicating an active UPR. At baseline, pancreata from aged animals exhibited a marked increase of a proapoptotic transcription factor, CHOP that was amplified by SD, whereas BiP induction was not observed, suggesting a maladaptive response to cellular stress with age. Acute SD increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in the pancreatic beta cells, since plasma insulin levels were not lower following acute SD. Accordingly, animals subjected to acute SD remained tolerant to a glucose challenge. In a chronic SD experiment, young mice were found to be sensitized to insulin and have improved glycemic control, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations. Our results show that both age and SD cooperate to induce the UPR in pancreatic tissue. While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, CHOP induction in pancreatic tissues suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells, and that these effects may be exacerbated by normal aging.

Endoplasmic reticulum proteostasis impairment in aging

“…Moreover, young mice under sleep deprivation showed an increase in BiP and eIF2α phosphorylation, which was not observed in aged mice, but there was an upregulation of GADD34, CHOP, and caspase‐12 (Naidoo et al ., ). Another study demonstrated similar observations in the pancreas of mice (Naidoo et al ., ). Additionally, aged macrophages exhibit diminished IRE1 activation and increased susceptibility to ER stress‐dependent apoptosis (Song et al ., ).…”

Report and Research Agenda of the American Geriatrics Society and National Institute on Aging Bedside‐to‐Bench Conference on Sleep, Circadian Rhythms, and Aging: New Avenues for Improving Brain Health, Physical Health, and Functioning

“…Age‐related SCR disturbances have implications for metabolic dysfunction, including obesity and diabetes mellitus (especially in adults aged ≥65) and the physiological and medical burden of these conditions . Findings from studies examining age‐related changes in SCR disturbance in rodent models have demonstrated their effect on health and metabolism . Changes in central and peripheral clocks contribute to age‐related changes in metabolic health, which may vary according to organ system and may be reversible.…”

“…5,[66][67][68][69] Findings from studies examining age-related changes in SCR disturbance in rodent models have demonstrated their effect on health and metabolism. [70][71][72][73] Changes in central and peripheral clocks contribute to age-related changes in metabolic health, which may vary according to organ system and may be reversible. These changes are potential targets for intervention.…”

Type 2 diabetes mellitus, drug addiction, bipolar disorder and epilepsy display overlapping aetiopathogenic mechanisms: Implication for prevention and pharmacotherapy

“…Poor sleep has been noted (Kamphuis et al, 2011) to be a potential causal factor in aggression and violence. Sleep deprivation, which is associated with impaired glucose homeostasis (Naidoo et al, 2014), facilitates the onset of epileptic seizures (Fountain et al, 1998;Diaz-Negrillo, 2013). High-fat diet increases sleep fragmentation (Kotz et al, 2012) and may decrease brain GABA levels Oriaifo et al 177 (Valladolid-Acebes et al, 2011).…”

“…Inadequate sleep, which is associated with low BDNF scores (Singh et al, 2014), has recently been recognised also as an important risk factor for insulin resistance and diabetes (Naidoo et al, 2014). The workers pointed out that even relatively short bouts of sleep deprivation reduce glucose tolerance by as much as 40% in aged rodents, though not in the absence of food.…”