Targeting telomere dynamics with plant-derived compounds: Molecular strategies against aging

Abstract

Telomeres, the repetitive DNA-protein complexes capping eukaryotic chromosomes, preserve genomic stability and regulate cellular replicative capacity. Progressive telomere shortening, coupled with diminished telomerase activity, is a hallmark of aging and contributes to cellular senescence, tissue degeneration, and the onset of age-related diseases. Conversely, telomerase overactivation in malignant cells enables uncontrolled proliferation, positioning telomere biology as a dual therapeutic target in longevity and oncology. Plant-derived compounds possess diverse structural classes such as polyphenols, flavonoids, triterpenoid saponins, polysaccharides, lignans, alkaloids, carotenoids, amino acids, and fatty acids that can modulate telomere length and telomerase activity via multiple molecular pathways. These include antioxidant and anti-inflammatory actions, regulation of key genes such as hTERT, SIRT1, and c-Myc, modulation of PI3K/Akt, JAK/STAT, and ERK signaling, and stabilization or destabilization of G-quadruplex DNA structures. Compounds such as resveratrol, epigallocatechin gallate, astragaloside IV, cycloastragenol, and ginsenoside Rg1 have demonstrated telomerase activation or inhibition in a context-dependent manner, influenced by concentration, cell type, and disease state. This review categorizes plant-derived positive and negative telomere/telomerase modulators, detailing their sources, mechanisms of action, experimental evidence, and the formulation challenges that hinder clinical translation, such as low bioavailability, instability, and variability in phytochemical content. By integrating molecular insights with pharmacological perspectives, this review highlights the potential of plant-derived agents as multi-target interventions in aging and cancer. Advancing this field will require rigorous pharmacokinetic profiling, standardized preparations, and longitudinal clinical studies to bridge the gap between laboratory findings and real-world therapeutic outcomes.

Keywords: Aging; Longevity; Natural products; Telomerase; Telomere.

Graphical abstract

Fig. 1

Mechanisms of senescence-associated aging driven by telomere dysfunction. With repeated cell divisions, telomeres gradually shorten. When telomeres become critically short, they are identified as double-strand DNA damage sites, initiating a DNA damage response that activates p53. This activation induces cellular senescence, primarily through the suppression of RB. Cellular senescence accelerates aging by causing stem cell depletion, functional decline, and the onset of chronic tissue inflammation. Together, these effects lead to the progressive loss of tissue homeostasis and regenerative capacity, which are hallmarks of aging.

Fig. 2A

Chemical structures of some natural compounds responsible for positive modulation of telomerase.

Fig. 2B

Chemical structures of some natural compounds responsible for negative modulation of telomerase.

Fig. 3

Molecular pathways involved in telomerase activation and inhibition by natural compounds.