Hesperetin Upregulates Metabolism and Longevity in Mice

This compound upregulates a very critical gene.


Sophora JaponicaSophora Japonica

Researchers publishing in Journal of Biomedical Science have concluded that hesperetin, a compound found in various herbs, improves longevity in mice by promoting the expression of the pro-longevity gene Cisd2.

Mitochondria and Cisd2

This paper begins with an explanation of mitochondrial dysfunction, one of the hallmarks of aging, and the function of Cisd2. Previous research has shown that Cisd2 expression is associated with longevity in mice as it aids in mitochondrial function [1] and that Cisd2 deficiency is associated with premature aging in mice [2].

These researchers have performed previous work showing that Cisd2’s effects on mitochondria are due to its effects on calcium homeostasis and that its deficiency causes problems in multiple organs [3], as mitochondria become overloaded with calcium ions. This led to a drug discovery process in which the researchers searched for compounds that might influence Cisd2.

An effective compound from an herbal dictionary

Using a transgenic mouse model and a cell line, the researchers screened 60 herbs derived from a book on Chinese traditional medicine. Careful analysis of the compounds present in these herbs singled out hesperetin, a structural analog of the sophricoside and genistein found in Sophora japonica, as a uniquely powerful Cisd2 activator.

The researchers chose to treat wild-type 21-month-old mice with an effective dose of 100 micrograms per gram of body weight. Hesperetin showed no significant toxicity at this dose. Cisd2, which is abundant in 3-month-old mice but significantly downregulated in untreated 26-month-old mice, was found to be upregulated in the treatment group in multiple tissues. This increase gave the treatment group even greater Cisd2 levels than those of young mice, although this difference was not statistically significant.


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The median lifespan of the treatment group was 28.2 months, while a vehicle-treated group lived for 25.95 months and a different control group lived for 26.5 months. There were also statistically significant improvements in lean-to-fat mass ratio, muscle fibers and strength, and heart function. Blood glucose was also notably improved, and the researchers showed that this is due to hesperetin’s beneficial influences on multiple enzymes relating to glucose synthesis and use.

This compound seemed to upregulate metabolism in general. Mice are more active at night, and measurements related to oxygen use and energy expenditure showed that 3-month-old mice, like their older counterparts, are inactive during the day; however, unlike their older counterparts, they are much more active at night. While not all the differences were statistically significant, hesperetin seemed to increase metabolism at all hours of the day rather than restoring this circadian rhythm.

Finally, the researchers examined gene expression. Unsurprisingly, many of the transcriptomic changes brought about by aging were partially reversed by this treatment, particularly in areas related to metabolism, the processing of reactive oxygen species, and protein maintenance.


With many downstream effects that restore youthful abilities, hesperetin clearly influences mitochondrial function in a way that leads to significant and positive effects on metabolism and longevity in mice. Of course, this is still only a mouse study. If hesperetin can be shown to have such a good safety profile with similar effects in human clinical trials, it may be developed as a treatment against metabolic disorders and ultimately become part of a standard regimen to increase lifespan and healthspan.

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[1] Wu, C. Y., Chen, Y. F., Wang, C. H., Kao, C. H., Zhuang, H. W., Chen, C. C., … & Tsai, T. F. (2012). A persistent level of Cisd2 extends healthy lifespan and delays aging in mice. Human molecular genetics, 21(18), 3956-3968.


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[2] Chen, Y. F., Kao, C. H., Chen, Y. T., Wang, C. H., Wu, C. Y., Tsai, C. Y., … & Tsai, T. F. (2009). Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes & development, 23(10), 1183-1194.

[3] Shen, Z. Q., Chen, Y. F., Chen, J. R., Jou, Y. S., Wu, P. C., Kao, C. H., … & Tsai, T. F. (2017). CISD2 haploinsufficiency disrupts calcium homeostasis, causes nonalcoholic fatty liver disease, and promotes hepatocellular carcinoma. Cell reports, 21(8), 2198-2211.

About the author
Josh Conway

Josh Conway

Josh is a professional editor and is responsible for editing our articles before they become available to the public as well as moderating our Discord server. He is also a programmer, long-time supporter of anti-aging medicine, and avid player of the strange game called “real life.” Living in the center of the northern prairie, Josh enjoys long bike rides before the blizzards hit.