Highlights:

  • Cycloastragenol eliminates cultured senescent human cells without affecting non-senescent cells.
  • Proteins involved in cell survival and growth were decreased in senescent cells treated with cycloastragenol.
  • Radiation-induced aged mice showed reversed signs of aging when treated with cycloastragenol, including better motor skills and reduced senescent cells.

Aging is an inevitable part of life; however, researchers are working on multiple therapies to try to stave off some of the effects of aging, including looking at senolytics. Senolytics are compounds that can eliminate senescent (aged) cells, which have been shown to reduce the effects of aging. A new study shows that cycloastragenol – a compound from Astragalus membranaceus, a plant commonly used in Chinese medicine – exerts senolytic effects.

The study, out of China and published in the International Journal of Molecular Sciences, focused on senescent human cells and mice with radiation-induced aging. Cycloastragenol was able to reduce senescent cells without affecting non-senescent cells. Cycloastragenol treatments also decreased proteins needed for cell growth and survival in senescent cells. Additionally, it inhibited cell movements associated with age-related inflammatory cells and processes. Aged mice treated with cycloastragenol were found to have decreased senescent cells and improved age-related physical dysfunction.

“Overall, our studies demonstrate that CAG [cycloastragenol] is a novel senolytic agent with… the potential to be used in the treatment of age-related diseases,” the scientists wrote.

Cycloastragenol Chemical Structure

Cycloastragenol Decreases Senescent Cells

Senescence is a known hallmark of aging, but researchers have found that eliminating senescent cells and their pro-inflammatory signaling molecules can help prevent age-related illnesses and even reverse them in some cases. Here, the investigators treated human cells with cycloastragenol and found that it effectively eliminated senescent cells without affecting non-senescent cells. Additionally, cell markers of senescent cells were significantly decreased with cycloastragenol treatment. 

(Zhang et al., 2023 | International Journal of Molecular Sciences) Cycloastragenol Effects Senescent Cells Only The viability (or health) of non-senescent cells (NCs – left 3 bars) was unaffected by cycloastragenol, while the health of senescent cells (VP16-SCs – right 3 bars) was greatly reduced with the highest dose of cycloastragenol, 100 micromoles.

Previous research has shown that the  PI3K/AKT/mTOR pathway – a signaling pathway involved in cell growth and survival – is associated with the inflammatory processes that are initiated by senescent cells, which help to promote senescence among surrounding cells. The researchers found that cycloastragenol helped to decrease proteins in this pathway, suggesting that the compound may work by blocking the PI3K/AKT/mTOR pathway to help prevent senescence. Furthermore, cycloastragenol was also shown to reduce the ability of senescent cells to promote senescence through the release of inflammatory molecules, growth factors, and immune modulators, in line with the suggestion that decreasing PI3K, AKT, and mTOR signaling can decrease the promotion of senescence among surrounding cells.

(Zhang et al., 2023 | International Journal of Molecular Sciences) Cell Growth and Survival Proteins Decreased with Cycloastragenol Treatment Proteins in the PI3K/AKT/mTOR pathway, which is involved in cell growth and survival were decreased in senescent cells treated with cycloastragenol in a dose-dependent manner, where higher doses lead to greater effects.

Cycloastragenol Decreases Signs of Aging in Mice

Following the results seen in human cells, Zhang and colleagues looked at the effects of cycloastragenol in mice exposed to radiation to induce aging. The mice were given either placebo or cycloastragenol orally for two weeks. Cycloastragenol treatment helped to reverse outward signs of aging, including gray fur and bone changes. Motor activity and bone density were also improved with cycloastragenol treatment. 

(Zhang et al., 2023 | International Journal of Molecular Sciences) Mice had Decreased Age-related Concerns with Cycloastragenol Treatment Mice with radiation-induced aging (TBI) given cycloastragenol (TBI+CAG) had decreased gray fur (bottom image), increased distance traveled in an open-field test (green on left graph), and increased total bone mineral density (green on right graph), as compared to untreated mice (TBI+Veh, red on both graphs).

In line with the results seen in human cells, the researchers found that cycloastragenol decreased the number of senescent cells, along with age-related inflammatory cell markers in the mice. Additionally, the levels of proteins in the PI3K/AKT/mTOR pathway were decreased in the treated mice, further indicating that cycloastragenol may work at eliminating senescence by blocking the PI3K/AKT/mTOR pathway in mice, using the same mechanism seen in cultured human cells.

Senolytics and Aging

Zhang and colleagues show here that cycloastragenol – which has long been used in its plant form by Chinese medicine practitioners for a myriad of ailments – has senolytic and anti-aging effects. Mice with induced aging had decreased gray fur, improved motor function, and increased bone density when treated with cycloastragenol.

Senolytics have shown promise in their anti-aging effects, with benefits seen across organ systems, including the brain, bones, and heart. But whether cycloastragenol has long-term, lasting effects remains to be seen. As the hunt for anti-aging products continues due to our aging population and increased lifespans, we should expect to see more clinical trials and long-term studies to determine the safety and efficacy of these therapies in humans.