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.

Graphical abstract

Highlights

• •Role of telomere biology and telomerase activity in aging, longevity, and cancer progression.
• •Classification of plant-derived compounds as positive or negative modulators of telomere dynamics.
• •Molecular pathways and gene targets underlying telomerase modulation by phytochemicals.
• •Formulation and bioavailability barriers impacting clinical translation of natural modulators.
• •Research priorities for standardization, pharmacokinetics, and long-term human studies.

1. Introduction

The process of aging is a biological phenomenon that is associated with a decrease in adaptability and resistance, degradation of structure and function of tissues and organs of an organism, leading to a surge in morbidity and mortality rate that is brought on by several chronic diseases (Bao et al., 2014; López-Otín et al., 2013). In recent decades, a decline in fertility rates and a rise in life expectancy has been observed due to a swift development of the socioeconomic status of the people, resulting in a high proportion of elderly people (Liu et al., 2019; Gao et al., 2023). Based on the data from the population division of UN DESA, it is estimated that 900 million people worldwide are aged 60 years or above, which is expected to rise to 21.5 % of the world's population by 2050. With age, various diseases that become prominent are diabetes, muscle weakness, macular degeneration, Alzheimer's disease, skin conditions, and a multitude of other conditions which are severely risky for human health (Liu et al., 2019). There are several physiological modifications that cause the progression of aging, including instability in genes, telomere dysfunction, mitochondrial disruption, irregularity of pathways associated with nutrient-sensing, cell death and many more (Chuang et al., 2014). To improve the quality of life of the aging population, it is important to focus on factors such as nutrition, lifestyle, genetic mutations, and exercise (Hosseini et al., 2021).

Telomeres are repeating DNA sequences located at the ends of eukaryotic chromosomes. Their primary function is to allow the cell to distinguish between natural chromosomal ends and harmful double-strand breaks. This distinction is crucial, as it protects the chromosomes from degradation, inappropriate recombination, and end-to-end fusions that would compromise genomic stability. These telomeres are involved in the preservation of the physical integrity of chromosomes by impeding the genomic DNA from being lost at their ends (Blackburn, 1991; Blackburn et al., 2015). With every division of a somatic cell, telomeres shorten and hence, telomere length is considered to be a hallmark of aging where shorter telomeres are linked to a greater risk of acquiring chronic age-related disorders and a lower life span (Crous-Bou et al., 2019; D'Angelo, 2023). Furthermore, inflammation and oxidative stress are known to exacerbate telomere attrition (Crous-Bou et al., 2019). Telomerase is a vital ribonucleoprotein enzyme that is primarily responsible for the protection and repair of the ends of chromosomes. Moreover, both environmental and behavioral factors can have an impact on the activity of telomerase which can affect life span. On the other hand, telomerase activity is remarkably low in human cells, leading to telomere shortening and contributing to cellular aging (Raina et al., 2023; Shen et al., 2017).

There is substantial research that provides proof that several phytochemicals may have antiaging benefits (Si and Liu, 2014). Natural products include varieties of endogenous chemical components that are obtained from plants, animals, microbes, insects, and other sources (Akter et al., 2021). For thousands of years, natural compounds have been utilized to either fully cure or significantly reduce the symptoms of various illnesses. About 60 % of all medications on the market are obtained from natural sources, either directly or indirectly (Gao et al., 2023). Furthermore, natural products having a range of pharmacological characteristics also aid in the discovery and development of new drugs (Mathur and Hoskins, 2017). A significant number of studies have been focusing on how natural products help prevent aging-related diseases such as cancer, metabolic disorders, neurological diseases, cardiovascular disorders, and many more (Gao et al., 2023). Natural substances obtained from food sources, such as saponins, polysaccharides, polyphenols, and alkaloids have been identified as antiaging agents that can prolong life via a variety of cellular and molecular mechanisms (Chen et al., 2022).

Unlike prior reviews that primarily catalog phytochemicals or summarize high-level associations, this review establishes a pathway-focused, bidirectional framework that clarifies when natural products activate versus inhibit telomerase. We have integrated PI3K/Akt, Ras/MEK/ERK, JAK/STAT, and AMPK signaling to connect molecular mechanisms directly to telomere maintenance and telomerase regulation, and we have explicitly contrasted activation mechanisms with inhibitory actions while emphasizing dose and cellular context. We have further linked chemical classes to structural targets including G-quadruplex DNA and shelterin (notably TRF1, with implications for POT1/TRF2) and summarized structure–activity cues that align subclasses with pathway bias. In addition, we have provided dedicated sections on formulation challenges and on contradictory findings and research gaps, elements that are often missing or only briefly treated in earlier reviews.

2. Overview of telomere and telomerase

2.1. Telomere

A key distinction between normal somatic cells and cancer cells is their limited capacity to divide. Normal cells undergo a finite number of divisions, controlled by a “mitotic clock.” This mechanism includes two critical aspects: (i) a system that tracks cell divisions and (ii) a division limit, known as the Hayflick limit or senescence phase (M1), which triggers an irreversible block in the cell cycle. The mitotic clock is regulated by telomeres, specialized structures at the ends of linear chromosomes (Udroiu et al., 2017).

In mammals, telomeres are composed of repetitive DNA sequences, (TTAGGG)n, spanning 10–15 kilobase pairs (kbp) in humans. These repeats are capped with a single-stranded DNA tail of a few hundred nucleotides (Chang, 2012). Unlike circular prokaryotic chromosomes, linear eukaryotic chromosomes face challenges due to exposed ends, which are prone to degradation by exonucleases and other harmful processes (Entringer et al., 2011). Telomeres act as protective caps, shielding chromosome ends from damage and preventing fusion with other chromosomes (Boccardi and Marano, 2024).

Telomeres play a vital role in resolving a fundamental problem in DNA replication. The replication machinery operates directionally, synthesizing DNA from 5′ to 3'. This process creates difficulties at the ends of linear chromosomes because the lagging strand, which depends on RNA primers, cannot fully replicate the terminal sequences (Hornsby, 2007). Telomeres function as sacrificial buffers, ensuring that essential genetic material is preserved. Without telomeres, the blunt ends of chromosomes might be mistaken for double-strand breaks, leading to genomic instability. By acting as protective buffers, telomeres maintain chromosome stability during cell division cycles (Shay and Wright, 2019; Stewart et al., 2003).

One of the most studied consequences of telomere shortening is its association with cellular senescence in laboratory-cultured cells. Senescence refers to the irreversible loss of the ability to divide after a certain number of cell replication in human primary cells (Deng and Chang, 2007). Telomere length progressively diminishes with each cell division, eventually leading to senescence. While the exact link between telomere shortening and senescence remains under investigation, this phenomenon raises intriguing questions about its connection to human aging (Mathon et al., 2001; Moore et al. 2015).

The number of cell divisions in the human body varies across organs and developmental stages. Researchers have attempted to track telomere lengths in accessible tissues at different ages or correlate the remaining cell divisions in lab cultures with the donor's age. Despite technical limitations, the overall trend suggests a connection between the in vitro observation of senescence with telomere shortening and its potential role in human development and aging in vivo (Tomita, 2018; Wang, 2013).

2.2. Telomerase

For unicellular organisms and multicellular organisms with separate germline and somatic lineages, a critical challenge exists- preventing the progressive shortening of telomeres with each cell division. Without a solution, each generation would inherit progressively compromised telomeres, jeopardizing the long-term viability of the species. Nature's elegant answer lies in telomerase, a ribonucleoprotein enzyme complex found in most living organisms (Cech, 2004). This complex acts as a guardian, counteracting telomere attrition. Telomerase harbors a catalytic component with reverse transcriptase activity, similar to an enzyme that can copy RNA into DNA, and an RNA template that serves as a blueprint for telomere extension (Puterman et al., 2013). In collaboration with telomere-associated proteins, telomerase lengthens chromosome ends, effectively buffering against telomere shortening. Researchers are actively investigating the intricate details of this complex biological interaction (Entringer et al., 2011).

Telomerase activity is strategically regulated. It is particularly active in germline cells, ensuring the transmission of healthy telomere lengths to future generations (Shay and Wright, 2019). During early development, telomerase remains active, but as various somatic cell types differentiate, its activity progressively declines. Even in somatic tissues, some cell types, specifically those with high turnover rates like stem cells, maintain a low level of telomerase activity. However, in somatic cells where telomerase is inactive, telomere shortening becomes inevitable, ultimately leading to cellular senescence (Pines, 2013).

3. Role of telomere and telomerase in aging and longevity

The aging process is inherently stochastic, characterized by a gradual accumulation of molecular disorder that sets in after reproductive maturity and exceeds the organism's inherent ability to maintain cellular integrity. This molecular decline arises from a multitude of factors, including oxidative stress, cross-linking, depletion of energy reserves essential for molecular integrity, and numerous other destabilizing events. Importantly, the aging process is not genetically predetermined (Hayflick, 2001).

Numerous studies have established a strong link between telomere length and the aging process. Experimental manipulation of telomere function or length in mice has demonstrated significant effects on lifespan. These findings emphasize the potential of telomerase gene therapy as a therapeutic strategy for reversing premature aging and extending lifespan in animal models (Armanios et al., 2009; Bernardes et al., 2012; Derevyanko et al., 2017; Steenstrup et al., 2017). Crocco et al., in 2021 challenged the idea of a strong genetic influence on leukocyte telomere length in the elderly. Their findings emphasized a minimal genetic impact in this age group, instead highlighting the critical role of genes involved in chromosomal structure integrity, such as TERF1 and TNKS2, in determining longevity (Crocco et al., 2021). Furthermore, a meta-analysis involving 48,000 individuals identified genetic loci, including telomerase RNA component (TERC) and telomerase reverse transcriptase (TERT), that are associated with leukocyte telomere length. These loci play a crucial role in telomere biology and have been linked to various cancers and age-related diseases, such as idiopathic pulmonary fibrosis. The study revealed a correlation between alleles linked to shorter leukocyte telomere length and an increased risk of coronary artery disease, suggesting a potential causal relationship between telomere length variability and specific age-related diseases (Codd et al., 2013). These findings collectively highlight the complex and critical role of telomeres in the biological processes driving aging and disease susceptibility.

Contrary to the previous belief that normal senescent cells undergo apoptosis, recent findings indicate their capacity for prolonged survival without cell division. These cells exhibit a senescence-associated secretory phenotype, releasing factors implicated in age-related diseases. Consequently, the gradual accumulation of senescent cells with advancing age is postulated as a contributing factor to various aspects of the aging process (Tchkonia et al., 2013).

The telomere theory suggests that aging is triggered by the shortening of telomeres, although the exact mechanism remains unclear. Telomere shortening is seen as a key factor in aging, leading to cellular senescence, which contributes to aging-related tissue damage. Cellular senescence can drive aging by various mechanisms (Zhu et al., 2019). Stem cell exhaustion and promotion of secretory phenotype known as SASP (Senescence-Associated Secretory Phenotype) are two of the factors discussed here.

Stem cells help maintain tissue health by renewing damaged cells, and their function can be influenced both directly and indirectly. One of the most common signs of aging is the overall decline in tissue regenerative ability. This decline is mainly driven by persistent growth arrest within stem cells themselves, known as cell-autonomous growth arrest (Sharpless and DePinho, 2007). When stem cells undergo senescence, they become exhausted and their function declines, leading to tissue deterioration. For example, the decline in stem cell self-renewal within skeletal muscles lead to a marked reduction in both muscle function and regenerative ability (Bernet et al., 2014). Studies have further demonstrated that muscle and fat progenitor cells in BubR1 progeroid mice exhibit a heightened susceptibility to cellular senescence (Baker et al., 2013).

Although stem and progenitor cells are crucial for maintaining the body, they typically remain in a quiescent state, meaning they do not divide but can proliferate in response to external signals. This quiescence is essential for the long-term repair function of stem cells. However, senescent cells can push stem cells to re-enter the cell cycle through the Senescence-Associated Secretory Phenotype (SASP), which speeds up stem cell exhaustion (Cosgrove et al., 2014).

In addition to causing persistent growth arrest in stem cells, senescence can disrupt the specialized microenvironment, or niche, that supports optimal stem cell function through the SASP (Jang et al., 2011; Pricola et al., 2009). Senescent cells release numerous factors that dramatically alter their secretome, including growth factors, chemokines, proinflammatory cytokines, and proteases (Coppé et al., 2010). Studies using genetic systems or drugs to eliminate senescent cells have shown that clearing these cells reduces inflammation and creates a more regenerative environment (Jeon et al., 2017). Additionally, research has found that the regenerative potential of aged stem cells can be significantly enhanced by exposure to a younger systemic environment (Brack et al., 2007). Senescent cells influence neighboring cells through paracrine signaling, secreting molecules such as IL-1β, TGF-β, and various chemokine ligands. This activity propagates the senescence phenotype and exacerbates age-related tissue decline (Acosta et al., 2013). Recent reviews suggest a tissue remodeling model where the senescence-associated secretory phenotype (SASP) attracts immune cells to remove senescent cells and inflammatory factors, allowing progenitor cells to regenerate damaged tissues. However, this process of clearance and regeneration becomes less efficient with age, resulting in the buildup of senescent cells and inflammatory factors that disrupt tissue structure (Muñoz-Espín and Serrano, 2014). Certain components of the SASP, like IL-6 and IL-8, have been shown to promote epithelial tissue fibrosis by triggering epithelial-mesenchymal transition (Takasugi et al., 2022). Furthermore, proteases secreted by senescent cells may degrade extracellular matrix proteins, signaling molecules, and other components of the tissue microenvironment, contributing to structural and functional alterations (Kosar et al., 2011). Research has revealed that clearing senescent cells decreases chronic inflammation markers like IL-6 and IL-1β in aging tissues, including the kidney, heart, liver, spleen, lung, and osteoarthritic knee. This finding underscores the link between SASP activity and chronic inflammation, commonly referred to as inflammaging (Jeon et al., 2017). Chronic inflammation is closely associated with aging-related conditions, including frailty and various age-associated diseases (Balestro et al., 2016; Franceschi and Campisi, 2014; Soysal et al., 2016). Although the SASP can recruit immune cells to clear senescent cells, the effectiveness of the adaptive immune system decreases with age, a process referred to as immunosenescence (Nikolich-Žugich, 2018). This decline in immune function may stem from issues with hematopoietic stem cells (Sahin et al., 2011). Senescent cells secrete inflammatory factors that perpetuate senescence both through autocrine signaling within themselves and paracrine signaling to neighboring cells. Over time, their diminished clearance leads to an accumulation that fosters chronic inflammation. This is driven by the release of proinflammatory growth factors, cytokines, and chemokines, which disrupt essential cellular environments, hinder tissue homeostasis, and speed up the aging process (He and Sharpless, 2017) (see Fig. 1). In summary, cellular senescence plays a central role in aging through diverse mechanisms. It contributes to stem cell exhaustion, thereby reducing the regenerative capacity of tissues. Furthermore, the secretory activity of senescent cells including the release of proinflammatory cytokines, chemokines, growth factors, and proteases, exacerbates inflammatory responses and damages the tissue microenvironment necessary for proper stem cell function.

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.

4. Telomere and telomerase modulation pathways

• i.PI3K/Akt: Protein kinase B (AKT) directly phosphorylates the shelterin subunit TRF1 at T248, T330, and S344, stabilizing TRF1–telomere binding and preventing fragile telomeres. PI3K/AKT inhibition depletes TRF1 from telomeres and increases telomeric DNA damage (Bejarano et al., 2019). Beyond structural protection, PI3K/Akt interfaces with hTERT transcription via c-Myc/Sp1/ETS nodes and nuclear localization, positioning Akt as a dual regulator of telomere integrity and telomerase expression (Yang et al., 2023; Khattar and Tergaonkar, 2017).
• ii.Ras/MEK/ERK: Growth-factor cues such as EGF activate Rat sarcoma/Mitogen-Activated Protein Kinase/Extracellular signal-Regulated Kinase (Ras/MEK/ERK), which enhances E26 Transformation-Specific (ETS) transcription factor occupancy at the hTERT promoter, increasing hTERT transcription. MEK inhibition or dominant-negative ETS blunts this response (Khattar and Tergaonkar, 2017; Ramlee et al., 2016). Oncogenic Mitogen-Activated Protein Kinase (MAPK) signaling can also activate mutant TERT promoters, linking BRAF/NRAS–ERK activity to telomerase reactivation through de novo ETS motifs created by TERT promoter mutations (Stern et al., 2015; Li et al., 2016a).
• iii.JAK/STAT: Hyperactive JAK/STAT promotes SASP programs and inflammatory tone associated with telomere attrition. STAT3 can directly bind the hTERT promoter to upregulate hTERT transcription in specific contexts, including breast cancer cells and leptin-stimulated models (Yang et al., 2023; Ramlee et al., 2016). A complementary immune mechanism shows antigen-presenting cells transfer telomeric DNA to T cells, extending T-cell lifespan and shaping telomere maintenance independently of telomerase (Lanna et al., 2022; Aman, 2022).
• iv.AMPK: AMP-activated protein kinase (AMPK) connects cellular energy status to telomere maintenance. Experimentally blocking AMPK reduces hTERT expression in certain tumor cells, demonstrating that AMPK activity can sustain hTERT function (Jo et al., 2018). Independently, AMPK signaling helps protect telomeres during replication stress. It achieves this by phosphorylating proteins that safeguard stressed replication forks and reduce oxidative damage, thereby preserving telomere integrity through an indirect mechanism (Li et al., 2019; Gong et al., 2020).

In non-cancerous settings and under various stress conditions, triterpenoid saponins like cycloastragenol (TA-65) and astragaloside IV demonstrate a consistent pattern. They generally increase telomerase activity and slow cellular aging. The evidence suggests they work by activating the ERK signaling pathway, which in turn increases hTERT expression and promotes cell survival. Both small clinical trials and preclinical studies have reported that these compounds can improve telomerase activity and other biomarkers of aging, particularly in models of metabolic and oxidative stress (de Jaeger et al., 2024).

At low concentrations, polyphenols like resveratrol and EGCG can support telomerase activity. Their action often involves the PI3K/Akt and ERK signaling pathways. This aligns with known mechanisms where AKT stabilizes telomeres by phosphorylating TRF1, and the MAPK/ETS pathway drives hTERT gene expression. However, these beneficial effects are not universal; they depend heavily on the dosage and the specific cell type. Furthermore, the effects can reverse, becoming negative, at higher exposure levels or in an oncogenic cellular environment (Bejarano et al., 2019; Ramlee et al., 2016).

In cancer contexts or at elevated concentrations, many phytocompounds shift toward inhibiting telomerase. Flavonoids like quercetin and high-dose EGCG, along with terpenoids such as tanshinone IIA and costunolide, typically suppress telomerase activity. They achieve this primarily by blocking hTERT transcription through key regulators like c-Myc, Sp1, and ETS factors. Other mechanisms include disrupting the movement of hTERT into the cell nucleus or promoting telomeric DNA structures, like G-quadruplexes, that prevent telomere elongation. This aligns with the established principle that the Ras-MEK-ERK pathway normally activates hTERT via ETS proteins. Therefore, directly or indirectly opposing this pathway tips the balance toward telomerase inhibition (Khattar and Tergaonkar, 2017; Ramlee et al., 2016; Sharma and Chowdhury, 2022).

The JAK/STAT pathway offers an important inflammatory perspective. When chronically active, it drives the SASP and immune dysfunction, processes linked to telomere shortening. However, the relationship is complex, as STAT3 can also bind to and activate the hTERT promoter in certain contexts, highlighting that its effects are highly dependent on the cellular environment. Furthermore, immune-specific mechanisms exist, such as the direct transfer of telomeres from antigen-presenting cells to T-cells, which can prolong T-cell lifespan without involving telomerase. This mechanism must be considered when evaluating the impact of plant-derived compounds in immunological studies (Lanna et al., 2022; Jin and Huang, 2023).

Finally, AMPK connects a cell's energy status to its telomerase activity. Experimental AMPK inhibition can down-regulate hTERT in telomerase-positive tumor cells. In normal, non-cancerous cells under stress, AMPK activation helps protect telomeres indirectly by reducing oxidative damage and slowing cell proliferation. This dual role helps explain why plant compounds that activate AMPK can support telomerase in healthy cells but suppress it in cancer contexts (Jo et al., 2018; Gong et al., 2020).

5. Natural products in telomere and telomerase modulation

Table 1 summarizes the major natural compounds reported to modulate telomere length or telomerase activity. Compounds are grouped by chemical class, along with their natural sources, experimental models, observed effects, proposed molecular mechanisms, and overall direction of telomerase activity. Fig. 2A, Fig. 2BA and 2B depict the chemical structures of some natural compounds responsible for positive and negative modulation of telomerase, respectively.

Table 1.

List of natural compounds acting as modulators of telomere biology.

Sl. no.	Class	Compound	Source	Study method	Effect on telomere and/or telomerase	Mechanism of action	Direction of effect	References
1	3-alkylindoles	Indole-3-carbinol	Broccoli, kale, brussels sprouts, cabbage, cauliflower and radish etc.	Studies involving prostate cancer cell lines	Inhibits telomerase activity thus reducing telomere length	Inhibits the hTERT mRNA expression in prostatic cell lines while inhibiting telomerase activity	Inhibition	Fragkiadaki et al. (2022)
2	Acyl carnitines	L-carnitine	Legumes such as beans and peas. Also, nuts, seeds, soybeans and eggs	In-vitro study conducted on cardiac differentiated bone marrow resident CD117+ stem cells	Significant association with increased telomere length	Significant increase in hTERT gene expression in cardiac differentiated bone marrow CD117+ stem cells, mRNA and protein expression via Wnt3/β-catenin and ERK1/2 signaling pathway components	Activation	Fathi et al. (2020)
3	α-amino acid	Evodiamine	Dried fruit of the Evodia	HG-induced endothelial cell senescence	Enhanced activity of telomerase with longer telomere length	Upregulation of SIRT1 gene expression causes increased activation of telomerase	Activation	Wang et al. (2023b)
		L-citrulline	Watermelon, pumpkin, cucumbers and squash	Study on human umbilical venous endothelial cells (HUVECs) with high glucose	Prevents the erosion of telomere	Provided protective action by acting as ROS scavenger and reducing its level	Activation	Tsuboi et al. (2018)
4	Aglycones of saponins	Sapogenins	Spirulina platensis	Telomeric Repeat Amplification Protocol and ELISA assay	Telomerase activity increased in breast cancer cells MCF-7 while the activity was decreased in human dermal fibroblasts, (HDF).	Unknown mechanism	Activation	Akbarizare et al. (2021)
5	Alkaloid	Berberine	Barberry, oregon grape, goldenseal, goldthread, tree turmeric and poppy	Study of telomerase inhibitor on a CRC cell line (HCT 116)	Significant correlation with decreased telomere length	Delaying the cell cycle and doubling time resulting in significant decrease in telomerase activity followed by telomere erosion.	Inhibition	Samad et al. (2021)
		Ascididemin	Didenum sp.	Studies involving human cancer cell lines and QSAR studies	Significantly inhibits telomerase activity and reduces telomere length	Inhibition of telomerase activity through stabilization of G-quadruplexes	Inhibition	Chen et al. (2011)
		Oxoisoaporphine	Menispermum dauricum	TRAP-silver staining assay	Inhibition of telomerase leading to reduction in telomere number	Stabilizes the structure of telomere by binding to G-quadruplex thus stopping telomerase from replicating telomeres	Inhibition	Fragkiadaki et al. (2022)
6	Aromatic polyketides	Rubromycins	Streptomyces collinus	Modified TRAP assay	Significantly associated with potent anti-telomerase activity	Binds to telomerase competitively with respect to the substrate primer and decreased its action	Inhibition	Chen et al. (2011)
7	Antibiotic	Chrolactomycin	Streptomyces sp.	Novel assay based on yeast strain possessing shortened telomeres	Exhibited antitumor antibiotic activity by inhibiting telomerase	Exo-methylene group present is responsible for its effect and forms covalent bond with sulfhydryl group of a cysteine residue close to the active site of telomerase by acting as Michael acceptor to cause irreversible inhibition of telomerase	Inhibition	Chen et al. (2011)
8	Acetylenic acids	(Z)-Stellettic acid C	Marine sponge Stelletta sp	MTT assay using human leukemic U937 cells	Decreased telomere and telomerase enzyme	hTERT expression and telomerase activities are decreased	Inhibition	Ganesan and Xu (2018)
9	Aporphine alkaloid	Boldine	Peumus boldus	Modified quantitative real-time telomere repeat amplification protocol (q-TRAP) by using several cancer lines such as telomerase positive embryonic kidney HEK293 breast cancer MCF-7 and MDA-MB-231 cells	Displayed inhibition of telomerase enzyme which could result in short telomere length	Inhibits the expression of hTERT gene expression	Inhibition	Ganesan and Xu (2018)
10	Azaphilones	Rubropunctatin	Red yeast rice	TRAP-PCR and Western blotting assay in an in-vitro cell culture system	Decrease in telomere length and telomerase activity	Mechanism unknown	Inhibition	Ganesan and Xu (2018)
11	Bisbenzyl isoquinoline alkaloid	Berbamine	Berberis vulgaris	TRAP assay	Significant anti-telomerase activity and telomere erosion	It interacts with G-quadruplexes and stabilizes it, inhibiting telomerase activity	Inhibition	Chen et al. (2011)
12	Benzylisoquinoline alkaloid	Papaverine	Papaver somniferum L.	Assay on HepG2 cell models	Decrease in telomere length and telomerase activity	By reducing the expression of hTERT gene and mRNA, telomerase activity is also reduced	Inhibition	Liu et al. (2020)
		Sanguinarine Chloride	Sanguinaria canadensis, Argemone mexicana, Chelidonium majus, Macleaya cordata and Papaver somniferum	Screening involving an endogenous hTERT reporter	Potent inhibition of telomerase enzyme expression and activity and telomere length erosion	Directly binds to hTERT and inhibit telomerase activity in-vitro	Inhibition	Yan et al. (2022)
13	Berberine alkaloid	Palmatine	Coptidis rhizoma	By using MMT, BrdU assay and Anexin V/PI staining on human estrogen receptor-positive breast cancer cells	Shortened telomere length via reduction of telomerase activity	Inhibition of telomerase activity by formation of C-myc22 G4 and Hum24 G4	Inhibition	Ganesan and Xu (2018)
14	Benzochromenone	Beta-Lapachone	Tabebuia avellanedae	Various human leukemia cell lines such as U937, K562, HL60 and THP-1	Decrease in telomere length and telomerase activity	Down-regulates the levels of hTR and c-myc expression to inhibit telomerase activity	Inhibition	Ganesan and Xu (2018)
15	Carotenoid	Lutein	Kale, spinach, peas, lettuce, broccoli, egg yolks, einkorn, wheat, corn, and yellow-orange fruits.	Cross-sectional cohort study (Australian Population)	Higher leukocyte telomere length was strongly associated with higher concentration of lutein	Significant protective action as an antioxidant to prevent telomere length erosion under oxidative stress.	Activation	(Wang et al., 2023b; Li et al., 2016b)
		Crocin	Crocus sativus L.	Study involving HepG2 cell model	Decrease in telomere length and telomerase activity	Suppresses transcriptional and post-transcriptional regulation with down-regulated telomerase telomerase activity and hTERT expression	Inhibition	Jacczak et al. (2021)
16	Cephalotaxus alkaloids	Homoerythrina alkaloid	Cephalotaxus sp.	Clinical trials involving leukemia patients	Exhibited potent antitumor and anti-telomerase activity with shortening of its length	C3-ester derivatives of it may inhibit telomerase by exhibiting apoptotic activity and by down-regulation of hTERT transcription	Inhibition	Chen et al. (2011)
17	Cladonia furcata polysaccharide	Lichenin CFP-2	Cladonia furcata	By using HL60 and K562 cell lines involving TRAP-ELISA assay and western blotting	Complete inhibition of telomerase enzyme and increased telomere erosion	Induction of apoptosis with subsequent inhibition of telomerase activity	Inhibition	Ganesan and Xu (2018)
18	Diazaphilonic acid	Azaphilone	Talaromyces flavus	TRAP assay	Showed complete inhibition of telomerase activity and telomere shortening	Exact mechanism of action is unknown	Inhibition	Chen et al. (2011)
19	Depside	Thielavin B	Thielavia terricola	TRAP assay	Moderate inhibition of telomerase and telomere length shortening	Polyphenolic hydroxyl groups present in it could be responsible for its telomerase inhibitory activity by reducing hTERT expression	Inhibition	Chen et al. (2011)
20	Diterpenoid epoxide	Triptolide	Tripterygium wilfordii	Studies involving HepG2 cell models and BALB/C nude mice	Displayed inhibition of telomerase activity and length shortening	hTERT transcription is inhibited through protein 1 transcription factor down-regulation	Inhibition	Liu et al. (2020)
21	Diterpenoid quinone	Salvicine	Salvia prionitis Hance	Human leukemia HL60 cell line	Shortens telomere length and decreases telomerase activity	Induction of apoptosis with subsequent inhibition of telomerase activity	Inhibition	Ganesan and Xu (2018)
22	Flavonoid	Kaempferol	Lettuce, tomato, onion, grapes, apples, kale, berries, red cabbage and soybeans	Aging mouse model	Quercetin	Acted as an antioxidant, to prevent reduction in telomerase activity and enhances SOD activity	Activation	Jacczak et al. (2021)
		Epigallocatechin gallate	Green tea, cranberries, kiwis, cherries, apples, pecans, avocados, hazelnuts and pears	On cervical adenocarcinoma	Provided regulation of telomerase activity and regulating the length of telomere	By reducing hTERT expression, provided concentration dependent telomere length regulation	Activation	Jacczak et al. (2021)
		Rutin	Evodia rutaecarpa (Juss.) Benth	On a study based on HG-induced endothelial cell senescence	Increased telomere length which is associated with heightened telomerase activity	Enhances the expression of SIRT1 and NRF2 gene expression which is associated with telomere maintenance	Activation	Wang et al. (2023b)
		Silibinin	Milk thistle	Human prostate carcinoma or LNCaP Cells	Reduction in telomerase activity and subsequent shortening of telomere length	Reduction in TERT expression which correlates to reduced telomerase activity and telomere length	Inhibition	Jacczak et al. (2021)
		Quercetin	Bupleurum scorzonerifolium	On H2O2-induced vascular smooth muscle cell (VSMC)- based senescence	Associated with inhibition of telomerase activity and shortening telomere length	Modulated the gene expression of various proteins associated with activation of telomerase enzyme	Inhibition	(Wang et al., 2023b; Bhatiya et al., 2023)
		Genistein	Soybeans, lupin, fava beans, psoralea and kudzu	Studies involving MCF-7 cell line (Human breast cancer)	Maintains telomerase activity and length	Telomerase expression upregulated through ERK pathway by inducing JAK2 expression which is a signal transducer and activates STAT5b and through the JAK/STAT pathway, modulates telomerase expression The exact mechanism of telomere protective effect is unclear and exerts bilateral effect on telomerase activity which reduces hTERT transcription and telomerase activity in higher concentration and promotes telomerase activation in lower concentration	Concentration dependent activation and inhibition	Jacczak et al. (2021)
		Apigenin	Common fruits and vegetables	Analysis involving human leukemia cell lines such as U937, THP-1 and HL60	Exhibited reduced telomere length and inhibited telomerase activity	Down-regulating hTERT expression by attenuation of c-Myc and special protein 1 (Sp1) binding to hTERT regulatory regions thus inhibiting telomerase activity	Inhibition	Ganesan and Xu (2018)
23	Fatty Acids	Oleic acid	Olive oil, palm oil, avocado oil, sunflower oil, almond oil, macadamia nuts, canola oil and peanuts etc.	Kinetic experiments	Demonstrated strong telomerase activity inhibition and telomere erosion	Oleic acid binds competitively to telomerase at the active site which is typically reserved for telomerase substrate primer. Also, a free carboxylic acid found in oleic acid is also essential for telomerase inhibition	Inhibition	Chen et al. (2011)
24	Flavone glycoside	Baicalin and wogonoside	Scutellaria baicalensis	Studies on HCT116, SW480, A549, Panc-1 cell models and BALB/C nude mice	Inhibition of telomerase activity with subsequent shortening of telomere length	Reduced regulation of hTERT and c-Myc mRNA levels causing telomerase inhibition	Inhibition	Liu et al. (2020)
25	Fungal immuno-modulatory protein-gts	Bioactive proteins	Ganoderma tsugae	Study involving A549 human lung adenocarcinoma cell line	Potent inhibition of telomerase enzyme and telomere length erosion	Decreases the expression of mRNA and protein simultaneously inhibiting gene expression of hTERT	Inhibition	Ganesan and Xu (2018)
26	Glycosyloxyflavone	Luteolin-7-0-glucoside	Melissa officinalis	Study involving RAW 264.7 cells	Shortened telomere length due to decreased telomerase length	Reduction in hTERT gene and telomerase activity are responsible for this	Inhibition	Ganesan and Xu (2018)
27	Glycoprotein	LJPG	Laminaria japonica	Studies involving AGS human gastric cancer cells	Complete inhibition of telomerase enzyme and increased telomere erosion	mRNA and protein expression are reduced with inhibition of hTERT expression	Inhibition	Ganesan and Xu (2018)
28	Indoloquinolone alkaloid	Cryptolepine	Cryptolepis triangulari, C.sanguinolenta	TRAP assay and SAR studies	Acted as G4 DNA-interactive compounds to inhibit telomerase activity and shorten telomere length	Stabilization of G4 causing the inhibition of telomerase activity	Inhibition	Chen et al. (2011)
29	Isothiocyanates	Erucin	Eruca sativa and other cruciferous vegetables	Studies involving HCC cells	Inhibits telomerase activity and reduces telomere length	Exact mechanism remains unclear	Inhibition	Fragkiadaki et al. (2022)
		Sulforaphane	Broccoli and cauliflower	In silico molecular docking by using drug-likeness and bioactivity prediction and biological activity prediction using PASS online method	Inhibited the activity of telomerase to reduce telomere length	Post-translational modification of hTERT prevents the activity of telomerase enzyme	Inhibition	Ganesan and Xu (2018)
30	Isobenzofuranones	Butylidenephthalide	Angelica sinensis	Treatment of human glioblastoma cells	Moderately decreases telomerase activity and telomere length	Dose dependent down-regulation of hTERT expression and subsequent telomerase activity	Inhibition	Ganesan and Xu (2018)
31	Isoflavones	Daidzein	Glycine max	Involves the use of human cervical cancer cells HeLa in-vitro and MTT assay, flow cytometry and real-time quantitative reverse transcription-polymerase chain reaction	Exhibited telomere enzyme inhibition and telomere erosion	Stabilization of G4 with inhibition of cell growth and cell cycle in G2/M phase causing apoptosis, inhibition of telomerase activity and reduced telomere length	Inhibition	Ganesan and Xu (2018)
32	Lipopolysaccharides	Axinelloside A	Axinella infundibula	TRAP assay	Potent inhibitors of human telomerase enzyme and significantly reduces telomere length	Exact mechanism is unknown	Inhibition	Chen et al. (2011)
33	Lignans	7′-Hydroxy-3′,4′,5′,9,9′-pentamethoxy 3,4-methylene lignan	Phyllanthus urinaria	TRAP assay involving human nasopharyngeal carcinoma cells	Inhibition of telomerase activity which would effect the telomere length by making it shorter	Directly inhibits telomerase activity	Inhibition	Ganesan and Xu (2018)
34	Lectin	Coloratum agglutinin	Viscum album and European mistletoe	Human hepatoma cells	Significant reduction in telomerase activity and length	Exact mechanism is unknown	Inhibition	Ganesan and Xu (2018)
35	Macrocyclic natural product	Telomestatin	Streptomyces anulatus	TRAP assay	Showed extremely potent inhibition of telomerase known to date with similar shortening of telomere length	Binds to human telomeric sequence d[T2AG3]4 with 2:1 stoichiometry with high selectivity for intramolecular binding and G-quadruplex structures which are poor telomerase substrate and shortens the telomere length steadily. Moreover, it induces TRF2 and POT1 dissociation thus facilitating uncapping of telomere ends causing rapid apoptosis	Inhibition	Chen et al. (2011)
36	Marine Alkaloids	Dictyodendrins	Dictyodendrilla verongiformis	TRAP assay	Exhibited telomerase inhibition and decrease in telomere length	Complete inhibition of telomerase, although exact mechanism is unclear	Inhibition	Chen et al. (2011)
37	Naphthoquinone pigment	Shikonin and its derivatives	Alkanna Lithospermum genus and Boraginaceae family	TRAP assay involving lung cancer cell lines	Inhibition of telomerase activity which would effect the telomere length by making it shorter	Stabilization of G4 causing the inhibition of telomerase activity	Inhibition	Ganesan and Xu (2018)
38	Nucleosides	Sinefungin	Streptomyces griseolus	Studies involving treatment of H1299 cells	Inhibition of telomerase activity which would affect the telomere length by making it shorter	TGS1-mediated 2,2,7-TMG capping of hTR is inhibited through sinefungin which blocks the recruitment of telomeres to telomerase.	Inhibition	Buemi et al. (2022)
39	i. Omega-3 ii. Omega-6 fatty acid	i. 5, 8, 11,14,17—eicosapentaenoic acid ii. Linoleic acid	Walnuts, soybean oil, canola oil, nuts, oily fish, flaxseed, corn oil, safflower oil	On Mouse model	Increase telomerase activity and telomere length	Provided antioxidant effect which was TERT miRNA-mediated via increase in SOD activity	Activation	Jacczak et al. (2021)
40	Orange red pigment	Alterperylenol	Alternaria sp.	TRAP assay	Displayed selective inhibition of telomerase activity and length shortening	Existence of enone in the structure is a possible reason for its biological activity	Inhibition	Chen et al. (2011)
41	Organooxygen compounds	Trichostatin A	Streptomyces sp.	By using normal human telomerase-negative cells and telomerase-positive tumor cells	Significantly reduces telomere length and telomerase activity	Telomerase activities are decreased alongside hTERT expression	Inhibition	Ganesan and Xu (2018)
42	Organosulfur compound	Diallyl disulfide	Allium sativum L.	TRAP and in-vitro binding assay by using human lymphoma cell line U937 and radiolabeled double-stranded DNA	Associated with reduced telomere length and decrease in telomerase activity	Exact mechanism is unknown	Inhibition	Ganesan and Xu (2018)
43	Polysaccharide	–	Cynomorium songaricum and potatoes, rice, peas, corn, grains, banana, onion, papaya and tomato	Subacute aging model mice	Significant increase in telomerase activity with subsequent telomere lengthening	Reduction of free radical enhances telomerase activity and prevents telomere erosion	Activation	Jacczak et al. (2021)
44	Phenylethanoid glycosides	Acteoside	Cistanche tubulosa, Striga asiatica and Olea europaea L. fruit	Aging mouse model	Increased telomerase activity and telomere length was associated with acteoside	Provided protective action as an antioxidant to enhance telomerase activity	Activation	Jacczak et al. (2021)
45	Polyphenol	Resveratrol	Peanuts, red grapes, blueberries, raspberries and mulberries	On endothelial and epithelial progenitor cancer cells	Strongly correlated to the regulation of telomerase activity while regulating the telomere length	Provided bilateral effect on telomerase activity by reducing hTERT transcription and activating telomerase in lower concentration (0.5 − 1.0 μM) while reducing telomerase activity in higher concentration (50 μM)	Concentration dependent activation and inhibition	Jacczak et al. (2021)
		Coumarin	Tonka bean, sweet clover, vanilla grass, cherry blossom trees and cassia cinnamon	Synthesis and characterization by X-ray diffraction analysis, NMR, ESI-MS, IR and elemental analysis	Decreased telomere length associated with coumarin	Inhibition of telomerase by targeting c-myc promoter elements resulting in telomere shortening	Inhibition	(Fragkiadaki et al., 2022; Meng et al., 2018)
		Curcumin	Turmeric	Study on glioblastoma and medulloblastoma cells	Significantly associated with inhibition of telomerase enzyme and telomere erosion	Downregulation of Bcl-2 and survivin alongside with hTERT mRNA expression downregulation caused reduction in telomerase activity and the telomere to shorten	Inhibition	Khaw et al. (2013)
		Stilbene	Pterocarpus indicus, Polygonum cuspidatum, Rhodomyrtus tomentosa, Rheum undulatum, Melaleuca leucadendron, Euphorbia lagascae, blueberry, almond, peanut, grape and pine tree	Studies involving various cancer cells such as ovarian, colon, prostate, lung, breast. Also, glioblastoma and hepatic stellate cell were also used	Decrease in telomere length and telomerase activity	Reduces hTERT, c-myc and mRNA expression. Thus, leading to decreased telomerase activity	Inhibition	Lee et al. (2019)
		Gingerol	Zingiber officinale Roscoe	Studies involving A549 lung cancer cells	Decrease in telomere length and telomerase activity	Reduces c-Myc (myelocytomatosis viral oncogene) and hTERT expression	Activation	Ganesan and Xu (2018)
46	Polyamine	Spermidine	Soybeans, mushrooms, green peas, nuts and leafy vegetables Soybeans, lupin, fava beans, psoralea and kudzu	in-vivo and cohort studies	Protective action on telomere, leading to its extension	The exact mechanism of telomere protective effect is unclear	Activation	Schellnegger et al. (2024)
47	Polyphenolic Lignan	Arctigenin	Fructus arctii	DPPH, ROS, Lifespan and juglone-induced oxidative stress assay with RT-PCR	Modulates the telomere length and telomerase activity	Through good antioxidant ability, it can extend the lifespan and telomere length. However, it can also decrease telomerase activity as well.	Activation and inhibition	Mechchate et al. (2022)
48	Pine pollen	Alpha and beta-pinene	Pinus massoniana	On human embryonic lung fibroblasts; Human diploid fibroblasts 2BS	Involved in the modulation of telomerase activity and telomere length and increased cell population	Delayed replicative senescence and reversed expression of senescence-associated molecular markers, such as p53, PTEN, and p27(Kip1)	Activation	Jacczak et al. (2021)
49	Pyranoxanthones	Gambogic acid	Garcinia hanburyi	SAR studies on different cell lines	Showed reduction in telomerase activity and length of telomere	Reduction in the activity of hTERT gene by downregulation of hTERT via inhibition of transcription activator c-myc	Inhibition	Chen et al. (2011)
50	Purine nucleoside	Purpuromycin	Actinoplanes ianthinogenes	Modified TRAP assay	Demonstrated increased telomerase inhibition and subsequent telomere erosion	Probable binding to the hTR and/or TERT subunits to display anti-telomerase activity	Inhibition	Chen et al. (2011)
51	Polyketide/alkaloid	UCS1025A	Acremonium sp.	TRAP assay	Illustrated to be a potent inhibitor of telomerase	Exact mechanism of action is yet to be determined	Inhibition	Chen et al. (2011)
52	Phenol glucuronides	CRM646-A	Acremonium sp.	TRAP assay	Exhibited dose-dependent inhibition of telomerase activity	General inhibition of RNA-dependent DNA polymerases to inhibit telomerase activity	Inhibition	Chen et al. (2011)
53	Phenylpiperidine	Meridine	Amphicarpa meridian	Studies involving human cancer cell lines and QSAR studies	Significantly inhibits telomerase activity and reduces telomere length	Inhibition of telomerase activity through stabilization of G-quadruplexes	Inhibition	Chen et al. (2011)
54	Polyacetylene	Dideoxypetrosynol A	Marine sponge Petrosia sp	Study involving U937 cells	Shortens telomere length and decreases telomerase activity	Down-regulates hTERT expression and subsequent telomerase activity	Inhibition	Ganesan and Xu (2018)
55	Phenolic acids	Cinnamic acids	Cordyceps militaris	Human lung carcinoma A549 cells	The telomerase activity was prevented with subsequent telomere length shortening	Telomerase activities are inhibited because hTERT gene expression is reduced, due to the regulatory region of hTERT binding to c-Myc and Sp1	Inhibition	Ganesan and Xu (2018)
56	Phenolic aldehyde	Gossypol	Cottonseed	Human leukemia cells	Showed complete inhibition of telomerase activity with shortened telomere length	Inhibition of telomerase activity by reducing phosphorylation with subsequent nuclear and post-translational modification of hTERT	Inhibition	Ganesan and Xu (2018)
57	Polyether-lactone	Pectenotoxin-2	Dinophysis fortii	Human leukemia cells	Exhibited reduced telomere length and inhibited telomerase activity	Reduces the phosphorylation and nuclear translocation of hTERT, thereby inhibiting telomerase activity	Inhibition	Ganesan and Xu (2018)
58	Ribosome-inactivating proteins type II	Mistletoe lectin	Viscum album and European mistletoe	Human hepatocarcinoma cells	Results in inhibited telomerase activity and shortened telomere length	Prevention of hTERT gene expression and reduced expression of protein and mRNA	Inhibition	Ganesan and Xu (2018)
59	Steroid	Withanolide	Withania somnifera (L.) Dunal	Human HeLa cell	Lengthened telomere by increasing telomerase activity	Decreased the effects of H2O2 induced damage on the DNA to enhance telomerase activity	Activation	Jacczak et al. (2021)
60	Steroidal glycoside	Cynbungenins	Cynanchum bungei	Aging mouse model	Significant increase in telomerase activity with subsequent increase in telomere length	Provided protective action as antioxidant via significant increase in SOD activity	Activation	Jacczak et al. (2021)
61	Saponin	Ginsenoside Rg1	Panax ginseng (Ginseng root)	On hemopoietic stem-cell in aging mice model	Reduction in telomere length erosion and increased telomerase activity	Significant increase in telomerase expression and restoration of telomerase activity	Activation	Jacczak et al. (2021)
62	Sesquiterpene lactone	Costunolide	Saussurea lappa, Magnolia sieboldii, Saussurea sp.	TRAP assay	Significantly inhibits telomerase activity and reduces telomere length	Reduces levels of hTERT, mRNA and proteins. Thus, decreasing the bindings of transcription factors in hTERT promoters and inhibits telomerase activity	Inhibition	Chen et al. (2011)
		Helenalin	Arnica and inula	On different human cell lines to determine anti-tumor activity	Shortened telomere length via reduction of telomerase activity	Possibility through inhibition of NF-kB, hTERT was downregulated to reduce telomerase activity	Inhibition	Chen et al. (2011)
63	Stilbenoids	Pterostilbene	Grapevines, cranberries, heartwood of red sandalwood and blueberries etc	Assay involving H460, H1299 cell models	Significant reduction in telomerase activity and length	Reduction in the expression of hTERT, leading to reduced telomerase activity	Inhibition	Liu et al. (2020)
64	Spirostanols	Diosgenin	Trigonella foenum-graecum	Molecular docking was used by constructing the protein-protein interaction (PPI) network, gene oncology, functional and pathway enrichment analysis and Kyoto encyclopedia of genes and genomes (KEGG)	Exhibited telomere enzyme inhibition	Expresses anti-telomerase activity and down regulates hTERT gene expression	Inhibition	Ganesan and Xu (2018)
65	Sesquiterpene	Atractylenolide	Atractylis lancea (Thunb.) DC	B16 melanoma cells	Significant reduction in telomerase activity and length	Inhibits the expression of hTERT gene and reduces the expression of both mRNA and protein	Inhibition	Ganesan and Xu (2018)
66	Triterpenoid	Astragaloside IV	Astragalus membranaceus	Study on human embryonic lung diploid fibroblasts	Increased telomerase activity which correlated to longer telomere length	Provided protective action to cells against oxidative stress by regulating expression of various proteins such as p16, c-C3 and BAX	Activation	Jacczak et al. (2021)
67	Triterpenoid saponin	Saikosaponin	Legumes such as alfalfa, soybean, chickpeas, beans, peanuts. Also, ginseng roots, liquorice roots and tea leaves, Centella asiatica	Study on peripheral blood mononuclear cells	Significant increase in telomerase activity resulting in increase of telomere length	Inhibited the negative effect of H2O2 on DNA thus preventing oxidative stress and increased the telomerase activity by nine-fold	Activation	Jacczak et al. (2021)
		Cycloastragenol	Astragalus membranaceus	Studies on its impact on Klb (β-Klotho) gene in mouse ovaries	Increased activation of telomerase enzyme activity with subsequent increase in telomere length	Telomerase expression upregulated through ERK pathway by inducing JAK2 expression which is a signal transducer and activates STAT5b and through the JAK/STAT pathway, modulates telomerase expression	Activation	Schellnegger et al. (2024)
		TA-65	Astragalus membranaceus	Randomized, double-blinded and placebo-controlled trial	Results in prominent activation of telomere telomerase activity. Thus, potentially leading to telomere extension		Activation	Schellnegger et al. (2024)
		Platycodin d	Platycodon grandiflorum	By using human leukemia cells U937, THP-1 and K562	Displayed inhibition of telomerase activity and length shortening	Induction of apoptosis by inhibiting cell growth and G2/M phase. This results in inhibition of telomerase activity and reduced telomere length	Inhibition	Ganesan and Xu (2018)
68	Tropolone	Thujaplicin	Reynoutria japonica Houtt.	Studies of myotubular insulin resistance model induced by palmitic acid	Increased activity of telomerase and telomere length	Prolongation of telomere length by inducing SIRT1 promoter activity	Activation	(Wang et al., 2023; Fumiaki et al., 2012)
69	Thiosulphuric acid esters	Allicin	Allium sativum	Study on fibroblast cells	Associated with inhibition of telomerase activity and shortening telomere length	Downregulates the expression of Bcl-2 and overexpression of Fas and BAX through secondary messengers such as cAMP and PKC associated with second signal system	Inhibition	(Jacczak et al., 2021; Sun, 2003)
70	Tanshinones	Tanshinone I and IIA	Salvia miltiorrhiza	In-vivo and in-vitro assay against cancer cells	Inhibits telomerase activity and reduces telomere length	Down-regulates telomerase activity or inhibits it and down-regulates hTERT expression	Inhibition	Chen et al. (2011)
71	Taxane	Paclitaxel	Taxus brevifolia	Assay involving MEFs cell models and mTREC−/−p53−/−mice	Shortens the telomere length eventually causing telomere erosion	Causes increased dysfunction in telomere, leading to shortened telomere length	Inhibition	Liu et al. (2020)
72	Triterpenes	Cucurbitacins	Trichosanthes cucumerina L.	TRAP assay and RT-PCR (qualitative and real time) performed by involving breast cancer cells	Halts the activity of telomerase and shortens telomere length	Exact mechanism is unknown	Inhibition	Ganesan and Xu (2018)
73	Vitamin B complex	Folate	Leafy green vegetables such as cabbage, spinach and kale. Also, broccoli, peas, kidney beans, liver.	Cross-sectional study	Increase of folate levels in women were strongly associated with longer telomere length	Folate could possibly influence the epigenetic regulation of telomeres through DNA methylation and the DNA structure itself as well	Activation	Tucker (2019)
74	Vinca alkaloids	Vinorelbine	Streptomyces sp.	By using Anip973 cells	Potential reduction in telomere length and telomerase activity	Decreased regulation in telomerase activity and hTERT expression	Inhibition	Ganesan and Xu (2018)

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.

5.1. Polyphenols

Polyphenols are common phytochemical compounds that are typically found in various plants. Main dietary sources of polyphenol include vegetables, herbs, whole grain and fruits such as apples, cherries, grapes, and pears. Other than that, coffee, tea, dry beans, chocolate, red wine are also polyphenol rich food sources. Flavonoid compounds such as rutin, genistein, and epigallocatechin gallate, and phenolic compounds including resveratrol and phenolic acid derivatives such as acteoside are all polyphenol compounds. Polyphenols are one of the leading compounds in anti-aging as well as against diseases that are caused by oxidative stress. However, recent studies show that polyphenols also prevent aging by exerting protective action towards the telomere. Factors responsible for telomere shortening might include inappropriate nutrition, oxidative stress and defective endonuclease III-like protein 1 (Nth1), which is responsible for the repair of DNA damage caused by oxidative stress. Polyphenols are an effective telomere protector than many other antioxidant compounds due to having large amounts of hydroxyl (-OH) groups. Many in vitro, in vivo and case-control studies found that polyphenols increase telomerase activity and subsequently leads to the preservation of telomere length due to the ROS scavenging ability of polyphenols that provides antioxidant effect to reduce the number of harmful free radicals (Maleki et al., 2020). Research indicates that polyphenols are positively associated with telomere length. This beneficial effect is largely attributed to their antioxidant properties. Polyphenols act as scavengers of harmful reactive oxygen and nitrogen species and function as metal chelators. Furthermore, they inhibit several enzymes linked to telomere shortening, including xanthine oxidase, lipoxygenase, and cyclooxygenase. Epigallocatechin gallate (EGCG) is a major catechin that can be found in green tea. Although it can be found in other food sources such as cranberries, kiwis, apples, pecans, cherries, pears, avocados, and hazelnuts. This compound has promising effects on telomere maintenance due to its antioxidant properties. EGCG constitutes a longer telomere with increased methylation of CpG sites of hTERT enzyme's promoter region in fibroblasts (Pointner et al., 2021). It also provides concentration dependent telomerase modulation and telomere length regulation by reducing hTERT expression (Jacczak et al., 2021). Resveratrol is a natural polyphenolic compound that is primarily found in red grapes. Peanuts, blueberries, raspberries, and mulberries are also enriched with resveratrol. Studies have shown that resveratrol is capable of reducing cell aging by regulating cell senescence and telomerase activity. Telomerase activity is induced by resveratrol via the PI3K-Akt cascade (Kang et al., 1999). Endothelial progenitor cells (EPCs) senescence was found to be prevented by dose dependent telomerase activation ability of resveratrol (Xia et al., 2008). In addition, resveratrol can produce bilateral effect on telomerase by reducing hTERT transcription and activating telomerase in lower concentration (0.5−1.0 μM) while reducing telomerase activity in higher concentration (50 μM) (Jacczak et al., 2021). Acteoside is a phenolic acid derivative which contains two phenylpropanoid groups. This glycoside is mostly found in dicotyledonous plants such as Cistanche tubulosa, Striga asiatica and Olea europaea L. fruit. This compound exerts a potent antioxidant effect. In an experiment conducted on D-galactose-induced ageing mice, acteoside enhanced the telomerase activity in heart and brain. Acteoside also provides protective action for telomere by acting as free radical scavenger (Shen et al., 2017).

Another predominantly found colorless and crystalline oxygenated heterocyclic polyphenolic compound is coumarin. This natural compound can be obtained from multiple sources like tonka bean, sweet clover, vanilla grass, cherry blossom trees, cassia cinnamon, turmeric, etc. (Khaw et al., 2013). Coumarin displayed a telomerase reduction effect and resulted in telomere length shortening by targeting c-myc promoter elements in cisplatin-resistant ovarian cancer cells, SK-OV-3/DDP (Fragkiadaki et al., 2022; Meng et al., 2018). This compound has also been found to be significantly associated with inhibition of telomerase enzyme and telomere erosion in a study conducted on glioblastoma and medulloblastoma cells. The mechanism of anti-telomerase activity involved was downregulation of Bcl-2 and survivin alongside with hTERT mRNA expression (Khaw et al., 2013). Silibinin, a polyphenolic flavonoid or flavonolignan present in milk thistle, showed telomerase enzyme inhibition in human prostate carcinoma or LNCaP cells and shortened telomere through reduction in TERT expression (Jacczak et al., 2021). CRM646-A is a phenol glucuronide isolated from Acremonium sp. Which exhibited dose-dependent telomerase inhibition in the TRAP assay via RNA-dependent DNA polymerase inhibition (Togashi et al., 2001). Thielavin B is a recognized inhibitor of RNA-dependent DNA polymerase. Its structure consists of polyphenolic hydroxyl groups, making it structurally similar to compounds like alterperylenol and EGCG. These shared structural features are considered crucial for its biological activity (Kiran et al., 2015). They moderately inhibit the activity of telomerase at a minimum concentration of 32 μM without disrupting DNA polymerase and therefore can be called telomerase inhibitors (Togashi et al., 2001). Pterostilbene selectively inhibits hTERT by competitively binding to the active site of telomerase and thus this compound may work as a lead compound to discover novel selective inhibitors of hTERT (Chen et al., 2020a). Stilbenes and their derivatives inhibit hTERT through multiple mechanisms. They can induce G2/M cell cycle arrest to shorten telomeres, activate the p53/p21 pathway, and suppress c-Myc and hTERT mRNA expression. This leads to reduced telomerase activity and S-phase arrest. Additionally, they activate the ATM/Chk2/p53 pathway, causing DNA damage and oxidative stress. These combined effects promote apoptosis, halt the cell cycle, and induce cell death by further inhibiting hTERT expression and disrupting Stat3/Akt signaling, ultimately restraining telomerase function (Lee et al., 2019). Gingerol reduces the expression of hTERT and c-Myc, although a high concentration of gingerol is required to suppress the expression of hTERT (Chen et al., 2020a). Gingerol has β-hydroxy group present in the hydrocarbon side chain which may attribute to its reduced activity in telomerase inhibition (Kaewtunjai et al., 2018). Luteolin-7-O-glucoside decreases telomerase activity by preventing hTR and hTERT along with other related proteins (Oršolić and Jazvinšćak, 2022). An experiment done in the cell line of leukemia cancer cells HL-60, U937 and THP-1 reported cytotoxicity that was induced by Apigenin. Apigenin works by activating the caspase pathway that leads to cell death and decreased hTERT levels and thus lowering telomerase functions. Furthermore, it is also seen to increase ROS level inside the cells, making it a potent antioxidant and inflammatory compound suitable for the treatment of many cancers (Bartoszewska et al., 2024). Gossypol downregulates the expression of TERT at transcription as well as the post-translation stage which results in inactive c-Myc proteins. In addition, Gossypol has the capacity to halt the Akt signaling pathway that is essential in the survival of cells which further leads to inactive TERT and its modification after translation. All of these actions were proven to lead to cell apoptosis in leukemia cancer cells (Paunovic et al., 2023). Daidzein is proven to suppress hTR and hTERT, substrates and related proteins of telomerase therefore inhibiting telomerase actions (Oršolić and Jazvinšćak, 2022). This compound promotes cell death through multiple mechanisms. It induces cell cycle arrest, preventing progression through the G2/M phase. Concurrently, it causes telomere shortening and stabilizes G-quadruplex (G4) DNA structures. These combined actions—cell cycle arrest, telomere attrition, and G4 stabilization—contribute to its overall inhibitory effect on telomerase function (Ganesan and Xu, 2018).

5.2. Flavonoids

Flavonoids are polyphenolic phytochemical compounds. Flavonoids can be found naturally in various food sources such as lettuce, tomato, onion, grapes, apples, kale, berries, red cabbage, and soybeans (Jacczak et al., 2021). Flavonoid is said to be a potent regulator of telomerase. It can also act as a strong antioxidant while simultaneously enhancing SOD activity in testes and brain tissues of aged mice. Through indirect mechanisms such as reducing oxidative stress, flavonoids can increase the activity of telomerase and provide subsequent protection for telomeres to increase their length. In D-galactose-induced ageing mice, rather than enhancing telomerase activity, flavonoid directly increases the length 2BS cells telomere (Shen et al., 2017). Rutin is a flavonoid glycoside that is primarily found in Evodia rutaecarpa (Juss.) Benth and also in various fruits, herbs, and vegetables. On a study based on HG-induced endothelial cell senescence, it was discovered that rutin can enhance the telomerase activity thus increase the length of telomere via increasing the expression of SIRT1 and NRF2 gene which are associated with telomere maintenance (Wang et al., 2023b). It also exerts antioxidant effect which also prevents telomere shortening by scavenging any free radicals (Li et al., 2016b). Genistein is another example of a flavonoid commonly found in soybeans, fava beans, lupin, kudzu, and psolarea. This compound is significant for its ability to maintain telomere length and increase telomerase activity. In a study involving MCF-7 cell line or the human breast cancer cell line, genistein showed bilateral effect in telomerase activity. The biological activity of this compound is primarily observed within 10–100 μM concentration range (Holick, 2004). The telomerase activity and hTERT transcription are reduced in the higher concentration range. Meanwhile, lower concentration range would enhance telomerase activation, thereby increasing the telomere length (Jacczak et al., 2021).

Several studies reported that wogonin negatively regulates Myc proto-oncogene and hTERT promoter therefore suppressing cell growth. It also reduces hTP1 and hTERT transcription that causes telomere attrition and death of HL-60 leukemia cells. Quercetin is a naturally occurring flavonoid extracted from Bupleurum scorzonerifolium capable of reducing oxidative stress and cellular damage due to possessing multiple hydroxyl groups which can quench free radicals. It showed anti-telomerase activity in a study on human aortic endothelial cell (HAEC) senescence and shortened telomere length via modulation of the gene expression of various proteins associated with activation of this enzyme (Kiran et al., 2015; Wang et al., 2023b). Since wogonoside and baicalin have similar molecular structure, it can be assumed that baicalin may have the same impact on cells following the same mechanism of action as wogonoside (Gu et al., 2022). Genistein stimulates the intercellular pathways associated with telomerase and a study done in the cell line of HL-60 exhibited negative regulation of hTERT in presence of this compound where the IC₅₀ value was 50 μM. Cell death was also accelerated in this study (Bartoszewska et al., 2024).

5.3. Triterpenoid saponin

Triterpenoids are a large group of phytochemicals that are C30 precursors derivative. With over 100 distinct skeletons, this class includes triterpenes, limonoids, steroids, and quassinoids (Lee et al., 2019). Primary food source for triterpenoid saponin includes legumes such as alfalfa, soybean, chickpeas, beans, peanuts. Also, ginseng roots, liquorice roots and tea leaves, and Centella asiatica. This compound is also a potent telomerase activator. In a study on peripheral blood mononuclear cells, triterpenoid saponins displayed a nine-fold increase in telomerase activity (Tsoukalas et al., 2019). At the same time, this compound displayed its antioxidant ability by inhibiting the negative effect of H₂O₂ on DNA, thereby establishing a protective action on telomeres, preventing its length from decreasing. Astragalosides are classified as small molecule triterpenoid saponins and consist of a series of phytochemicals that are related and isolated from Astragalus membranaceus. Astragaloside IV is a part of that series and is shown to have many pharmacological actions including telomerase activation. This compound is shown to enhance the telomerase activity in human embryonic lung diploid fibroblasts. Here, it acts as an antioxidant by reducing oxidative stress on cells via regulating p16, c-C3, and BAX protein expression (Jacczak et al., 2021). This prevents the telomere length from shortening. In addition, the expression profile of TERT in nucleus pulposus cells (NPCs) demonstrated the ability of Astragaloside IV's ability to activate TERT (Hong et al., 2021). Activation of TERT can lead to stabilization of telomere length and cellular immortalization (Yuan et al., 2019). Cycloastragenol is another naturally occurring triterpenoid saponin that could typically be found in dried roots of some legume species including A. membranaceus and A. mongolica. Cycloastragenol (CAG) promotes telomerase activity and cell proliferation in human cells. In mouse ovarian cells, it activates telomerase through a specific pathway. CAG induces the expression of JAK2, a key signaling protein. This activation triggers the JAK/STAT pathway, leading to STAT5b activation. Through this ERK and JAK/STAT-mediated signaling, CAG ultimately modulates and increases telomerase expression (Schellnegger et al., 2024). Moreover, in human neonatal keratinocytes, the telomerase activation ability of CAG promotes scratch wound closure in vitro. In addition, in PC12 cells and primary neurons, CAG induces cAMP response element binding (CREB), TERT, and bcl2 expression thereby inducing telomerase activity and increasing telomere length (Ip et al., 2014). This compound was found to be effective in producing antiaging effect by telomere length prolongation via enhancing telomerase activity in human fibroblasts, keratinocytes, and immune cells (Akbarizare et al., 2021).

5.4. Saponins

Ginsenoside Rg1 is a naturally occurring saponin and predominantly present in the root of Ginseng. A positive association of ginsenoside with telomerase activity and telomere length was established in a study conducted by Jacczak et al. (2021) on hematopoietic stem cells in an aging mice model. Findings of the study demonstrated enhanced telomerase activity and stopped telomere length erosion via a significant increase in telomerase expression and restoration of telomerase activity (Jacczak et al., 2021). TA-65 (Cycloastragenol) is a naturally occurring saponin derived and purified from the root of A. membranaceus. This compound prevented DNA damage, elongated telomere length and increased telomerase activity by increasing mTERT levels in mouse embryonic fibroblasts and ultimately increased health span of mouse (Bernardes et al., 2012). Research using T98G human glioblastoma and rat C6 cell lines has demonstrated that diosgenin, a natural sapogenin, downregulates TERT expression. These experimental results establish an inverse relationship between diosgenin exposure and telomerase activity. A study was done to test the anticancer properties of Platycodin D on cell lines of K562, U937 and THP-1 where it showcased cytotoxic effects and a reduction in hTERT, c-Myc and SP1 expression as well as inhibiting interactions with DNA. Furthermore, nuclear translocation of hTERT and dephosphorylation that evidently showcases antitelomerase activity in both the translational and post-transcriptional phase (Bartoszewska et al., 2024).

5.5. Terpinoids

Helenalin is a natural sesquiterpene lactone commonly present in Arnica montana and Inula helenium flowers. Helenalin was found to shorten telomere length via reduction of telomerase activity in previously conducted studies. The anti-telomerase activity was observed in HL-60 and hematopoietic cancer cells Jurkat in TRAP assay and the mechanism involved was downregulation of hTERT and inhibition of NF-kB. Tanshinones I and IIA are diterpenoids which are extracts of Salvia miltiorrhiza, a widely popular Chinese root. Tanshinone-I is shown to suppress the expression of hTERT, therefore decreasing the activity of telomerase (Paunovic et al., 2023). Tanshinone-IIA is also reported to showcase inhibitory action against telomerase in K562 and HL‐60 leukemia cancer cells and the inhibitory rate was 50.8 % and 30.8 % respectively (Bajaj et al., 2020). Costunolide downregulates the activity of Special Protein (Sp1) and c-Myc, the transcriptional factors of telomerase and hTERT as well as inhibiting the functionality of telomerase shown in MDA-MB-231 and MCF-7 breast cancer cells. Additionally, Costunolide inhibited the expression of hTERT through a pathway that is receptor-mediated and accelerated cell death in NALM-6 human leukemia cancer cells (Lin et al., 2015). Studies on FaDu pharynx tumor cells demonstrate that paclitaxel induces telomere erosion and apoptosis. When telomerase function in these cells is disrupted by antisense targeting of hTR, the cells exhibit telomere shortening and reduced growth rates. This telomerase deficiency also renders the cells extremely sensitive to paclitaxel treatment. Moreover, studies in cell lines of breast cancer show that synergistic activity of paclitaxel combined with BIBR1532 reduced activity of telomerase as this specific combination prevented the S cells to move forward to G2/M phase which induced cytotoxicity in tumor cells (Bajaj et al., 2020). Triptolide down regulates the signaling pathway of hTERT and by doing so, it decreases the growth of tumor and induce aging of cells (Chen et al., 2020a). Atractylenolide and its active derivates atractylenolide II and atractylenolide III are reported to restrict the proliferation of lung cancer cells by inhibiting telomerase through reduced expression of c-Myc, hTERT and mRNA (WA E, 2021). Cucurbitacin B, a derivative of Cucurbitacin is an effective telomerase inhibitor that erodes telomeres and downregulates hTERT and c-Myc as well as prevents the cells to go into G2/M phase during their division (Garg et al., 2018).

5.6. Acidic compounds

L-citrulline (L-Cit) is a phytochemical that is also a water-soluble α-amino acid that is a Citrullus derivative. The dietary source for this compound includes watermelon, pumpkin, cucumbers, and squash (Qazi and Ahmed, 2023). L-Cit was discovered to reduce high glucose (22 mM) induced endothelial senescence on human umbilical venous endothelial cells (HUVECs) with high glucose by measuring SA-β-gal marker activity, DNA damage and p16^INK4a expression. Thus, under increased glucose level, L-Cit induced restorative action on telomerase enzymes to return it to its normal glucose level condition. L-Cit also prevents telomere length from shortening via its antioxidant effect by reducing ROS production, which is measured by CM-H₂DCFDA as well as p67^phox (major NADPH oxidase component) expression (Tsuboi et al., 2018). Spermidine is a polyamine compound that can be found in soybeans, mushrooms, green peas, nuts, and leafy vegetables. Through various in vivo and cohort studies it was discovered that spermidine could increase telomere length and enhance the activity of telomerase enzymes (Schellnegger et al., 2024). Moreover, half a year administration of spermidine in the drinking water of aged mice reduced any age-associated phenotype (Wirth et al., 2021). Although the exact protective mechanism of this compound remains unclear, it is theorized that this spermidine-mediated anti-ageing effect is due to increase in telomere length, thereby proposing a novel cellular mechanism behind this ability of spermidine. Two omega-3 fatty acids, 5, 8, 11,14,17—eicosapentaenoic acid and linoleic acid predominantly found in Walnuts, soybean oil, canola oil, nuts, oily fish, flaxseed, corn oil, safflower oil demonstrated telomerase activity augmentation and telomere length elongation by providing anti-inflammatory and antioxidant effects. The molecular mechanism of the provided antioxidant and anti-inflammatory effects was TERT miRNA-mediated through an increase in SOD activity and a decrease in IL-6 levels, respectively (Jacczak et al., 2021; Ogłuszka et al., 2022; Kiecolt-Glaser et al., 2011).

Oleic acid is a potent telomerase inhibitor as it competitively binds to the substrate primer of telomerase (Bartoszewska et al., 2024). A mono-unsaturated 16–20 carbon long chain having cis configuration is needed to induce such activity. Among all the configurations, oleic acid having an 18-carbon long chain had the strongest inhibitory action with an IC₅₀ of 8.6 μM (Chen et al., 2011). (Z)-stellettic acid C is reported to be selectively cytotoxic against human cancer cells. An experiment done on U937 cells showed that the compound decreases the activity of telomerase most effectively at a concentration of 30 μg/mL without altering the expressions of hTERT mRNA and TEP-1 and other necessary factors involved in the transcription of c-Myc and hTERT—Sp-1 (Bartoszewska et al., 2024). Phenolic acids prevent the bond formation between c-Myc and Sp1 and specific sites of hTERT responsible for regulatory activity which further decreases hTERT levels and therefore ultimately inhibits telomerase (Chen et al., 2020a).

5.7. Polysaccharides

Polysaccharides are a class of compounds with long chains of carbohydrate molecules. Foods rich in carbohydrates such as potatoes, rice, peas, corn, grains, banana, onion, and papaya are the main sources for polysaccharides. Polysaccharides can have multidirectional pharmacological effects such as antioxidant effects and improving immunity. A study conducted on subacute aging model mice demonstrated the telomerase-activating ability of polysaccharides by reducing free radicals and causing subsequent lengthening of telomeres (Jacczak et al., 2021). Moreover, polysaccharides found in Cistanche deserticola can directly affect telomeres by increasing telomerase activity in heart and brain tissues on a study performed on aged mice (Li et al., 2014). Evodiamine is an alkaloid that can be found in the dried fruit of the Evodia rutaecarpa (Juss.) Benth plant. This compound has multiple pharmacological properties that could control or prevent cellular aging such as anti-inflammatory, antioxidant and anti-aging ability. In a study based on higher glucose level induced endothelial cell senescence, evodiamine increased telomere length and telomerase activity by enhancing SIRT1 gene expression, which is responsible for enhanced telomerase activity (Wang et al., 2023a). Evodiamine can also indirectly impact telomerase activity and telomere length by targeting PHK1/NRF2 signaling pathway to inhibit oxidative stress, demonstrated on a study based on traumatic brain injury (TBI) caused by controlled cortical shock (Bollong et al., 2018). Thereby, reducing telomere length erosion. Axinelloside A contains a large amount of sulfur and is shown to inhibit the telomerase activity having an IC₅₀ value of 2 mg/ml. However, the precise mechanism by which the inhibition occurs is yet to be elucidated (Chen et al., 2011). CFP 2 is a derivative of lichen that decreased telomerase functions and caused cell death which led to decreased viability of HL-60 and K562 cancer cells in experimental studies (Chen et al., 2020a; WA E, 2021).

5.8. Lignans

Arctigenin is a lignan that can be found in Fructus arctii plant. This compound is a potent antioxidant that can modulate the length and activity of telomere and telomerase respectively. This ability was found in a study based on lifespan and juglone-induced oxidative stress assay with RT-PCR. Here, using Caenorhabditis elegans as a model, the potential antioxidant and free radical scavenging ability of arctigenin are apparent (Mechchate et al., 2022). Due to being a potent antioxidant compound, this reduces oxidative stress on telomere length, thus preventing them from shortening. 7′-hydroxy-3′,4′,5,9,9′-pentamethoxy-3,4-methylene dioxy lignan is a telomerase inhibitor which acts as an inducer in the activation of caspase 8 and caspase 3 and suppresses bcl2, a mechanism that is crucial in cell apoptosis (Siu, 2011). Arctigenin is also shown to restrict telomerase activity at times (Mechchate et al., 2022).

5.9. Alkaloids

Evodiamine is an alkaloid that can be found in the dried fruit of the Evodia rutaecarpa (Juss.) Benth plant. This compound has multiple pharmacological properties that could control or prevent cellular aging such as anti-inflammatory, antioxidant and anti-aging ability. In a study based on higher glucose level induced endothelial cell senescence, evodiamine increased telomere length and telomerase activity by enhancing SIRT1 gene expression, which is responsible for enhanced telomerase activity (Wang et al., 2023a). Research demonstrates that evodiamine can indirectly protect telomeres by targeting the PHK1/NRF2 signaling pathway. A study on traumatic brain injury (TBI) induced by controlled cortical impact showed that this mechanism reduces oxidative stress. By mitigating this cellular damage, evodiamine helps slow the erosion of telomere length (Bollong et al., 2018). Berberine is an alkaloid present in barberry, oregon grape, goldenseal, goldthread, tree turmeric and poppy. Samad et al., studied its effect on telomerase and their findings demonstrated inhibitory action on telomerase and thus, decreased telomere length in colon cancer cells, HCT 116 by delaying the cell cycle and doubling the time (Samad et al., 2021). Cephalotaxus alkaloids inhibit the regulation of hTERT in transcriptional and posttranscriptional stages (Bajaj et al., 2020). In addition, they also suppress the synthesis of proteins, and its C3-ester derivatives induce apoptosis by inhibiting the activity of telomerase. Similar action has been observed with HHT and harringtonine along with down regulating the transcription of hTERT (Chen et al., 2011). Berbamine is shown to inhibit the telomerase activity in HL‐60 human leukemia cancer cells and this inhibition occurs as it stabilizes the structure of G-quadruplexes by strongly interacting with G-quadruplexes rather than bonding with duplex DNA (Bajaj et al., 2020; Chen et al., 2011). Cryptolepine is a moderate telomerase inhibitor having an IC₅₀ value of 9.4 μM as it interacts with G-quadruplexes although the mechanism of such interaction is not clear (Chen et al., 2011). Dictyodendrins bind with metal cations, particularly Cu²⁺ to form reactive compounds that affect the cellular mechanisms in various ways and thus can inhibit telomerase through several different mechanisms. Furthermore, its sulfate containing derivatives exhibited more potent inhibitory actions rather than the desulfated ones (Somani and Patel, 2016). Ascididemin and Meridine are G-quadruplex stabilizers and this stabilization hinders TERC to recognize the overhang of the telomeres which are single-stranded and unfolded which restricts the telomerase functionality (Chen et al., 2011; Trybek et al., 2020). The IC₅₀ values of these two compounds are reported to be > 80 μM for ascididemin and 11 μM for Meridine, respectively (Chen et al., 2011). Papaverine has telomerase inhibitory activity with IC₅₀ value of 60 μM as shown in HepG-2 cells due to reduced expression of hTERT (Bajaj et al., 2020; Noureini and Wink, 2014). Sanguinarine chloride binds directly to hTERT and thus acts as a telomerase inhibitor by directly impacting telomerase/hTERT. Prolonged exposure to this compound results in telomere shortening and inhibited cell growth, ultimately inducing cellular senescence. This process is characterized by the upregulation of telomere dysfunction-induced foci (TIFs) and activation of the p16/p21/p53 pathways. Consequently, cells accumulate and show increased activity of senescence-associated β-galactosidase (SA-β-gal), a recognized marker of senescent cells (Yan et al., 2022). Inhibitory actions of Vinorelbine against telomerase was seen in the lung cancer Anip973 cell line where it induced cell death. Suppressed level of hTERT is considered to be the cause behind this inhibitory action (Bajaj et al., 2020). Boldine exhibited cytotoxicity in the cell line of T24, U87, MGC6, U138‐MG and HepG‐2 in a time and dose dependent manner. Boldine restricted telomere lengthening via an unclear mechanism. However, it may be possible that Boldine produced shorter hTERT‐mRNA by cutting the hTERT- mRNA during their immature phase which makes it nonfunctional and therefore reduces the level of hTERT (Chen et al., 2020a). The carbon in the unsaturated ring and conjugated aromatic ring structure of Palmatine with positively charged nitrogen ions at center is responsible for its anti-telomerase activity. It stimulates G4 formation and increases its stability which accelerates differentiation of cells or cell aging (Chen and Zhang, 2016).

5.10. Proteins

The Fungal Immunomodulatory Protein (FIP-gts) suppresses telomerase by targeting hTERT at multiple levels. Research shows it reduces both hTERT mRNA and protein levels. When produced recombinantly in E. coli (reFIP-gts), this protein demonstrates selective anti-cancer activity against A549 lung cancer cells. It operates through a c-Myc-responsive mechanism to downregulate hTERT expression, resulting in reduced telomerase activity and inhibition of cancer cell proliferation (Badria and Aboelmaaty, 2019). reFIP-gts localizes in the endoplasmic reticulum (ER) of A549 cancer cells and increases ER stress that increases the level of ER stress markers like CHOP/GADD153. This causes release of calcium in A549 cancer cells which lead to suppression of telomerase (Chen and Zhang, 2016). Furthermore, it also reduced the phosphorylation of hTERT, another crucial mechanism behind its anti-telomerase activity (Badria and Aboelmaaty, 2019). Cells treated with Glycoprotein LJPG were shown to have decreased levels of hTERT along with c-Myc and SP1 in a dose-dependent manner therefore downregulating telomerase activity in these cells (Han et al., 2011). Mistletoe Lectin showed apoptotic activity in cell lines of Hep3B (p53-negative) and SK-Hep-1 (p53-positive) and a suppressed telomerase activity through a pathway that is controlled by mitochondria unaffected by p53. It further removes the phosphorus from Akt survival signaling cascade and activates the caspase-3 and downregulates hTERT therefore decreasing telomerase activity as shown in A253 cell lines (Chen and Zhang, 2016).

5.11. Quinones

Shikonin and its derivatives N‐acetyl glucosaminosides exhibited strong anti-telomerase activity by showing strong binding affinity to G4 complex (Bajaj et al., 2020). β-lapachone selectively inhibits DNA topoisomerase I. In studies conducted on leukemia cell lines including K562, THP-1, U937, and HL-60, treatment with β-lapachone resulted in cytotoxicity and apoptosis. This effect occurred due to impaired telomerase function and reduced expression of hTERT. Additionally, it aids in the actively cleaves caspase-3 and poly (ADP-ribose) polymerase (Bartoszewska et al., 2024). It also downregulates the expression of c-Myc and hTR, contributing more to its telomerase inhibitory actions (Chen and Zhang, 2016). Telomerase activity was reduced in HL60 cells that were treated were treated with salvicine at 10 μM that proved its antitumor potential (Bartoszewska et al., 2024). The compound therefore restricts telomerase functions and induces cell death.

5.12. Miscellaneous

Withanolides are a group of compounds that can be classified as steroidal lactones and can be found in nature from Withania somnifera (L.) Dunal plant that is commonly known as ashwagandha or Indian ginseng. This compound can increase telomerase activity at the same time, reducing DNA damage induced by H₂O₂ on human HeLa cells (Jacczak et al., 2021). Ashwagandha extracts contain withanolides as a key component, and it can enhance telomerase activity by 45 % in cells treated with 10–50 μg of Ashwagandha root extract (Raguraman and Subramaniam, 2016). L-carnitine is a quaternary ammonium compound with potent anti-aging effect. The main dietary sources for this compound are legumes such as beans and peas. Also, nuts, seeds, soybeans, and eggs. In an in vitro study conducted on cardiac differentiated bone marrow resident CD117+ stem cells, L-carnitine significantly increases hTERT gene expression in cardiac differentiated bone marrow CD117+ stem cells, mRNA and protein expression via Wnt3/β-catenin and ERK1/2 signaling pathway components (Fathi et al., 2020). Moreover, in L-carnitine treated adipose tissue-derived mesenchymal stem cells, the hTERT gene expression and telomere length significantly increases (Farahzadi et al., 2018). Thujaplicin or isopropyl cycloheptatrienolone mainly refers to three isomeric tropolone-related phytochemicals that are mainly found in plants of the Cupressaceae family such as Reynoutria japonica Houtt. In a study of myotubular insulin resistance model induced by palmitic acid, thujaplicin increases the telomere length by inducing SIRT1 promoter activity (Fumiaki et al., 2012). Moreover, thujaplicin demonstrates its antioxidant ability by modulating the NRF2 signaling pathway and by inhibiting HIF-1α/NOX4 in human retinal epithelial cell injury (Wang et al., 2023b). Antioxidants are said to reduce telomere length erosion by mitigating the erosion rate (Pineda-Pampliega et al., 2020). Lutein is carotenol that is one of the two major carotenoids found in the human eye. Kale, spinach, peas, lettuce, broccoli, egg yolks, einkorn, wheat, corn, and yellow-orange fruits are all dietary sources rich in lutein. Lutein demonstrated increase in leukocyte telomere length proportionately with its concentration on cross-sectional cohort study performed on the Australian population (Abdel-Aal et al., 2013; Borras et al., 2012). Lutein primarily acts as an antioxidant to reduce the oxidative damage to telomere, thereby maintaining its length. Increased levels of carotenoid can cause longer telomere length (Min and Min, 2016). Thereby, lutein also has a positive effect on telomere length. They are a group of phytochemicals that are derived from cholesterol. They are a key component of the Cynanchum bungei plant. Other sources of this compound include fungi and marine algae. On an aging mouse model, via increasing SOD activity and providing protection against telomere length erosion, steroidal glycosides can contribute significantly to maintain telomere length (Jacczak et al., 2021). The antioxidant ability of these compounds contributes to enhancing telomerase activity. Natural compounds, alpha and beta-pinene belonging to pine pollen showed association with telomerase activity and telomere length modulation in human lung embryonic fibroblasts and human diploid fibroblasts 2BS cells. Cell population was increased due to this modulation via delayed replicative senescence and reversed expression of senescence-associated molecular markers, such as p53, PTEN, and p27 (Kip1). These two compounds were promising as antiaging agents and retarded age-related diseases (Jacczak et al., 2021; Mao et al., 2012).

Other than the mentioned classes of compounds that negatively modulate telomere and telomerase activity, there are various other telomerase inhibitors. Research demonstrates that allicin, an organosulfur compound from garlic (Allium sativum), induces telomere shortening in fibroblasts by reducing telomerase activity. The mechanism involves downregulation of the anti-apoptotic protein Bcl-2 and overexpression of the pro-apoptotic factors Fas and BAX. These effects are mediated through secondary messengers including cAMP and protein kinase C (PKC), components of the cellular secondary signaling system (Akter et al., 2021; Jacczak et al., 2021; Sun, 2003). Gambogic acid, a xanthone that naturally occurs in Garcinia hanburyi, showed a significant association with telomerase activity and telomere length modulation. Gambogic acid produced its anti-telomerase activity and decreased telomere length in various human cancer cells such as breast cancer, leukemia, lung cancer, pancreatic cancer, gastric carcinoma, and hepatoma via depletion in the activity of hTERT gene by downregulation of hTERT via inhibition of transcription activator c-myc. Aromatic polyketides, beta- and gamma-rubromycins extracted from Streptomyces colinus potentially suppressed telomerase activity and resulted in telomere length shortening in a modified TRAP assay. These compounds bind to telomerase competitively with respect to the substrate primer, particularly to the hTR and/or TERT subunits and decreased its action. In the same study purpuromycin, a naphthoquinone antibiotic isolated from Actinoplanes ianthinogenes demonstrated potent telomerase inhibition and subsequent telomere length erosion. Chrolactomycin, an antibiotic isolated from Streptomyces spp. 569N-3 showed anti-telomerase activity in a yeast strain-based novel assay causing telomere shortening. This compound caused irreversible inhibition of telomerase through covalent bond formation of exo-methylene group present in it with sulfhydryl group of a cysteine residue close to the active site of telomerase by acting as Michael acceptor. Diazaphilonic acid, an azaphilone isolated from Talaromyces flavus, exhibited complete telomerase inhibition and shortening of telomere length at 50 mM concentration in the TRAP assay performed previously. Furthermore, alterperylenol (orange red pigment) obtained from Alternaria spp. demonstrated selective inhibition of telomerase activity and length shortening in the TRAP assay and the enone group present in its structure was responsible for this inhibition. Several studies have reported telomestatin to have the ability to bind with d[T2AG3]4 which is a telomeric sequence specific for humans and is highly selective for G-quadruplex structures as well as intermolecular bonds. Telomere attrition takes place due to these G-quadruplex structures being weak substrates of telomerase. Furthermore, telomestatin also induces uncapping of telomeres by dissociating POT1 and TRF279 which are binding proteins specific for telomeres, making it a potent telomerase inhibitor (Chen et al., 2011). The IC₅₀ value of this compound is 760 nM according to in vitro studies (Man et al., 2016). Sinefungin, a naturally occurring nucleoside analogue, inhibits telomerase recruitment through a specific molecular mechanism. It functions by depleting trimethylguanosine synthase 1 (TGS1). This depletion leads to the production of telomeric 3′ overhangs, a process mediated by Exonuclease 1. These overhangs being unprotected by telomerase take part in the activation of Alternative Lengthening of Telomeres (ALT) pathway that is recombinant driven and is dependent on RAD51 protein (Buemi et al., 2022). Oxoisoaporphine directly binds to the enzymes of telomerase and reduces its activity (Bartoszewska et al., 2024). Docking experiments showcased the compound interacting to the active sites of telomerase like Ade 150, Cyt 149 and Cyt 148 (Bajaj et al., 2020). Indole-3-carbinol is proven to be a potent telomerase inhibitor as it decreased the expression of hTERT mRNA in cell lines of prostate cancer. The potency is increased when it works as a combination with diethylstilbestrol (DES) that increases telomerase inhibition significantly, viability to cells and expression of genes (Fragkiadaki et al., 2022). Butylidenephthalide treated cells were seen to have reduced expression of hTERT mRNA without altering hTR RNA (Lin et al., 2011). In addition, it also downregulated TERT and decreased telomerase activity in human glioblastoma cell lines which resulted senescent tumor cells (Fan et al., 2019). Crocin and its derivatives, specially Crocin-1 have multiple pharmacological effects including cell signaling, formation of adenosine triphosphate (ATP), regulation of oxidation and reduction reactions along with lowering telomerase functionality that was experimented on HepG2 cells (Bartoszewska et al., 2024). This inhibitory action may be due to the decreased expression of hTERT gene which is the catalytic subunit of telomerase (Veisi et al., 2020). Dideoxypetrosynol A has been reported to exert cytotoxic actions against multiple cancerous cell lines, one of which is U937 where this compound downregulated the expression of hTERT mRNA at a concentration of 0.6 μg/mL. Other than this, the compound showed no activity towards TEP-1, hTERT and c-myc mRNA. Trichostatin A deacetylases histone protein acting as an inhibitor for Histone Deacetylase (HDAC) is shown to be responsible in decreasing the level of hTERT mRNA gene at a concentration of 75 nM without effecting the level of TEP-1 in U937 cell line (Bartoszewska et al., 2024). Therefore, it acts as a blocker of hTERT gene and stimulates Mitotic Arrest Deficient 1 (Mad1) and Mothers Against Decapentaplegic Homolog 3 (Smad3) expression level (Chen et al., 2020a). Pectenotoxin-2 prevents the expression of hTERT along with c-Myc and SP1 which hinders them from binding to the regulatory regions of hTERT. Additionally, through dephosphorylation of Akt cascade, it reduces the nuclear translocation and phosphorylation of hTERT resulting in decreased telomerase activity. This inhibitory action was displayed in multiple cancer cell lines including HL-60, U937 and THP-1 (Bartoszewska et al., 2024). Coloratum agglutinin inhibits telomerase activity although the mechanism is yet to be explored (Chen et al., 2020a). Diallyl disulfide (DADS) was shown to hinder the SP1 and c-Myc to bind to their designated sites on hTERT that caused lower levels of hTERT which in turn reduced the activity of telomerase in U937 cell lines. These transcription factors are cleaved due to treatment with DADS which causes the inactivation. In addition to that, an overexpression of a repressor protein termed as Mad1d was seen in the treated cells (Dasgupta and Bandyopadhyay, 2015). Verbascoside causes cell death by halting the G2/M phase of cell cycle and therefore inhibiting the growth of cells. It also leads to telomere shortening and reduces telomerase functionality (Ganesan and Xu, 2018). Rubropunctatin halts telomerase activity via an unclear mechanism of action (Chen et al., 2020a).

Fig. 3 illustrates the key molecular pathways through which various natural compounds exert telomerase activation or inhibition, highlighting the contrasting signaling mechanisms and targets involved in telomere regulation.

Fig. 3.

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

6. Challenges

6.1. Limitations of current evidence

Current evidence for plant-derived compounds that affect telomere length or telomerase activity remains limited. This is primarily due to a lack of large-scale human clinical trials that are specifically designed with telomere-related measurements as their primary objective. Most studies are in vitro or animal experiments, limiting direct clinical inference (Vaiserman and Krasnienkov, 2021). A handful of clinical studies (e.g., TA-65/astragalus-based interventions) report changes in immune aging markers and/or telomere indices, but sample sizes are modest, follow-up is short, and outcome measures vary- hindering meta-analytic synthesis (de Jaeger et al., 2024; Bawamia et al., 2023; Salvador et al., 2016). There is also substantial heterogeneity in telomere measurement methods (e.g., qPCR, TRF, Flow-FISH) with differences in precision, accuracy, and cross-platform agreement, complicating cross-study comparisons and pooled analyses (Lai et al., 2018; Verhulst et al., 2015; Pearce et al., 2021). In clinical contexts, Flow-FISH often shows superior diagnostic reproducibility compared with qPCR for leukocyte telomere length, underscoring the need for assay harmonization in trials (Lai et al., 2018). The limitations in study design further weaken the conclusions. Many studies use intervention periods that are too short to detect meaningful changes in telomere length. They also frequently involve small sample sizes and lack standardized endpoints and blinding/reporting rigor (Lai et al., 2018; Lindrose et al., 2020). In vitro studies often depend on effects seen only in specific cell lines. They sometimes use concentration much higher than what would be found in the human body. This raises valid questions about how well these findings translate to real human exposure, a common limitation noted in reviews of telomere research (Vaiserman and Krasnienkov, 2021). Furthermore, lifestyle and demographic factors are often inconsistently accounted for in these studies. Variables such as physical activity, smoking status, sleep patterns, age, and sex are each independently linked to telomere metrics. When these confounders are not properly adjusted for in the analysis, they can introduce bias into the observed effects of an intervention (Chen et al., 2024; Barragán et al., 2021; Galiè et al., 2020). Future trials should be adequately powered and longer-term, adopt harmonized telomere/telomerase assays (with cross-platform calibration), rigorously control confounding, and predefine clinically meaningful outcomes, enabling robust synthesis and translational clarity.

6.2. Conflicting findings and research gaps

• i.Dose-context reversals: Many plant-derived compounds exhibit a dual nature. At low concentrations in healthy cells, they often activate pathways like PI3K/Akt or ERK to support telomerase function. In contrast, at higher doses or in cancerous environments, the same compounds typically suppress telomerase by repressing key regulators such as c-Myc, Sp1, and ETS, or by stabilizing G-quadruplex DNA structures. This dose-dependent and context-specific behavior, observed with compounds like resveratrol and EGCG, represents a genuine biological complexity rather than experimental inconsistency. These findings highlight the need for systematic dose-response studies across comparable cellular models (Ramlee et al., 2016; Sharma and Chowdhury, 2022).
• ii.Telomerase activity vs telomere length: Research often reveals a mismatch between TRAP-measured telomerase activity and actual changes in telomere length, particularly in short-term studies. This discrepancy highlights that telomere maintenance involves separate processes with different timings. These include the regulation of hTERT gene expression and the physical protection of telomere ends from damage. Consequently, studies should simultaneously measure telomerase activity, telomere length, and markers of telomere dysfunction to get a complete picture (Lai et al., 2018).
• iii.Promoter-centric vs post-translational control: Research findings often point to different mechanisms for telomerase regulation. Some studies indicate that regulation happens primarily at the genetic level, through the regulation of the hTERT promoter by pathways like ERK-ETS or factors like c-Myc/Sp1. Other evidence highlights the importance of post-translational events, such as the AKT-mediated phosphorylation of the shelterin protein TRF1, which stabilizes the telomere complex. Relying on a single type of measurement can therefore lead to an incomplete or incorrect conclusion about whether a compound activates or inhibits telomerase. A more accurate assessment requires studies that simultaneously examine promoter activity, the movement of hTERT into the nucleus, and the dynamics of the shelterin complex (Bejarano et al., 2019; Ramlee et al., 2016).
• iv.Immune-system variation: Chronic inflammation, driven by JAK/STAT signaling, is widely recognized for promoting cellular senescence and telomere shortening. However, the biology is more complex, as STAT3 can also activate hTERT expression under certain conditions. Furthermore, a telomerase-independent mechanism, where telomeres are physically transferred from antigen-presenting cells to T cells, can also prolong T-cell lifespan. This complexity means that interpreting results from immunology studies requires careful consideration. Therefore, clinical trials should incorporate detailed immune cell analysis alongside standard measurements of telomere length and telomerase activity (Lanna et al., 2022; Jin and Huang, 2023).
• v.ALT pathway and telomere dysfunction markers: Many investigations operate on the assumption that telomerase is the primary regulator of telomere length. However, in some cellular models, outcomes are actually driven by ALT pathways or the accumulation of TIFs. To resolve apparent contradictions such as when telomere length remains stable despite clear signs of genomic stress, studies should incorporate specific ALT markers, like ALT-associated PML bodies (APBs), alongside assays for TIFs. This integrated approach provides a more complete picture of telomere maintenance and health (Sharma and Chowdhury, 2022).
• vi.Exposure and target engagement: Current research rarely connects realistic human intake levels of compounds with their direct effects on key cellular pathways. For instance, it is often unclear whether a dietary exposure actually activates the ERK-ETS pathway at the hTERT promoter or induces the phosphorylation of the telomere protein TRF1 in normal human cells. Future studies need to integrate measurements of compound levels in the body (biomarkers and pharmacokinetics) with direct assessments of pathway activity and functional telomere outcomes within a single experimental design (Bejarano et al., 2019; Ramlee et al., 2016).
• vii.Priority study designs: To move the field from associative observations to mechanistic understanding, researchers should implement comprehensive factorial experiments. These studies would systematically test the interaction of dosage, cell type, and specific pathway perturbations such as inhibiting MEK or AKT, or knocking down STAT3. The experiments must measure all relevant endpoints: telomere length, telomerase activity, and markers of telomere damage. Following this, adequately powered human trials using standardized laboratory methods are essential to translate these mechanistic insights into clinically relevant evidence.

6.3. Pharmacokinetic variability

Although phytochemicals like flavonoids, polyphenols, saponins, terpenoids etc. play crucial role in the regulation of telomerase and hold potential for anti-aging formulations, it becomes quite a challenge due to their chemical and molecular properties. For example, a study assessing the pharmacokinetic parameters of tea catechins (epicatechin gallate (ECG), epicatechin (EC) and epigallocatechin gallate (EGCG)) in rats found extreme low values of absolute bioavailability-0.06 %,0.39 % and 0.14 % respectively which might be a result of wide tissue distribution, high first pass effect and slow absorption (Zhu and Chen, 2000). Similarly, quercetin suffers from low solubility, poor permeability which limits its bioavailability in humans, making it less suitable for clinical formulations (Cai et al., 2013). Polyphenols such as resveratrol, EGCG, and quercetin are rapidly conjugated in the intestine and liver by glucuronidation and sulfation, which leads to fast clearance, short plasma half-life, and very low circulating levels of the parent bioactive form. Extensive first-pass metabolism and phase II conjugation are consistently reported for green tea catechins like EGCG and for resveratrol, limiting systemic exposure despite high in vitro potency (Hayashi et al., 2022). Resveratrol in particular shows rapid metabolism and a very short half-life in humans, and exhibits strong dose-dependent behavior (hormesis), where low concentrations can have adaptive/pro-survival effects and higher concentrations become cytotoxic or anti-proliferative. This biphasic response complicates dose selection for clinical use (Calabrese et al., 2010). Reduced permeability is another barrier. Many triterpenoid saponins and related telomerase-active molecules are large, amphipathic, and poorly lipid soluble, so they cross the intestinal epithelium inefficiently and show very low oral bioavailability. These same compounds can also interact with cell membranes and even cause hemolysis at higher concentrations, which narrows their safe therapeutic window. Such permeability and safety issues significantly limit direct oral translation without formulation changes (Salman et al., 2025). Basic, highly polar longevity candidates such as L-carnitine, L-citrulline, and polyamines like spermidine tend to distribute preferentially to aqueous compartments and are cleared quickly by the kidney, which means tissue exposure may be transient. Sustained telomerase modulation in target tissues would likely require controlled delivery systems or repeated/high-frequency dosing to overcome rapid renal elimination (Rajapaksha et al., 2024).

Again, medicinal and pharmaceutical industries face significant challenges like less purity, limited yield and complex sources when utilizing terpenoids (Câmara et al., 2024). Saponins cause hemolysis and are less permeable and less likely to absorb in the GI tract due to their higher molecular weight, extensive hydrogen bonding capacity and molecular flexibility (Ma et al., 2024; Paarvanova et al., 2023). Phenolic compounds like gallic acid are subjected to poor bioavailability as they are affected by digestive enzymes and gastrointestinal pH (Qin et al., 2022). After absorption, many polyphenols are immediately acted on by intestinal and hepatic enzymes (UGTs, SULTs) and by efflux transporters (for example P-glycoprotein/ABCB1, MRP2/ABCC2, and BCRP/ABCG2). These transporters actively pump phytochemicals and their conjugates back into the intestinal lumen or bile, further reducing effective exposure (Fan et al., 2023; Kikuchi et al., 2022; Martins-Gomes and Silva, 2023). Astragaloside IV and its deglycosylated derivative cycloastragenol (commercially formulated as TA-65) can activate telomerase and have been linked to telomere length maintenance in lymphocytes and improved immune cell senescence markers in small human studies. However, both show limited oral bioavailability due to poor intestinal absorption and extensive metabolism, so relatively high oral doses or specialized formulations are required (Salvador et al., 2016; Singaravelu et al., 2021). Alkaloids such as berberine has extremely poor absorption rate (<1 %) and due to its chemical structure, it is less soluble in aqueous solution and cannot easily pass the through the lipid membranes of the cells in the intestine (Zieniuk and Pawełkowicz, 2025). Proteins get hydrolyzed and degraded when subjected to GI enzymes and pH which makes them biologically inactive (Hammer et al.; Zhu et al., 2021).

6.4. Standardization difficulties

Natural telomerase modulators face high batch-to-batch variability driven by genotype/chemotype, plant part, harvest season, and post-harvest processing, which alters marker and co-factor profiles and complicates dose equivalence across studies. Recent quality-control reviews emphasize building specs that account for this natural variation rather than treating botanicals like single-entity APIs (Wang et al. 2023a). Standardization requires fit-for-purpose authentication (voucher specimens, DNA barcoding) and orthogonal chemical fingerprinting (e.g., HPLC/UPLC-MS ± NMR) with similarity metrics to verify identity and composition across lots (Noviana et al., 2022). Use of reference materials and validated methods (e.g., NIST/USP reference standards; AOAC-validated assays) is recommended to anchor potency and impurity limits and to enable cross-laboratory comparability (van Breemen, 2015; Hosbas et al., 2021). Regulatory bodies and pharmacopeias now emphasize the need for comprehensive system specifications, not just a single marker. These specifications should include the drug-extract ratio (DER), solvent system, plant part used, and critical process parameters. This detailed approach helps prevent “therapeutic drift,” where a product's effectiveness changes over time (Upton et al., 2024). For clinical trials, experts recommend predefining the botanical product's identity, purity, strength, and composition. It is also critical to document analytical comparability between different production lots. The bioassays used in the trial should directly align with the proposed mechanism of action. For instance, an ERK-ETS reporter assay would be appropriate if studying hTERT transcription (Koonrungsesomboon et al., 2024). Furthermore, many active compounds, particularly polyphenols, can degrade or undergo epimerization during storage and handling. To ensure that the nominal dose consistently delivers a comparable amount of active compounds, stability-indicating methods must be part of the product specifications. This may involve the use of antioxidants or pH control to maintain product integrity up to the point of use (Chen et al., 2020b; Xie et al., 2021).

7. Current update on formulation

Many phytochemicals such as quinones are less stable in formulations as they produce reactive oxygen species (de Oliveira et al., 2025). Such limitations, backed by the overall challenges of phytochemicals, have made their formulation very difficult. Lipid-based carriers like liposomes, niosomes, solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) etc. have been studied for the encapsulation and effective delivery of the phytocompounds. Liposomes can be used for the loading of both hydrophobic and hydrophilic compounds but the capacity of drug loading is low and are less chemically stable. They might be prone to leakage or degradation and need to be stabilized or PEGylated (Ranjbar et al.). Several studies have highlighted their efficacy in encapsulating quercetin and displayed anti-tumor properties, kidney-protective activity leading to lower progression of diabetic neuropathy (Jing et al., 2022; Tang et al., 2020). Niosomes are liposomes analogues that are lower in cost and are made from nonionic surfactants that offer more stability than liposomes. They have successfully been employed in encapsulating flavonoids and produced better solubility, antibiotic and antioxidant properties (Ranjbar et al.; Yang et al., 2020). SLNs contain a solid lipid core and have displayed a high encapsulation efficiency (∼89 %) along with enhanced oral absorption. However, storage problems due to drug expulsion and poor drug loading capacity can be seen in case of SLNs (Han et al., 2022). NLCs are a lipid system that produce structural imperfections in the solid core by incorporating liquid lipid into the lipid matrix. They provide sustained drug release and an increased bioavailability as seen in NLC loaded with oxyresveratrol (177 % more bioavailability compared to unformulated oxyresveratrol) (Han et al., 2022; Sangsen et al., 2015). In addition, phytosomes are also used for better absorption and bioavailability of phytocompounds which are complexes made with phytochemicals and phospholipids. Many commercial phytosome formulations are available for example, grape seed phytosome, quercetin phytosome, silybin and green tea phytosome that have showcased cardioprotective, antioxidant and hepatoprotective activity. Furthermore, a clinical trial with a combination of dasatinib and quercetin phytosome is in phase 2 (NCT04313634) (Ranjbar et al.). Moreover, hydrogels (chitosan-coated nanohydrogels) and nanoformulations based on protein have shown to be effective in the encapsulation of both hydrophilic and lipophilic compounds like caffeine and curcumin under simulated gastric environment (Helal et al., 2019). Other delivery system like mesoporous silica can be loaded with polyphenol effectively and preclinical studies are being done to deliver resveratrol and curcumin for sonotherapeutics (Joma et al., 2024). In addition to the mentioned systems, dendrimers have also shown improved anticancer properties when used for the delivery of both curcumin and resveratrol together and produced an enhanced and synergistic effect as compared to unformulated compounds (Vieira et al., 2023). Although studies are being done on the development of new formulation systems to overcome the challenges associated with phytocompounds, more clinical trials under controlled conditions are required for these to be more commercially acceptable.

8. Conclusion

Telomere biology has emerged as a central focus in aging research, with telomere shortening and telomerase dysfunction recognized as key contributors to cellular senescence, tissue degeneration, and age-related disease onset. Plant-derived compounds, encompassing diverse classes such as polyphenols, flavonoids, triterpenoid saponins, polysaccharides, lignans, alkaloids, carotenoids, amino acids, and fatty acids, exhibit notable capacity to modulate telomere length and telomerase activity through multiple molecular pathways. The present review synthesizes evidence indicating that these natural products exert their effects via antioxidant activity, regulation of gene expression (e.g., hTERT, SIRT1, c-Myc), modulation of key signaling cascades (e.g., PI3K/Akt, JAK/STAT, ERK), and stabilization or destabilization of telomeric structures such as G-quadruplexes.

Several compounds, including resveratrol, epigallocatechin gallate, astragaloside IV, cycloastragenol, and ginsenoside Rg1, have demonstrated bidirectional or context-dependent effects on telomerase activity, underscoring the importance of concentration, cellular context, and disease state in determining biological outcomes. While in vitro and in vivo findings highlight promising telomere-protective or telomerase-inhibitory potential, translational advancement remains limited by variability in extract composition, bioavailability constraints, and a scarcity of robust human clinical trials. The therapeutic implications are twofold: telomerase activation and telomere length maintenance may hold value in delaying physiological aging and mitigating degenerative diseases, whereas telomerase inhibition offers a strategy for targeting cancer cells dependent on telomere elongation for survival. Balancing these opposing strategies demands precise characterization of pharmacodynamics, safety profiles, and long-term effects.

Future research should prioritize standardized extract preparation, dose-response characterization, and integration of pharmacokinetic data to improve reproducibility and translational potential. Moreover, clinical studies employing validated telomere length measurement techniques and longitudinal designs are needed to substantiate preclinical observations. Given the intersection of telomere dynamics with oxidative stress, inflammation, and genomic stability, plant-derived compounds represent a versatile and promising avenue for the development of safe, multi-targeted interventions in aging and age-associated disorders. Harnessing their full potential will require a coordinated effort to bridge molecular insights with clinical applicability.

CRediT authorship contribution statement

Raushanara Akter: Conceptualization, Supervision, Writing– original draft. Adwiza Chakraborty Bishakha: Writing– original draft, Writing – review & editing. Raisha Rajib: Writing – original draft. Asef Raj: Supervision, Writing – original draft, Writing – review & editing. Mashwiyat Samrin Roja: Writing – original draft. Fouzia Noor: Writing – original draft.

Funding declaration

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Declaration of competing interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Data availability

No data was used for the research described in the article.