Astragalus Compounds Target Telomere Aging to Fight Atherosclerosis

Telomere shortening has emerged as a measurable biological clock for vascular aging. As endothelial cells and vascular smooth muscle cells replicate over a lifetime, their telomeres progressively erode, eventually triggering a DNA damage response that drives replicative senescence, the senescence-associated secretory phenotype (SASP), chronic vessel-wall inflammation, and plaque formation. Meta-analyses and Mendelian randomization studies across diverse ethnic populations now link shorter leukocyte telomere length to significantly elevated risk of coronary atherosclerosis, myocardial infarction, and ischemic heart disease, establishing a causal rationale for telomere-targeting therapies.

Astragalus membranaceus, a root widely used in traditional Chinese medicine, contains over 200 bioactive compounds. The review focuses on three principal constituents: astragaloside IV (AS IV), a triterpenoid saponin; cycloastragenol (CAG), its aglycone derivative; and TA-65, a patented encapsulated form of CAG commercially available since 2008. These compounds activate telomerase—the reverse transcriptase that adds protective repeat sequences to chromosome ends—through distinct but overlapping intracellular signaling cascades, including MAPK, Akt (which phosphorylates the TERT subunit post-translationally), JAK/STAT, and Src/MEK/ERK pathways. Systemic AS IV supplementation has been shown to boost TERT activation in multiple tissues—brain, liver, heart, lungs, and bone marrow—in aged mice, alleviating telomere attrition across organ systems.

In vascular cells, AS IV demonstrates broad endothelial-protective activity. In vitro studies show it promotes HUVEC proliferation, migration, and tube formation via PI3K/Akt and ERK1/2 signaling. It restores nitric oxide bioavailability under oxidative injury by inhibiting ROS/NF-κB signaling and reducing eNOS uncoupling. It also activates the NRF2/HO-1 antioxidant axis and suppresses pro-inflammatory cytokines including IL-6, IL-8, and TNF-α. In atherosclerosis-relevant models using oxidized LDL, AS IV reduces foam cell formation, macrophage lipid accumulation, and vascular smooth muscle cell proliferation. Mechanistically, it modulates PPARγ, ABCA1, and LXR-α pathways to promote reverse cholesterol transport, and inhibits PCSK9 expression to enhance LDL receptor recycling.

Human clinical evidence, while still limited, is encouraging. A placebo-controlled study in 117 CMV-positive adults aged 53–87 found low-dose TA-65 (250 units) significantly increased telomere length over 12 months versus placebo-group telomere shortening. A large placebo-controlled trial in 500 healthy adults showed all doses of TA-65 (100–500 units, 9 months) reduced CD8+CD28− senescent T cells. A randomized double-blind six-month trial in 40 healthy volunteers using an Astragalus-based supplement showed significant increases in median and short telomere lengths.

Despite this evidence, the authors identify critical gaps. Most vascular studies are in vitro or in animal models; direct evidence that Astragalus compounds improve telomere biology specifically in human vascular cells is lacking. Bioavailability of AS IV is poor due to low solubility, and optimal dosing, formulation, and long-term safety in cardiovascular populations remain undefined. The authors call for rigorous randomized controlled trials in patients with established atherosclerosis, better mechanistic studies linking telomere effects to plaque outcomes, and improved delivery strategies to enhance bioavailability of these compounds.