Inhibiting DREAM Complex while dreaming facilitates rejuvenation in mice

#1

In a nutshell, what is the DREAM Complex (per ChatGPT):

  • The DREAM complex is a transcriptional repressor that helps keep cells in a quiescent state by turning off cell cycle and DNA repair genes. Because it represses DNA repair in non-dividing cells, its activity may contribute to the accumulation of DNA damage and influence aging and age-related disease processes.

Short benefit summary (per Grok):

  • Sleep deprivation [and circadian rhythm disturbance] keeps DREAM active (preventing chromatin relaxation for repair), accelerating cellular decline. Pharmacological inhibitors (e.g., harmine or alternatives) fully reverse sleep disruption effects in mice (100% recovery of cellular function despite no sleep), restoring repair and proteostasis. This is tied to aging hallmarks (e.g., poor sleep links to diabetes, heart disease).

Excerpts from the study itself:

  • DREAM elevation confers increased chromatin compaction and shields DNA from damage while altering fundamental cellular processes such as translation, stress responses and OXPHOS. Conversely, DREAM levels are lowered during sleep enabling cellular maintenance and repair. When sleep or clock are altered, DREAM levels remain high, and repair activities remain suppressed triggering cellular and organismal deterioration that can be reversed by genetic and pharmacological inhibition of DREAM in vivo and in vitro . We thus reveal the potential of DREAM inhibitors to replicate the benefits of sleep in sleep-deprived and clock-impaired organisms.

  • From the translational standpoint, we additionally show that pharmacological and genetic inhibition of DREAM can possibly mimic the restorative effects of sleep at the cellular level. […]. We propose that the administration of DREAM inhibitors shall be restricted to the time designated to sleep as opposed to the 24h-long chronic administration, thus replicating the natural circadian fluctuations of DREAM activity. In follow-up studies, we anticipate to functionally test these hypotheses in vivo in vertebrates.

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#2

“DREAM activity predicts the varied lifespans observed across 92 mammals, with low activity marking longer-lived species.”

Also see:

#3

A potential approach to lowering nocturnal DREAM activity: swertia bimaculata extract at bedtime?

Desmethylbellidifolin (DMB) is an inhibitor of the DREAM complex, acting indirectly through its potent inhibition of DYRK1A kinase. It is present naturally in the herb swertia bimaculata. “DMB from Swertia bimaculata was found to be a novel and potent DYRK1A inhibitor (1)

Swertia bimaculata is commercially available as an herbal extract. Although sources are limited. Example

Research summary from Grok:

Swertia bimaculata, a member of the Gentianaceae family, is a traditional medicinal herb widely used in East Asia, particularly within Tibetan and Chinese medicine. Often utilized as a substitute for the more famous Swertia chirayita, research has begun to validate its specific pharmacological profile, particularly concerning metabolic and hepatic health.

Chemical Composition

The therapeutic potential of S. bimaculata is attributed to its “bitter” bioactive metabolites. Key constituents include:

  • Xanthones: Specifically corymbiferin, which is highly abundant in certain extracts, as well as swerchirin and mangiferin (Khanal et al., 2015; Wan et al., 2013).
  • Secoiridoids: Including sweroside, swertiamarin, and amarogentin (Khanal et al., 2015).
  • Flavonoids: Predominantly mangiferin, which contributes to its antioxidant and anti-diabetic properties (Khanal et al., 2015).

Research in Lab Animals

Animal studies provide the bulk of the “heavy lifting” regarding the plant’s health claims. Research has focused on its role in managing diabetes and liver disease.

1. Anti-diabetic and Hypoglycemic Effects

In models of streptozotocin-induced diabetic rats, extracts of S. bimaculata—particularly those enriched with corymbiferin—showed significant therapeutic activity (Wan et al., 2013):

  • Glucose Regulation: It significantly decreased fasting blood glucose levels and improved oral glucose tolerance.
  • Insulin Sensitivity: It enhanced insulin sensitivity by increasing the expression of the insulin receptor substrate-2 and the PI3K/Akt signaling pathway (Wan et al., 2013).
  • Organ Protection: Treatment led to histopathological improvements in both the liver and pancreatic β-cells.

2. Hepatoprotective and Antioxidant Activity

The plant is traditionally used for hepatitis and jaundice. In lab models, its extracts have shown:

  • Enzyme Inhibition: While S. bimaculata shows lower β-glucuronidase inhibitory activity compared to S. chirayita, it still possesses protective qualities against liver damage markers (Nag et al., 2016).
  • Oxidative Stress: It improves antioxidant capacity, helping to neutralize reactive oxygen species (ROS) that contribute to diabetic complications (Wan et al., 2013).

Research in Humans

Direct clinical trials specifically focusing on S. bimaculata as a standalone supplement are scarce. Most human evidence comes from its use in traditional polyherbal formulations.

  • Traditional Use: In the Tibetan and Yunnan regions of China, it is known as “Zangyinchen” and is a cornerstone for treating gallbladder and liver disorders (Yang et al., 2022).
  • Formulated Medicine: It is a component of the Tibetan formula Lang Qing Ata (LQAtta), which has received clinical approval in China for treating liver fibrosis and non-alcoholic steatohepatitis (NASH). Clinical practice has shown it to be effective in improving liver function and repairing tissue (Wan et al., 2025).

Toxicity and Safety

While generally considered to have a favorable safety profile compared to synthetic drugs, certain precautions are noted:

  • General Toxicity: It is typically categorized as having “low toxicity” in standard dosages (Yang et al., 2022).
  • Side Effects: Some reports indicate potential gastrointestinal discomfort, such as nausea, particularly when used in high concentrations (Mallick, 2019).
  • Bioavailability: A major hurdle in its clinical use is the low bioavailability and rapid metabolic degradation of its primary compounds, like sweroside, meaning that while it is safe, it might not always reach the target tissues effectively without advanced delivery systems (Yang et al., 2022).

Summary Table

Feature Findings
Primary Benefit Significant blood sugar reduction and liver protection.
Active Compound Corymbiferin is the star for anti-diabetic effects.
Human Data Mostly via traditional formulations; limited standalone trials.
Toxicity Low; occasional nausea reported.

Note: Because it can lower blood sugar, individuals already taking glucose-lowering medications should be cautious to avoid hypoglycemia.

References

  • Khanal, S., Shakya, N., Thapa, K., & Pant, D. R. (2015). Phytochemical investigation of crude methanol extracts of different species of Swertia from Nepal. BMC Research Notes, 8, 751. https://doi.org/10.1186/s13104-015-1753-0
  • Nag, G., Adhikari, S., & Ghoshal, S. (2016). Metabolic profile and β-glucuronidase inhibitory property of three species of Swertia. Revista Brasileira de Farmacognosia, 26(6), 708–715. Redirecting
  • Wan, L., Chen, C. P., Xiao, Z. Q., Wang, Y., Min, Q. X., Yue, M., & Yan, C. Q. (2013). Hypoglycemic Activity and Antioxidative Stress of Extracts and Corymbiferin from Swertia bimaculata In Vitro and In Vivo. Evidence-Based Complementary and Alternative Medicine, 2013, 647346. https://doi.org/10.1155/2013/647346
  • Yang, J., Zhao, M., & Wang, Q. (2022). Sweroside: unveiling broad therapeutic potential—from mechanistic insights to clinical potential. Frontiers in Pharmacology, 13, 962698. https://doi.org/10.3389/fphar.2022.1017268