Human Hibernation Genes Offer Potential for New Medical Treatments
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Humans share DNA with hibernating mammals that could hold the key to treating a range of medical conditions, according to groundbreaking research published Thursday, July 31, in the journal Science. Scientists are increasingly focused on understanding the genetic mechanisms behind hibernation, believing they could unlock “a whole bunch of different biometrically important superpowers,” as described by a senior study author.
The research centers on the unique ability of hibernating animals to drastically slow their metabolism, conserve energy, and protect their bodies from the stresses of prolonged inactivity. This process relies on specific genes, and surprisingly, humans possess similar genetic material. Early studies suggest that harnessing these genes could lead to innovative therapies for conditions like type 2 diabetes and stroke.
The Metabolic Secrets of Hibernation
One compelling example lies in the metabolic adjustments of ground squirrels. These animals develop a reversible insulin resistance before hibernation, allowing them to rapidly gain weight. This resistance then fades as they enter their dormant state. Understanding how these animals “flip this switch” could provide valuable insights into tackling insulin resistance in humans, a hallmark of type 2 diabetes.
Beyond metabolism, hibernating animals exhibit remarkable protection of their nervous systems. When they emerge from hibernation, blood flow is restored to the brain – a process that would typically cause significant damage, akin to a stroke. However, these animals have evolved mechanisms to prevent this damage. Researchers believe that tapping into hibernation-related genes in people could unlock similar neuroprotective benefits.
Identifying a ‘Hub’ of Hibernation Genes
The studies pinpointed key genetic “levers” that control hibernation-related genes, revealing differences between hibernating and non-hibernating animals. To investigate these levers, researchers used the gene-editing technique CRISPR to deactivate five conserved noncoding cis elements (CREs) in lab mice. While mice do not truly hibernate, they can enter torpor – a short-term state of decreased metabolism and body temperature triggered by fasting. This made mice a suitable model for the study.
The targeted CREs are located near the fat mass and obesity-related locus (FTO locus), a gene cluster also found in humans. Variations within this cluster have been linked to an increased risk of obesity and related health issues. The FTO locus is broadly understood to play a crucial role in regulating metabolism, energy expenditure, and body mass.
By deactivating these CREs, the researchers observed changes in the mice’s weight, metabolic rates, and foraging behaviors. Some deletions accelerated or slowed weight gain, while others altered metabolic rates. Notably, changes were also observed in how quickly the mice’s body temperatures recovered after torpor.
Implications for Obesity and Foraging Behavior
These findings are “highly promising,” particularly given the established role of the FTO locus in human obesity, according to a specialist on hibernation biology at the University of Alaska Fairbanks. Specifically, deactivating CRE E1 in female mice led to increased weight gain on a high-fat diet. Deleting CRE E3 altered foraging behavior in both male and female mice, impacting how they searched for hidden food.
“This suggests that important differences in foraging and decision processes may exist between hibernators and non-hibernators and the elements we uncovered might be involved,” explained a senior researcher.
Future Research and Potential Therapies
While the underlying genes are largely consistent across mammals, the key lies in how these genes are activated and deactivated. “It’s how [the mammals] turn those genes on and off at different times and then for different durations and in different combinations that shape different species,” one researcher noted.
However, translating these findings to humans is not straightforward. As a professor specializing in functional genomics at the University of California, Santa Cruz, pointed out, humans cannot enter fasting-induced torpor, which is why mice are used as a model. Future research should explore animals incapable of torpor and investigate the broader effects of deleting these CREs.
Researchers also acknowledge that torpor in mice is triggered by fasting, while true hibernation is driven by hormonal, seasonal changes, and internal clocks. Therefore, the identified CREs and genes may represent a metabolic “toolkit” responsive to fasting, rather than a single “master switch” for hibernation.
Looking ahead, researchers envision the possibility of developing drugs to modulate the activity of these “hibernation hub genes” in humans. The goal would be to achieve the benefits of gene activation – such as neuroprotection – without requiring patients to actually hibernate. Further investigation is needed to understand how the observed effects differ between male and female subjects and how changes in foraging behavior might translate to humans. The team also plans to study the effects of deleting multiple hibernation-linked CREs simultaneously.
