Cycloastragenol

Cycloastragenol: A Comprehensive Reference Article

1. Identity and Chemical Characterization

1.1 Names and Classification

Cycloastragenol is a triterpenoid saponin isolated from various legume species in the genus Astragalus that is purported to have telomerase activation activity. More precisely, cycloastragenol (CAG) with steroid-skeletal characteristics is a cycloartan saponin of Astragaloside IV (AG-IV). Its full systematic chemical name is 9,19-cycloanostane-3,6,16,25-tetrol, 20,24-epoxy-(3β,6α,16β,20R,24S). Its molecular formula is C₃₀H₅₀O₅, and it is registered under CAS numbers 78574-94-4 and 84605-18-5. It presents as a white to off-white loose powder.

Cycloastragenol has been reported as the only telomerase activator in the extract of traditional Chinese medicine. In commercial and research contexts it is most widely known under the trade name TA-65, under which it was developed and studied extensively.

1.2 Botanical Sources

Cycloastragenol (CAG) is a triterpenoid saponin compound and a hydrolysis product of the main active ingredient in Astragalus membranaceus (Fisch.) Bunge. It is isolated from the dried roots of legumes Astragalus mongolicus or Astragalus membranaceus. CAG is a secondary metabolite isolated from Radix Astragali, the dried root of these plants, and is present in all known Astragalus spp. For commercial extraction, CAG has been derived from the dried ground roots of Astragalus trojanus that had been wild-harvested from the mountainous steppes of Turkey, illustrating that the compound is not restricted to a single species or geographic range.

1.3 Relationship to Astragaloside IV

Astragaloside IV (AST) undergoes intestinal bacterial biotransformation, and the main resultant metabolite, cycloastragenol (CAG), can be more readily absorbed to reach systemic circulation. In practical terms, chemical synthesis of CAG typically starts with Astragaloside IV, involving multiple reaction steps to construct the unique cycloartane skeleton and the C-20,24-epoxy structure of CAG. CAG can be obtained from Astragaloside IV through methods such as acid hydrolysis, Smith degradation, and enzymatic and microbial hydrolysis. However, this approach faces challenges such as overall low yields, environmental pollution, and the separation and purification of the product.

1.4 Common Forms and Preparations

Extracts, teas, and other preparations of Astragalus roots (e.g., Radix Astragali) are historically recognized traditional medicines and foods. Cycloastragenol (CAG), a bioactive triterpene aglycone from Astragalus root extracts, is being developed as a modern dietary ingredient. Commercially, it is most frequently sold as oral capsules containing a proprietary extract. Poor water solubility, faster metabolic conversion and lower oral bioavailability still restrict the clinical application of cycloastragenol, driving ongoing research into enhanced formulations.

2. Traditional and Historical Use

2.1 Astragalus in Traditional Chinese Medicine

Cycloastragenol itself was not identified as a discrete compound until the modern era; its documented historical use is entirely embedded within the traditional use of its parent herb, Astragalus membranaceus (Huangqi / Huang Qi). The application of Huangqi can be traced back to the Han Dynasty and was first recorded in Shennong Ben Cao Jing (Han Dynasty, BCE 202–220), where it was categorized as a high-quality product. Li Shizhen's "Compendium of the Materia Medica" (Bencao Gangmu, Ming Dynasty, AD 1552–1578) lists Huangqi as the first tonic herb, which mainly reinforced healthy qi, dispelling pathogenic factors, promoting diuresis, and reducing swelling.

Huang Qi, or Astragalus Root (Astragali Radix), is a cornerstone of traditional Chinese medicine (TCM) with a history dating back to the Han Dynasty. First documented in the Shennong Bencao Jing as a top-grade herb, it is derived from the dried roots of Astragalus mongolicus or Astragalus membranaceus, primarily sourced from Inner Mongolia, Shanxi, and Hebei. Known as the "holy medicine for replenishing Qi," Huang Qi is celebrated for its sweet, slightly warm nature and its ability to support the spleen and lung meridians.

Astragalus membranaceus (Huangqi) is a major medicinal herb that has been commonly used in many herbal formulations in the practice of traditional Chinese medicine (TCM) to treat a wide variety of diseases and body disorders, or marketed as life-prolonging extracts for human use in China, for more than 2000 years. It is known to enhance immune functions; protect the liver; act as a diuretic; and have anti-aging, anti-stress, antihypertensive, and extensive antibacterial properties.

2.2 Traditional Preparations

Huang Qi is commonly used as a decoction or "tea" alone or with other plants in traditional medicines such as Shi-ka-ron (a combination with herbs Lithosperium erythrorhizon and Ligusticum wallachii) and Ren-shen-yang-rong-tang (a combination of twelve herbs including Radix Astragali). Three main chemical compound classes are contained in Astragali Radix (Huangqi), including polysaccharides (heteropolysaccharide and dextran), saponins and flavonoids. In TCM, the root was administered for purposes including immune support, energy restoration, and as an adaptogenic tonic for long-term vitality rather than acute disease treatment.

3. Key Constituents and Chemical Context

The major components of Astragalus membranaceus are polysaccharides, flavonoids, and saponins. Among the saponin fraction, cycloastragenol occupies a central pharmacological role. The main active components in Astragali Radix include astragaloside IV, cycloastragenol, astragalus polysaccharide, calycosin-7-O-β-d-glucoside, and calycosin.

Cycloastragenol has a steroidal skeleton of tetracyclic triterpene and possesses diverse pharmacological activities such as anti-aging, anti-inflammatory, anti-fibrosis, pro-wound healing, liver protection and endothelial protection. The compound's cycloartane-type backbone distinguishes it structurally from the more common oleanane and ursane triterpenes found in other medicinal plants.

4. Established Mechanisms of Action

4.1 Telomerase Activation (hTERT Pathway)

Cycloastragenol induces telomerase activity and induces CREB (cAMP response element binding) activation in human neonatal keratinocytes, PC12 cells, and primary neurons. Its mode of action is purported to be the activation of the human enzyme telomerase. At the molecular level, CAG-mediated induction of telomerase activity was found to be regulated by NRF2. CAG not only increased the expression of hTERT but also its nuclear localization via upregulating the Hsp90-chaperone complex.

The telomerase activity contributes to the extension of somatic cell lifespan and is mediated through the regulation of the mitogen-activated protein kinase (MAPK) and protein kinase B (AKT) signaling pathways, which are key regulators of cellular proliferation, differentiation, motility, survival, and stress responses. Additionally, it induces CREB activation followed by tert and bcl2 expression.

4.2 Anti-inflammatory Signaling

From a molecular mechanism perspective, CAG can simultaneously and precisely regulate multiple core inflammation-related pathways: by inhibiting NF-κB p65 nuclear translocation and blocking the assembly and activation of the NLRP3 inflammasome, it directly suppresses the release of pro-inflammatory factors such as TNF-α, IL-6, and IL-1β; by activating the Nrf2/HO-1 antioxidant pathway, it eliminates excessive reactive oxygen species (ROS) and restores cellular redox balance, thereby mitigating the oxidative stress that underlies inflammation initiation; and it simultaneously regulates autophagy-related signaling networks and immune cell functional phenotypes, achieving a triple synergistic effect of anti-inflammation, antioxidant activity, and immune modulation.

These compounds target critical signaling pathways, including TLR4/NF-κB, PI3K-AKT, AMPK, and PPARγ. Specifically, in the abdominal aortic aneurysm (AAA) model, CAG significantly reduces inflammatory responses by inhibiting the MAPK signaling pathway (particularly the phosphorylation of ERK and JNK). This mechanism not only blocks the macrophage-mediated inflammatory cascade but also directly protects the function of vascular smooth muscle cells.

4.3 Autophagy and Apoptosis Modulation

Cycloastragenol triggered both autophagy and apoptosis. Specifically, cycloastragenol promoted apoptosis by facilitating the accumulation of phorbol-12-myristate-13-acetate-induced protein 1 (NOXA), a critical apoptosis-related protein. Moreover, cycloastragenol induced a protective autophagy response through modulation of the AMPK/ULK1/mTOR pathway.

4.4 Farnesoid X Receptor (FXR) and Lipid Metabolism

Through one identified pathway, CAG directly stimulates the FXR to improve hepatitis. Extensive pharmacological effects have been attributed to CAG, including telomerase activation, telomere elongation, anti-inflammatory and anti-oxidative properties; CAG has also been reported to improve lipid metabolism.

5. Pharmacokinetics

5.1 Absorption

CAG rapidly passes through the Caco-2 cell monolayer by passive diffusion. CAG is absorbed through the intestinal epithelium via passive diffusion and undergoes first-pass hepatic metabolism.

5.2 Metabolism and Bioavailability

Four different glucuronide conjugates and two oxidized CAG metabolites were found in both compartments of the Caco-2 model, suggesting that first-pass intestinal metabolism of CAG occurs upon passage through the intestinal epithelium. CAG underwent extensive metabolism in rat and human liver microsomes with only 17.4% and 8.2%, respectively, of the starting amount of CAG remaining after 30 min of incubation. Monohydroxylation of the parent and oxidization of the hydroxylated CAG were found in the liver samples.

CAG is efficiently absorbed through intestinal epithelium; however, extensive first-pass hepatic metabolism would limit the oral bioavailability of this compound. In rat studies using a PEG-400 formulation, the oral bioavailability of CAG was approximately 25.70% at 10 mg/kg. CAG was excreted through bile and feces and eliminated predominantly by the kidney in rats.

Studies on rat and human liver microsomes demonstrate that CAG is rapidly metabolized, with its metabolites exhibiting enhanced anti-inflammatory, antioxidant, and immunomodulatory activities, as well as broader systemic distribution.

5.3 Relationship Between Astragaloside IV and Cycloastragenol Bioavailability

Studies focusing on the pharmacokinetics and bioavailability of astragaloside IV suggest that astragaloside IV has low bioavailability after oral administration, which is only 2.2%–3.7% in rats and 7.4% in dogs. High molecular weight, high hydrogen-bonding capacity, high molecular flexibility, poor membrane permeability, and poor absorption through the gut may contribute to the poor bioavailability of AST. AST undergoes intestinal bacterial biotransformation, and the main resultant metabolite, cycloastragenol (CAG), can be more readily absorbed to reach systemic circulation.

6. Scientific Evidence by Area of Use

6.1 Telomere Biology and Cellular Aging

In Vitro and Animal Evidence

A preliminary in vitro study on human CD4 and CD8 T cells found that cycloastragenol may moderately increase telomerase activity and inhibit the onset of cellular senescence. CAG stimulates telomerase activity in human neonatal keratinocytes and rat neuronal cells. It induces CREB activation followed by tert and bcl2 expression.

Maria Blasco's work published in Aging Cell found no increase in murine median or mean lifespan but some physiological anti-aging effects without augmenting cancer incidence. This murine study is among the most-cited animal data on CAG's effects on lifespan, and its finding of improved healthspan without increased longevity or cancer risk has been broadly noted.

Human Clinical Evidence

A randomized, double-blind, placebo-controlled study of TA-65 (a proprietary cycloastragenol preparation) examined telomere length changes over one year in 117 relatively healthy cytomegalovirus-positive subjects aged 53–87 years. Subjects taking the low dose of TA-65 (250 U) significantly increased telomere length over the 12-month period (530 ± 180 bp; p = 0.005), whereas subjects in the placebo group significantly lost telomere length (290 ± 100 bp; p = 0.01). The high dose of TA-65 (1000 U) showed a trend of improvements in telomere length compared with the placebo group; however, the improvements did not reach statistical significance.

A separate 2024 randomized, double-blind, placebo-controlled trial examined a multi-component Astragalus-based supplement including cycloastragenol. This six-month trial compared an Astragalus-based supplement versus placebo on telomere length in 40 healthy volunteers (mean age 56.1 ± 6.0 years). Twenty subjects received the supplement and 20 received placebo capsules. All participants completed the study and no adverse side effects were reported at six months. Subjects taking the Astragalus-based supplement exhibited significantly longer median telomere length (p = 0.01) and short telomere length (p = 0.004), along with a lower percentage of short telomeres, over the six-month period, while the placebo group showed no change. It should be noted that the telomerase activator complex tested was ASTCOQ02, a blend of Astragalus extracts (including astragaloside IV and cycloastragenol), olive fruit extract, zinc oxide, and grape seed extract, meaning this study cannot be attributed solely to cycloastragenol.

Evidence Strength

The telomere-lengthening evidence from human clinical trials is preliminary but exists from multiple randomized controlled designs. Significant limitations include: small study populations, the fact that telomere length changes are a biomarker rather than a clinical endpoint, industry funding for several major trials, and the use of combination products rather than isolated cycloastragenol. Publications in high-impact peer-reviewed journals are lacking, and much of the online documentation supporting its use is sponsored by its manufacturers.

6.2 Immune System Modulation

The "Patton protocol-1" clinical observation provided 37 subjects with a comprehensive dietary supplement pack containing CAG for 12 months. This concluded that CAG lengthens critically short telomeres and remodels the relative proportion of circulating leukocytes in CMV-positive subjects toward a more "youthful" profile. It is noteworthy that the Patton protocol-1 did not establish a control before initiating the study, which may have affected the trial results.

Cycloastragenol enhances the antiviral response in human CD8+ T lymphocytes. The immunosenescence phenotype is characterized by the accumulation of late-differentiated CD8+CD28− T cells, and multiple trials studying the TA-65 preparation have investigated reduction of this phenotype as an outcome.

6.3 Metabolic, Cardiovascular, and Bone Health

The Patton protocol-1 supplement pack improved biomarkers of metabolic, bone, and cardiovascular health, such as fasting glucose, insulin, cholesterol, blood pressure, and bone mineral density (BMD). These effects are mostly attributed to CAG. A study reported by Harley et al. reported an increase in BMD in naturally aging rats; clinical trials have further verified this function. However, these clinical observations were from an uncontrolled study design, limiting causal attribution.

Previous studies have demonstrated that CAG and AG-IV are able to alleviate and reverse a number of degenerative diseases, such as metabolic syndrome, arthritis and age-related macular degeneration, by activating telomerase.

6.4 Neurological and Psychiatric Applications

Oral administration of CAG attenuates the immobility behavior of mice in the forced swim test, demonstrating therapeutic potential against depression in animal models. This effect was attributed to telomerase activation and consequent neuroprotection. Designing therapies based on telomerase maintenance is therefore an attractive approach for treating neurodegenerative diseases and aging.

CAG can significantly improve the behavioral indicators of Parkinson's disease mice, enhance neuronal vitality, and improve neuroinflammatory levels by inhibiting the expression of inflammatory factors. Parkinson's disease is a neurodegenerative disease, and neuroinflammation is an important factor in its pathogenesis. These results are exclusively preclinical; no human trials in Parkinson's disease have been published with cycloastragenol as the intervention.

6.5 Hepatic Effects

Cycloastragenol improves hepatic steatosis by activating farnesoid X receptor signalling. Research in animal models has demonstrated CAG's ability to act directly on FXR signaling to reduce lipid accumulation in liver tissue. Human clinical evidence in this specific domain remains absent.

6.6 Reproductive / Ovarian Biology

CAG-mediated telomerase activation significantly enhanced the level of Klb (β-Klotho) and recovered ovarian follicles in a D-galactose-induced ovarian ageing mouse model. Doxorubicin-induced ovarian damage, which changes ovarian hormones and inhibits follicular growth, was successfully neutralized by CAG-activated telomerase and its recovery of β-Klotho level. TERT-dependent β-Klotho regulation in ovarian tissues is one mechanism which can overcome female infertility. This work is exclusively preclinical.

6.7 Skin Wound Healing

Cycloastragenol exhibits anti-inflammatory properties and promotes wound gap closure. In vitro and animal studies of cycloartane-type saponins from Astragalus species have demonstrated growth stimulatory effects in skin cells and enhanced wound healing.

6.8 Anti-cancer Research

Research sheds light on the antitumor efficacy and mechanism of action of cycloastragenol in non-small cell lung cancer (NSCLC), providing a scientific basis for exploring combination therapies using cycloastragenol and inhibiting the AMPK/ULK1/mTOR pathway. All anti-cancer findings are currently at the preclinical stage. As disordered telomerase function is a feature of almost all cancers, there is an unproven but theoretical risk of oncogene-mediated cancer promotion through the use of telomerase activators. The animal study by Blasco et al. published in Aging Cell did not observe increased cancer incidence, but this question requires continued monitoring in human populations.

7. Body Systems and Health Areas

The following organ systems and health areas have been investigated in preclinical or clinical research:

• Cellular biology / Aging: Telomere maintenance, inhibition of cellular senescence, telomerase (hTERT) upregulation.
• Immune system: CD8+ T cell antiviral function, reduction of immunosenescent cell populations, macrophage polarization.
• Cardiovascular system: Blood pressure, cholesterol, and endothelial protection via anti-inflammatory and antioxidant pathways.
• Musculoskeletal system: Bone mineral density, chondrogenic differentiation of mesenchymal stem cells, intervertebral disc degeneration.
• Nervous system: Neuroprotection, depression-like behavior in animal models, Parkinson's disease neuroinflammation.
• Hepatic system: Hepatic steatosis, FXR activation, liver protection.
• Reproductive system: Ovarian aging, follicle recovery, β-Klotho regulation.
• Integumentary system: Wound healing, keratinocyte function.
• Ophthalmology: Age-related macular degeneration (pilot study data only).
• Metabolic system: Fasting glucose, insulin sensitivity, lipid metabolism.

Pharmacological research indicates that the extract component of Astragalus membranaceus can increase telomerase activity, and has antioxidant, anti-inflammatory, immunoregulatory, anticancer, hypolipidemic, antihyperglycemic, hepatoprotective, expectorant, and diuretic effects.

8. Dosage Forms and Reported Dosages

Cycloastragenol is commercially available almost exclusively as oral capsules. The following dosages have been reported in published studies:

• Human clinical trial (Salvador et al., 2016, RCT): Subjects taking the low dose of TA-65 (250 U) significantly increased telomere length over 12 months (p = 0.005). The high dose of TA-65 (1000 U) showed a trend of improvement that did not reach statistical significance.
• Human clinical trial (de Jaeger et al., 2024, RCT): The dosage form was an oral capsule taken twice daily for 6 months. The daily dose included astragalus extract: 250 mg as part of a blend also containing astragaloside IV, olive fruit extract, zinc oxide, and grape seed extract.
• Preclinical subchronic toxicity study (Szabo, 2014): Rats ingested 0, 40, 80, or 150 mg/kg/d CAG by oral gavage for ≥91 consecutive days.
• Preclinical pharmacokinetic study (Ma et al., 2017): Rats were orally administered CAG at 10, 20, and 40 mg/kg or intravenously administered at 10 mg/kg to determine pharmacokinetic parameters.

No established human therapeutic dose has been determined from controlled dose-finding studies. The TA-65 commercial preparation uses proprietary "unit" dosing not directly equivalent to milligrams of isolated cycloastragenol.

9. Safety Considerations and Interactions

9.1 Subchronic Toxicity and Genotoxicity

In a subchronic study with recovery component, rats ingested 0, 40, 80, or 150 mg/kg/d CAG by oral gavage for ≥91 consecutive days. No treatment-related mortalities occurred and no cardiac effects were identified. Although several monitored endpoints exhibited statistically significant effects, none was adverse.

The oral no-observed-adverse-effect level (NOAEL) for CAG was >150 mg/kg/d in male and female rats. CAG (≤5000 μg/plate) did not induce mutagenicity in Salmonella typhimurium or Escherichia coli tester strains. Although the in vitro chromosome aberration assay gave a moderately positive response (likely due to poor solubility) for one intermediate concentration with metabolic activation, responses were negative in all other conditions.

9.2 Drug-Drug Interactions: UGT Enzyme Inhibition

When the plasma CAG concentration exceeds 0.034 μM (UGT1A8 inhibition threshold) or 20.98 μM (UGT2B7 inhibition threshold), it can delay glucuronidation metabolism of commonly used UGT substrate drugs such as morphine, valproic acid, mycophenolic acid, and acetaminophen, resulting in increased exposure of such drugs in the body, and the occurrence of dose-dependent toxic reactions should receive special attention.

Deglycosylation of AST to CAG could strongly increase the inhibitory effects towards almost all tested UGT isoforms, with an IC50 of 0.84 μM for UGT1A8. These findings are based on in vitro studies and their clinical significance at typical supplement doses requires further human pharmacokinetic investigation.

9.3 Cancer Risk Consideration

As disordered telomerase function is a feature of almost all cancers, there is an unproven, but theoretical risk of oncogene-mediated cancer promotion through the use of telomerase activators. Cycloastragenol is a telomerase activator. Fortunately, experimental results did not show an increased risk of cancer and other adverse effects. The Blasco et al. murine study notably found no increase in cancer incidence in treated animals.

9.4 General Safety Profile and Limitations of Evidence

Within a certain dose range, oral CAG is relatively safe; however, underlying mechanisms associated with CAG are not clear, and we should be aware of potential adverse reactions associated with CAG. According to existing studies and clinical trials, CAG is safe and has broad application prospects. However, further studies are required to fully understand its efficacy and potential adverse reactions, and to ensure the proper use of CAG is applied to treat diseases clinically.

Toxicity testing is limited and safety for the human consumer has not been adequately demonstrated in long-term human trials. More research is needed to address key issues such as mechanistic complexity and long-term safety to achieve widespread use in clinical treatment.

Allergic reactions were the most commonly reported adverse events in Astragalus studies; however, not all studies reported adverse events. Caution is advised in pregnancy.

TA Sciences was served with a consent order by the Federal Trade Commission for deceptive advertising implying that TA-65 can reverse aging and repair DNA damage.

References

• Cycloastragenol: An exciting novel candidate for age-associated diseases – PMC / Spandidos Publications (2018)
• Szabo NJ. Dietary safety of cycloastragenol from Astragalus spp.: Subchronic toxicity and genotoxicity studies. Food Chem Toxicol. 2014;64:322–334
• A comprehensive review of cycloastragenol: Biological activity, mechanism of action and structural modifications – ScienceDirect (2022)
• Cycloastragenol in inflammation-related diseases: mechanisms, pharmacokinetics, and translational prospects – Frontiers in Pharmacology / PMC (2025)
• Salvador L et al. A Natural Product Telomerase Activator Lengthens Telomeres in Humans: A Randomized, Double Blind, and Placebo Controlled Study. Rejuvenation Res. 2016;19:478–484
• de Jaeger et al. A Natural Astragalus-Based Nutritional Supplement Lengthens Telomeres in a Middle-Aged Population: A Randomized, Double-Blind, Placebo-Controlled Study. Nutrients. 2024;16(17):2963
• Ip FC et al. Cycloastragenol Is a Potent Telomerase Activator in Neuronal Cells: Implications for Depression Management. Neurosignals. 2014;22:52–63
• Zhu J et al. In vitro intestinal absorption and first-pass intestinal and hepatic metabolism of cycloastragenol. Drug Metab Pharmacokinet. 2010;25(5):477–486
• Ma P et al. Pharmacokinetics, metabolism, and excretion of cycloastragenol, a potent telomerase activator in rats. Xenobiotica. 2017
• Ran R et al. Evaluation and Comparison of the Inhibition Effect of Astragaloside IV and Aglycone Cycloastragenol on Various UDP-Glucuronosyltransferase (UGT) Isoforms. Molecules. 2016;21:1616
• Liu P et al. Anti-Aging Implications of Astragalus Membranaceus (Huangqi): A Well-Known Chinese Tonic. Aging Dis. 2017;8(6):868–886
• Frontiers in Pharmacology: A review of the botany, phytochemistry, traditional uses, pharmacology, toxicology, and quality control of Astragalus membranaceus (2023)
• PubChem CID 13943286: Cycloastragenol – National Library of Medicine
• Macrophage polarization in disease therapy: insights from astragaloside IV and cycloastragenol – PMC (2025)
• The role of cycloastragenol at the intersection of NRF2/ARE, telomerase, and proteasome activity – Free Radical Biology and Medicine. 2022
• Cycloastragenol targets Fpr2 to inhibit the TLR4/NF-κB signaling pathway and alleviate neuroinflammation in Parkinson's disease – PubMed (2025)
• Cycloastragenol activation of telomerase improves β-Klotho protein level and attenuates age-related malfunctioning in ovarian tissues – PubMed (2022)
• Cycloastragenol and Astragaloside IV activate telomerase and attenuate intervertebral disc degeneration – Exp Ther Med. 2021
• Frontiers in Pharmacology: Cycloastragenol in inflammation-related diseases (full text) – PMC (2025)
• Cycloastragenol – Wikipedia (for regulatory and intellectual property context)