Sleepless? You Might Be Aging Faster! Unmasking the Metabolic Link Between Sleep Deprivation and Early Aging

Sleepless nights got you feeling old? You're not alone. A new study published in the journal Sleep suggests sleep deprivation (SD) can mimic the metabolic effects of aging in young mice. Researchers compared the metabolism of young and old mice after 5 hours of sleep deprivation, finding that SD significantly impacted the young mice's liver and blood, altering ketone body metabolism and other pathways in a way that resembled aged mice. Old mice, however, already showed these SD-like changes, suggesting they're less susceptible to further sleep disruption. Interestingly, a specific set of metabolites was similarly affected by SD in young mice's blood and liver, reflecting an aging-like signature. This research paves the way for understanding the link between sleep and aging, and potentially developing ways to combat the negative effects of sleep deprivation.

Key Points

Problem: Sleep deprivation (SD) and aging share similar effects on learning and memory, but the underlying mechanisms remain unclear. This study explored the metabolic changes caused by acute SD in young and old mice to see if they resembled aging.

Methods: Young and aged mice were sleep-deprived for 5 hours, and their blood, hippocampus, and liver were analyzed for metabolic changes using a sophisticated technique called UPLC-MS/MS.

Results:

• Young mice: SD significantly impacted their metabolism, particularly in the liver and blood plasma, altering ketone body metabolism and other pathways. These changes resembled the metabolic signatures of aged mice.

• Old mice: They already exhibited SD-like metabolic features at baseline, suggesting they're less responsive to further sleep disruption.

• Shared metabolites: A set of nine metabolites, involved in pathways like nicotinamide metabolism, were similarly affected by SD in young mice's plasma and liver, reflecting an aging-like signature.

Conclusions:

• Acute SD in young mice induces metabolic changes similar to those seen in aging, potentially explaining their vulnerability to SD-related memory decline.

• Aged mice are less susceptible to further metabolic disruption from SD, likely due to pre-existing ageing-related changes.

• Specific metabolites may serve as markers for both SD and aging, offering potential insight into their interconnectedness.

Implications:

This study sheds light on the metabolic underpinnings of SD's aging-like effects and paves the way for further research into potential interventions to mitigate these negative consequences.

In a groundbreaking study, we delve into the intricate relationship between sleep deprivation (SD) and its impact on the metabolic profile of young adult (2–4 months) and aged (22–24 months) male C57BL/6NIA mice. Obtained from the esteemed National Institute of Aging mouse colony, these mice became the focal point for our investigation into the overlapping molecular and clinical phenotypes induced by both aging and SD.

Experimental Setup

The meticulous experiment design involved individual housing on a 12-hour light/dark schedule, with ad libitum access to food and water. The mice were randomly assigned to either the control or experimental (SD) group. A crucial aspect was the gentle handling method employed for at least 5 days before the SD, ensuring consistent and stress-free handling.

Sleep Deprivation Methodology

The SD group underwent a carefully executed 5-hour sleep deprivation regimen using the gentle handling method during the first half of the light phase (ZT 0—ZT 5). This method, comprising manual cage tapping, jostling, and nestlet disturbance, has shown effectiveness in inducing memory consolidation and epigenetic processes.

Metabolic Profiling Insights

Overlapping Phenotypes

Our study uncovered a striking overlap in molecular phenotypes induced by both aging and SD. Comprehensive metabolic profiling revealed shared impacts on attention, memory, lipid oxidation, and telomere depletion. Transcriptomic data from the medial prefrontal cortex further highlighted overlapping gene expression changes between SD in young adult animals and the natural aging process.

Kynurenine and Aging Phenotypes

Notably, the elevation of kynurenine in blood plasma emerged as a key metabolite impacted similarly by aging and SD. This metabolite, derived from tryptophan, is associated with aging phenotypes like sarcopenia and bone loss, as well as low-grade chronic inflammation. Our findings suggest a potential link between chronic SD and aging-associated phenotypes.

Amino Acids and Derivatives

Amino acids and derivatives, including serine, acetylornithine, arginine, and cystine, exhibited elevation in response to both SD and aging. Serine's role in sleep regulation and its involvement in immune cell proliferation and epigenetic regulation underscore its significance in the peripheral metabolic environment induced by SD.

Hepatic Metabolic Pathways

Ketone Body Metabolism

In the liver of young adult animals subjected to SD, ketone body metabolism was highly enriched. Significant elevations in acetoacetate and 3-hydroxybutyrate indicated increased fatty acid oxidation, aligning with previous findings of SD promoting ketosis in rodents. This elevation extended to the plasma, impacting brain energy metabolism and glutamate release.

Nicotinamide Metabolism

Significant impacts on nicotinamide metabolism were observed in the young adult liver, with downstream degradation products of NAD evident in blood plasma. Elevated nicotinamide mononucleotide and nicotinamide riboside, signatures overlapping between aging and SD, suggest a potential link to NAD biosynthesis and mitochondrial function alterations.

Global Metabolic Changes

Urea Cycle-Related Disorders and Neurological Impacts

Young adult animals post-SD exhibited enrichment in urea cycle-related enzymatic disorders and neurological disorders, including seizure events. The relationship between aging, SD, and these disorders suggests a complex interplay, possibly mediated by sirtuin activity and NAD availability.

Aged Animals' Resilience

Surprisingly, aged animals displayed resistance to the metabolic effects of SD, with fewer impacted metabolites compared to young adults. This could be attributed to a higher metabolic baseline in older mice, potentially minimizing the room for SD-induced changes. These findings challenge the notion that aged animals recover better from SD-induced impairments.

Conclusion

Our comprehensive analysis illuminates the intricate connections between sleep deprivation, aging, and metabolic alterations in young adult and aged mice. The differential impact of SD on young and aged animals sheds light on the complex interplay of aging and SD at the molecular level. As we uncover these metabolic nuances, our study contributes valuable insights into understanding the aging process, sleep deprivation effects, and their intersection in the realm of metabolism.

Reference Article

Arjun Sengupta, Jennifer C Tudor, Danielle Cusmano, Joseph A Baur, Ted Abel, Aalim M Weljie, Sleep deprivation and aging are metabolically linked across tissues, Sleep, Volume 46, Issue 11, November 2023, zsad246, https://doi.org/10.1093/sleep/zsad246

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