Unlocking the Secrets of Hibernation Genes
Mammals that hibernate have specific genes that help them adjust their metabolisms to enter a low-energy state, and interestingly, humans share some of that hibernation-related DNA. Recent studies suggest that understanding and possibly utilizing this DNA could lead to new treatments for certain health conditions.
Hibernation presents a variety of biological advantages, or “superpowers,” as described by Christopher Gregg, a human genetics expert at the University of Utah. For instance, ground squirrels are known to develop a form of reversible insulin resistance, allowing them to quickly gain weight before hibernation, which then begins to diminish as they enter this dormant state. Gregg believes that comprehending how these animals manage this metabolic switch could provide insights into the insulin resistance associated with type 2 diabetes.
Additionally, animals that hibernate have protective mechanisms to safeguard their nervous systems from damage due to sudden blood flow changes when they emerge from hibernation. “When they wake up, their brain receives a rush of blood, which could potentially cause significant damage, like a stroke. These animals have developed strategies to prevent that,” Gregg explained. He and his team are optimistic that harnessing hibernation-related genes in humans could lead to similar protective measures.
A Center of Hibernation Genes
In a pair of recent studies published in *Science*, Gregg and his research group identified crucial factors that regulate hibernation-related genes, illustrating how these genes differ in hibernating versus non-hibernating animals. The experiments included lab mice, which, although they don’t hibernate, can enter a state of torpor—characterized by decreased metabolism and lower body temperature—after fasting for a specific period.
The researchers employed the gene-editing technique CRISPR to deactivate one of five conserved noncoding cis elements (CREs) in the mice. These CREs function as controls for genes that code for critical proteins in biological processes. The targeted CREs were associated with the fat mass and obesity-related locus, or FTO locus, which is also relevant in humans. Variants within this gene cluster are linked to heightened risks of obesity and metabolic disorders. Broadly, the FTO locus plays a vital role in regulating metabolism and energy usage.
After modifying the CREs, the scientists observed varying changes in the mice’s weight, metabolic rates, and foraging behaviors. Some alterations resulted in increased or decreased weight gain, while others affected metabolic rates and temperature recovery post-torpor.
These findings hold significant promise, especially given the FTO locus’s recognized involvement in human obesity, noted Kelly Drew, an expert in hibernation biology. One particular CRE deletion increased weight gain in female mice on a high-fat diet compared to control mice, while another CRE modification influenced foraging behaviors in both male and female mice, indicating potential differences in decision-making processes between hibernating and non-hibernating animals.
Challenges Ahead
The study authors assert the relevance of their findings to humans because the genetic makeup of mammals is quite similar. However, as Joanna Kelley, a functional genomics expert, points out, applying the same genetic changes to humans isn’t straightforward. Humans lack the ability to enter fasting-induced torpor, which makes mice an appropriate model for this type of study. She suggests that future research could include animals that do not undergo torpor and focus on unraveling the effects of the deleted CREs.
Drew mentions that in mice, torpor is triggered by fasting, while true hibernation is influenced by hormonal and seasonal factors, making the biological mechanisms complex. Thus, the identified CREs may not act as a simple switch for hibernation.
Despite the uncertainties, Gregg highlights many unknowns that still need to be explored, including the differing impacts of certain deletions on male versus female mice and how the observed changes could translate to humans. The research team is also interested in investigating the effects of deleting multiple hibernation-linked CREs simultaneously.
In the long run, Gregg envisions a future where it might be possible to modify the activity of humans’ “hibernation hub genes” through medication, potentially providing neuroprotective benefits without requiring individuals to hibernate.
