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Senolytics Have Sex-Dependent Effects on Young Mice

Both fisetin and the dasatinib/quercetin combination have sex-dependent impacts.

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In a research paper published in GeroScience, researchers investigated the impact of senolytics on young mice and found some surprising results [1].

Senescent cell removal and other properties

Senolytics, when given to older mice, clear senescent cells. Senolytics such as fisetin and quercetin also have anti-inflammatory properties and can be used as chemotherapeutics and senotherapeutics [2]. Another senolytic, dasatinib, is used to treat leukemia, and when used with quercetin, its senolytic potency is higher [3].

Promising research results in older animals has led to senotherapeutics being marketed as anti-aging therapies. In particular, compounds such as fisetin and quercetin, which are naturally occurring plant-derived flavonoids, can be used as dietary supplements. However, there is a lack of knowledge on how such supplementation can impact organisms before they accumulate senescent cells.

In this new paper, researchers gave mice a cocktail consisting of either fisetin or a combination of dasatinib and quercetin once per month, starting from 4-month young adulthood until 13 months of age.

Fisetin’s positive impact on male mice

First, these researchers measured gene expression to investigate senescence markers, including the senescence-associated secretory phenotype (SASP) profile of the mice. The SASP is the result of senescent cell accumulation [4]. It is comprised of inflammatory molecules, growth factors, and proteases, which are enzymes that break down proteins.

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In fisetin-treated male mice, expression of SASP markers was reduced to the levels of 4-month-old mice, while no or minor changes were observed in female mice.

The researchers then measured physiological parameters. Fisetin treatment didn’t impact the weight or food consumption of the male and female mice. On the molecular level, fisetin treatment improved glucose metabolism in male mice, enhancing glucose clearance and increasing adiponectin, a molecule involved in regulating glucose levels. Females didn’t show changes in adiponectin levels.

Researchers also observed improvements in energy metabolism, as measured by oxygen consumption and energy expenditure. Fisetin treatment increased oxygen consumption and energy expenditure in male mice, suggesting enhanced energy metabolism in those animals.

Previous research has shown that senolytic compounds can destroy senescent cells in models of neurodegenerative disease and lead to functional improvement [5, 6]. Monthly treatment of young male mice with fisetin showed improved cognitive performance and learning. However, researchers didn’t see changes in cognitive tests in female mice.

Overhaul, researchers observed improvements in male mice treated with fisetin, but fisetin treatment did not affect female mice. The authors suggest that it is potentially due to the slower rate of biological aging in these mice.

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Detrimental effects on female mice

This study also included an assessment of SASP markers in dasatinib and quercetin-treated mice. The effects of this cocktail on mice differed from those of fisetin. Contrary to expectations, the researchers observed increased expression of SASP markers in female mice. There were no effects in male mice except for one marker.

Just like with fisetin, dasatinib and quercetin treatment didn’t impact the weight of the male mice. However, the body weight of female mice treated with dasatinib and quercetin increased. Body composition analysis attributed this weight gain to increased white adipose tissue deposits.

On the molecular level, researchers learned that females treated with dasatinib and quercetin had increased fat synthesis and less fat burning for heat. Both of those changes can result in increased white adipose tissue deposits, which could explain the additional SASP.

Additionally, white adipose tissue in treated female mice can result from reduced energy metabolism, as researchers observed that those mice have reduced oxygen consumption and energy expenditure.

Overall, treatment with dasatinib and quercetin had minimal effects on male mice but was detrimental to female mice, leading to changes in metabolism and reduced cognitive performance. The reasons why these senolytics have a negative impact on female mice were not explained in this study.

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Further research in humans is essential

Fisetin and quercetin are plant-derived flavonoids. Since they are natural compounds available as supplements, they can be taken by young people in the hope of delaying aging. However, the research so far is not clear on the potential impacts on human health and longevity for young people.

Lifespan measurements need to be performed to properly assess the anti-aging effect of senolytics taken during young adulthood, and this mouse research cannot be directly translated to humans. It is essential to follow this study with human research on how senolytics can impact health and lifespan when taken by younger people.

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Literature

[1] Fang, Y., Medina, D., Stockwell, R., McFadden, S., Quinn, K., Peck, M. R., Bartke, A., Hascup, K. N., & Hascup, E. R. (2023). Sexual dimorphic metabolic and cognitive responses of C57BL/6 mice to Fisetin or Dasatinib and quercetin cocktail oral treatment. GeroScience, 10.1007/s11357-023-00843-0. Advance online publication.

[2] Jafarinia, M., Sadat Hosseini, M., Kasiri, N., Fazel, N., Fathi, F., Ganjalikhani Hakemi, M., & Eskandari, N. (2020). Quercetin with the potential effect on allergic diseases. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology, 16, 36.

[3] Aguilera, D. G., & Tsimberidou, A. M. (2009). Dasatinib in chronic myeloid leukemia: a review. Therapeutics and clinical risk management, 5(2), 281–289.

[4] Kirkland, J. L., & Tchkonia, T. (2020). Senolytic drugs: from discovery to translation. Journal of internal medicine, 288(5), 518–536.

[5] Bussian, T. J., Aziz, A., Meyer, C. F., Swenson, B. L., van Deursen, J. M., & Baker, D. J. (2018). Clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline. Nature, 562(7728), 578–582.

[6] Zhang, P., Kishimoto, Y., Grammatikakis, I., Gottimukkala, K., Cutler, R. G., Zhang, S., Abdelmohsen, K., Bohr, V. A., Misra Sen, J., Gorospe, M., & Mattson, M. P. (2019). Senolytic therapy alleviates Aß-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an Alzheimer’s disease model. Nature neuroscience, 22(5), 719–728.

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About the author
Anna Drangowska-Way

Anna Drangowska-Way

Anna graduated from the University of Virginia, where she studied genetics in a tiny worm called C. elegans. During graduate school, she became interested in science communication and joined the Genetics Society of America’s Early Career Scientist Leadership Program, where she was a member of the Communication and Outreach Subcommittee. After graduation, she worked as a freelance science writer and communications specialist mainly with non-profit organizations.