Key Points:
- Several long-lived, resilient mammals have the remarkable capability of overcoming neurodegeneration, cardiovascular damage, metabolic decline, and lung injury.
- Taking what we know about the biology of these animals, Dr. Zehnder and colleagues have already developed a new age-slowing pharmaceutical for humans.
Dr. Ashley Zehnder is the CEO of the aging research biotech company FaunaBio and a veterinarian scientist at the intersection of animal biology and human health. Her company has utilized a slew of hibernating animals that overcome extreme physiological degeneration during the months that they hibernate for aging research. With their study of long-lived hibernating animals, they have already developed a non-FDA approved drug under investigation against lung scarring called FAUN1003 that appears to suppress genes associated with aging.
Hibernation is a fascinating survival strategy used by some animals to get through the harsh conditions of winter or dry seasons, when food is scarce and temperatures are unfavorable. Beyond simply serving as a way to conserve energy, hibernation also provides animals with opportunities for physical repair and recovery.
Since humans cannot repair their organs to the degree of hibernating animals, Dr. Zehnder and colleagues are studying genes associated with these biological restorations — gene signatures — and applying them to human diseases. They have used these animals’ gene signatures for restoring organ function to design pharmaceuticals. By recapitulating hibernating animals’ gene signatures without the actual need for hibernation, these pharmaceuticals confer protective effects against age-related diseases. In this way, Zehnder and colleagues have applied their findings to the development of new investigational pharmaceuticals against human age-related diseases like lung scarring, heart failure, and obesity.
In a YouTube presentation, Dr. Zehnder shares how her team has identified certain gene activity signatures during the period where animals awake from hibernation that when applied in humans can allay age-related diseases. Using this strategy, Zehnder and colleagues have generated FAUN1003 for use against age-related lung scarring that also suppresses genes associated with aging and a dysfunctional cellular state associated with aging (senescence).
So far, her team has studied and applied gene activity signatures from one hibernating species — the 13-lined ground squirrel — for human drug discovery. Because squirrels are not the only animals that hibernate, studying other species besides the 13-lined ground squirrel may provide new insights for the development of pharmaceuticals. Such insights could be applied to a wider array of human age-related diseases.
Identifying Long-Lived Animals’ Gene Activity Signatures for Human Pharmaceutical Development
Dr. Zehnder and colleagues have chosen to look at gene activation signatures in extremely resilient and long-lived hibernating mammals within genes that have high similarity to humans. This is because DNA sequences within genes that show little change over millions of years of evolution are more likely to have important roles in our biology. Furthermore, since these genes play such important roles in our biology, they are more likely to cause human diseases as their malfunction results in the dysfunction of key proteins that hold our physiology together.
Zehnder and colleagues’ analyses of gene activity signatures in the 13-lined ground squirrel for these important genes in human age-related diseases have revealed that many of them have suppressed activation. This has allowed her team to develop drugs that suppress these genes in humans to recapitulate the protective effects seen in the 13-lined ground squirrel.
To apply these gene activity signatures from the 13-lined ground squirrel, Zehnder and colleagues developed a drug discovery pipeline called Convergence. The Convergence technique utilizes artificial intelligence (AI) algorithms that incorporate and compare the protective gene activity signatures between the squirrel and humans. It then validates the roles of the genes in human diseases based on human cell models. Next, the AI-based Convergence pipeline predicts compounds to mimic protection against age-related diseases by initiating the suppressed gene activity signatures from the ground squirrel to human cells.
By using this technique, Zehnder and colleagues have already generated a few pharmaceutical interventions against age-related diseases like lung scarring and heart failure. Interestingly, when their anti-lung scarring drug FAUN1003 is applied to human cells, it has also been shown to suppress key age-related genes identified in mice, rats, and humans. These genes include the biomarker gene for cellular aging (senescence) called Clusterin along with the inflammation-associated gene Cathepsin S and the aging-promoting gene Complement C1q B Chain.
Determining Whether Learning from Resilient Species Helps Identify New Drugs Against Aging
Because only one species, the 13-lined ground squirrel, has been used to design pharmaceuticals against human age-related diseases, the possibilities of future discoveries using other long-lived hibernating mammals remain tantalizing. Moreover, whether FaunaBio’s FAUN1003 drug for pulmonary fibrosis receives FDA approval will reveal if this new long-lived animal-based drug discovery pipeline is worth the attention. Positive findings for drugs designed using this pipeline could show that learning from the genetics of resilient species serves as a new way to make discoveries for pharmaceuticals against age-related diseases.
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