Terpenoids as Emerging Senotherapeutics: Mechanistic Insights and Therapeutic Potential

Abstract

Cellular senescence, characterized by stable cell cycle arrest, drives organismal aging and functional decline. Senescent cells (SnCs) increase in multiple tissues with age and contribute to pathology by resisting apoptosis, impairing regeneration, and releasing senescence-associated secretory phenotype (SASP) factors. Senotherapeutics, including senolytics and senomorphics, aim to reduce the impact of SnCs by selectively clearing SnCs or suppressing SASP production. Natural terpenoids are structurally diverse plant- and fungus-derived metabolites with antioxidant, anti-inflammatory, and cytoprotective properties. Growing evidence supports their ability to counteract senescence-associated phenotypes, including senescence-associated β-galactosidase (SA-β-gal) activity and the expression of p53, p21, and p16. In this review, we examine mono-, sesqui-, di-, and triterpenoids that modulate cell cycle regulation, SASP attenuation, redox homeostasis, mitochondrial function, autophagy, and apoptosis-related mechanisms. We also outline the principal pathways underlying these anti-senescence activities and highlight natural terpenoids as emerging modulators of cellular senescence.

1. Introduction

Cellular senescence refers to persistent and irreversible cell cycle arrest triggered by diverse forms of cellular stress, accompanied by macromolecular damage, secretory features, and altered metabolism [1]. Cellular senescence is typically promoted by multiple factors, including DNA damage, oxidative stress, and ionizing radiation [2], and is widely recognized as a hallmark of organismal aging that contributes to the decline in physical function [1,3].

During aging, senescent cells (SnCs) progressively accumulate across multiple organs. SnCs adopt an enlarged and flattened shape, often displaying an accumulation of lysosomal and mitochondrial contents [4]. Beyond their morphological changes, SnCs exhibit a pro-inflammatory secretory profile known as the senescence-associated secretory phenotype (SASP) [5]. SASP factors comprise not only inflammatory cytokines and chemokines but also enzymatic regulators, such as matrix metalloproteinases (MMPs) and serine/cysteine proteinase inhibitors (SERPINs) [5]. This secretory repertoire is highly context-dependent, with its molecular signatures tailored to the cell type and stress source.

Sustained secretion of SASP molecules induces inflammaging, which disrupts tissue remodeling, the immune system, and homeostatic control [6]. Furthermore, once stem cells and progenitor cells undergo cell cycle arrest, they fail to replenish damaged tissues, thereby impairing the regenerative capacity of the organs [5]. Thus, cellular senescence plays a leading role in the onset and progression of various age-related diseases, such as cardiovascular disease, obesity, type 2 diabetes, pulmonary fibrosis, and sarcopenia [7,8].

Notably, genetic or pharmacological clearance of SnCs significantly enhanced physical function and extended lifespan in aged mice [9,10,11,12,13]. Hence, therapeutic interventions against SnCs have gained prominence as a compelling strategy for retarding aging and delaying the onset of age-related pathologies. Senotherapeutics are agents that target and eliminate or modulate SnCs to mitigate the aging process. They are categorized based on their strategy: senolytics focus on the selective elimination of SnCs through apoptosis, whereas senomorphics/senostatics aim to neutralize the SASP without inducing cell death [14,15].

To validate whether senotherapeutics attenuate the SnCs phenotype, various cellular senescence markers have been identified [2,4,15]. SnCs universally exhibit elevated activity of senescence-associated beta-galactosidase (SA-β-gal), the most widely used biomarker of senescence. Cell cycle inhibitors, including p53, p21^WAF1/CIP1, p16^INK4a, and RBs, are established molecular markers that directly induce and maintain cellular senescence. In contrast, SnCs feature a lack of Ki67 and PCNA, the cell proliferation markers. In addition, SnCs harbor unrepaired DNA damage, which is identified by distinct foci arising from the accumulation of phosphorylated H2AX (γ-H2AX), 53BP1, and MDC1 at the damage sites. The loss of Lamin B1, a protein that supports the nuclear envelope, is also a key characteristic of aged cells. Senescence status can be evaluated by measuring SASP factors at the mRNA and protein levels as well [2,4,15].

While SnCs maintain survival even in damaged or harsh environments, targeting the specific mechanisms that allow them to evade apoptosis can exert potent senolytic activity. Senolytics targeting antiapoptotic pathways, specifically through the inhibition of the BCL-2 family (ABT-263 and ABT-737) [16,17], p53/MDM2 (UBX0101 and RG7112) [18,19], and HSP90 (17-DMAG, 17-AAG, and geldanamycin) [20] have been discovered. Meanwhile, compounds such as metformin [21], rapamycin [22], and sirtuin activators [23] have been reported to exhibit senomorphic effects by downregulating p38 MAPK, NF-κB, JAK/STAT, and mTOR signaling pathways [14], which are key factors driving excessive SASP production.

Conventional small-molecule senolytic drugs have often been hindered in their clinical application by systemic toxicity and adverse effects. For example, ABT-263 (navitoclax) may trigger severe thrombocytopenia [24], and patients with idiopathic pulmonary fibrosis treated with dasatinib and quercetin (D + Q) exhibited a higher incidence of mild side effects (unwellness, cough, nausea, fatigue, weakness, and headache) than those in the placebo group [25]. Considering these limitations, the use of natural compounds as senotherapeutics has emerged as a promising intervention to counteract the senescent cell burden and its pathological consequences.

Phytochemicals with senotherapeutic activity have been extensively explored in polyphenolic classes, including fisetin [26], quercetin [27], EF-24 (a curcumin analog) [28], o-vanillin [19], kaempferol [29], apigenin [29], and luteolin [30]. In this context, multiple reviews have reported the senolytic or senomorphic activities of polyphenols [31,32,33]. In contrast, terpenoids remain relatively underexplored as senotherapeutics; however, their potential anti-senescence activity may be inferred from mechanistic parallels with polyphenols [34,35]. Accumulating evidence indicates that terpenoids can modulate the core features of senescence, including cell cycle arrest, SASP production, mitochondrial dysfunction, and oxidative stress [36]. Accordingly, a dedicated review integrating evidence across terpenoid subclasses, senescence models, and molecular pathways is warranted to define the senotherapeutic relevance of the relatively underexplored compound class. In this review, we aimed to delineate the current findings to define the anti-senescence potential of terpenoids and provide a mechanistic framework for their action as senotherapeutic candidates.

2. Senotherapeutic Effects of Terpenoids

Terpenoids, chemically diverse compounds, represent a large class of plant secondary metabolites. They are biosynthesized from five-carbon isoprene units and can be commonly classified as mono-(C10), sesqui-(C15), di-(C20), and tri-(C30) terpenes, based on their carbon number [37]. Although terpenoids originate from simple units, their structures are highly diverse due to elongation and cyclization. The structural diversity of terpenoids enables them to interact with multiple molecular targets, contributing to their wide range of biological activities [38]. Ample evidence from both in vitro and in vivo studies has shown that terpenoids can alleviate cellular senescence. This section provides a comprehensive overview of terpenoids in aging, with a particular focus on cellular senescence. The effects of terpenoids are pleiotropic, and they regulate senescence markers both directly and indirectly (

Table 1. Senotherapeutic activity of terpenoids.

Compound	Senescence and Aging Models	Senescence Markers	Effects and Mechanisms	Ref.
Monoterpenoids
Limonene	UVB-irradiated HaCaT cells	p53 ↓ MMP2 ↓	Activation of Nrf2 via JNK/SAPK and AKT phosphorylation	[39]
	D-galactose-induced Swiss albino mice	IL-6, IL-1β, TNF-α ↓	Attenuation of epidermal thinning Inhibition of NF-kB activation	[40]
Thymol	H2O2-induced MSCs	SA-β-Gal ↓ p53, p16, RB2 ↓ pSRC/SRC ↓	Induction of caspase-independent apoptosis via AIF translocation	[35]
	SAMP8 mice	Epigenetic age ↓	Suppression of NF-kB and IL-6/JAK/STAT3 signaling	[41]
	tert-Butyl hydroperoxide-treated KGN cells	SA-β-Gal ↓ p53, p21, p16 ↓	Inhibition of JAK1/STAT3 signaling	[42]
Carvacrol	H2O2-induced MSCs	SA-β-Gal ↓ γ-H2AX ↓ p53, p21, p16, p27, RB2 ↓	Induction of caspase-dependent apoptosis	[35]
Eugenol	H2O2-induced MSCs	SA-β-Gal ↓ γ-H2AX ↓ p53, p21, p16, p27, RB2 ↓ pSRC/SRC ↓	Induction of caspase-independent apoptosis via AIF translocation	[35]
Sesquiterpenoids
Dihydroartemisinin	H2O2-induced NIH3T3 cells	SA-β-Gal ↓ p53, p21, p16 ↓ PTGS2 ↑	Initiation of autophagy-dependent ferroptosis via the AMPK/mTORC1 pathway	[43]
	R848-treated myeloid-derived suppressor cells	SA-β-Gal ↓ p53, p21, p16 ↓ IL-1β, IL-6, IL-8, TNF-α ↓	Activation of the Nrf2/HO-1 pathway Protective effect against systemic lupus erythematosus manifestations	[44]
	Pristane-induced lupus BALB/c mice
	TNF-α-induced nucleus pulposus cells	SA-β-Gal ↓ p21, p16 ↓ IL-1β, IL-6, IL-8, MMP3, MMP9 ↓ IL-10 ↑	Inhibition of the NF-kB pathway induced by TNF-α Suppression of PI3K/AKT signaling	[45]
	Puncture-induced rats	p16 ↓ IL-6, MMP13 ↓	Attenuation of intervertebral disc degeneration onset and progression
	Renal ischemia/reperfusion injury surgical model ICR mice	SA-β-Gal ↓ γ-H2AX ↓ p21, p16 ↓ CDK4, Cyclin D1 ↑ Il6, Il8, Tnf, Cxcl1 ↓	Induction of autophagic flux in renal tubular epithelial cells	[46]
	Unilateral ureteral obstruction model ICR mice
	Blood-induced murine primary chondrocytes	SA-β-Gal ↓ p53, p21, p16 ↓ MMP3, MMP13 ↓	Activation of the Nrf2 signaling pathway in cartilage by enhancing Keap1 ubiquitination and Nrf2 translocation	[47]
	F8-/- hemarthrosis C57BL/6J mice	p16 ↓ MMP13 ↓	Alleviation of cartilage hemarthrosis through Nrf2/Keap1 signaling Attenuation of subchondral bone loss
Handelin	UVB-induced HaCaT cells	p38, ERK1/2 ↓ MMP2, MMP9 ↓	Inhibition of p38 MAPK phosphorylation	[48]
	TNF-α induced C2C12 myotube	Il6, Il1b, Tnf, Cxcl1 ↓ p65 ↓	Activation of AKT-mTORC1 signaling Suppression of NF-kB pathway	[49]
	LPS-induced C57BL/6 mice		Activation of IGF-1/AKT signaling Alleviation of skeletal muscle loss and atrophy through Hsp70 activation
β-caryophyllene	C. elegans	Lipofuscin ↓	Longevity promotion mediated by skn-1 and sir-2.1	[50]
	Replicative senescent HUVECs	p16INK4a ↓ IL1B, IL6, TNF ↓ miR-146a, miR-21 ↓	Induction of SIRT1 expression Mitigation of inflammaging	[51]
	LPS-stimulated THP-1 monocytic cells
Diterpenoids
Ginkgolide B	H2O2-induced C2C12 myoblast	SA-β-Gal ↓ γ-H2AX ↓ Cdkn1a, Cdkn2a, Trp53 ↓ Il6, Ifn-γ ↓	Suppression of Runx1 expression in muscle Mitigation of age-related muscle wasting by restoring miR-27b-3p levels	[52]
	Naturally aged C57BL/6 female mice	γ-H2AX ↓ Cdkn2a, Cdkn2d, Cdkn1c ↓ Il6, Ifng ↓
	BaCl2-induced C57BL/6 mice	Il1b, Tnf, Tgfb1 ↓	Reactivation of osteocalcin-GPRC6A signaling Enhancement of muscle regeneration	[53]
Oridonin	Cisplatin-induced A549 cells	SA-β-Gal ↓ p21, p16 ↓	Induction of senolysis via ROS-activated p38 signaling	[54]
	Bleomycin-induced BJ cells	IL-6, IL-8, CCL20 ↓	Downregulation of NF-kB Inactivation of p38 pathway	[55]
	Doxorubicin-induced WI-38, 2BS cells	SA-β-Gal ↓ p53, p21 ↓ Il1a, Il1b, Il6, Il8 ↓	Inhibition of the AKT-mediated FOXO1 phosphorylation Suppression of NLRP3 inflammasome	[56]
Tanshinone IIA	High glucose-induced HPMCs	SA-β-Gal ↓ p21, p16 ↓	Prevention of cell cycle arrest and telomere shortening	[57]
	H2O2-induced HUVECs	SA-β-Gal ↓ p21, p16 ↓	Activation of the SIRT1/eNOS axis	[58]
Sodium tanshinone IIA sulfonate	High glucose-treated primary endothelial cells	SA-β-Gal ↓ p21 ↓ IL-1β, IL-18 ↓	Inhibition of the NF-κB pathway and NLRP3 inflammasome activation Attenuation of vascular senescence	[59]
	High glucose-treated VSMCs
	High glucose-induced endothelial progenitor cells	SA-β-Gal ↓ γ-H2AX ↓ p21 ↓ IL-1β ↓	Inhibition of the NLRP3 inflammasome via RAGE-TXNIP pathway	[60]
Andrographolide	HFD-fed C57BL/6 mice	SA-β-Gal ↓ p53, p21, p16 ↓ Il6, Il1a, Il1b, Cxcl10 ↓ Mmp9 ↓	Activation of AMPK signaling in the kidney Mitigation of renal fibrosis	[61]
	Palmitic acid-induced HK-2 cells	SA-β-Gal ↓ p53, p16 ↓	Alleviation of mitochondrial damage
	Dexamethasone-induced BMSCs	SA-β-Gal ↓ p53, p21, p16 ↓	Promotion of osteogenic differentiation via PI3K/AKT activation	[62]
	Dexamethasone-induced C57BL/6 mice	p53, p21, p16 ↓	Attenuation of bone loss in femurs
Triterpenoids
Ginsenoside Rg1	HSPCs co-cultured with D-galactose-induced BMSCs	SA-β-Gal ↓ p53, p21 ↓ IL-1β, IL-6, TNF-α ↓	Suppression of TLR2/NF-κB signaling via TLR2 receptor binding	[63]
	hBM-MSCs from aged donors	SA-β-Gal ↓ p53, p16 ↓	Suppression of WNT/β-catenin signaling via inhibition of GSK-3β phosphorylation	[64]
	D-galactose-induced BM-MSCs	SA-β-Gal ↓ p53, p21, p16 ↓ γ-H2AX ↓ Il1b, Il6, Mmp3, Mmp12 ↓	Activation of the Nrf2 pathway via p62- mediated KEAP1 degradation	[65]
	D-galactose-induced C57BL/6J mice		Elevation of Nrf2 nuclear translocation in heart, liver, and lung tissues
	H2O2-induced ADSCs	SA-β-Gal ↓ p21, p16 ↓ γ-H2AX ↓ IL1B, IL6, TNF ↓	Activation of the PI3K/AKT signaling pathway to restore stemness	[66]
	D-galactose-induced NSCs	SA-β-Gal ↓ p53, p21, p16, RB ↓	Downregulation of the AKT/mTOR signaling pathway in neural stem cells	[67]
	D-galactose-induced C57BL/6 mice
	D-galactose-induced NSCs	SA-β-Gal ↓ p53, p21, p16 ↓ Il1a, Il6, Tnf, Tgfb1, Ccl5 ↓	Activation of the SIRT1/Nrf2/BDNF signaling pathway in both primary neural stem cells and hippocampal tissue	[68]
	D-galactose-induced C57BL/6 mice
	Paraquat-induced MLE-12 cells	SA-β-Gal ↓ p21, p16 ↓ Il1b, Il6, Tnf, Mmp3, Mmp9, Mmp13 ↓	Promotion of autophagy via ATG12 induction and activation of caspase-3 in both MLE-12 cells and lung tissue	[69]
	Paraquat-induced C57BL/6 mice
	Sugen/hypoxia-induced rats	p21, p16 ↓ IL-6 ↓	Inhibition of the cGAS/STING signaling pathway in lung tissue	[70]
	SAMP8 mice	SA-β-Gal ↓ IL-1β, TGF-β1 ↓	Inhibition of NLRP3 inflammasome in renal cortex and glomerular tissue	[71]
	D-galactose-induced C57BL/6J mice	SA-β-Gal ↓ p53, p21 ↓	Inhibition of caspase-1 activity in kidney tissue	[72]
	D-galactose-induced C57BL/6J mice	SA-β-Gal↓ p53, p21↓ IL-1β, IL-6, CCL2 ↓	Inhibition of FOXO1 phosphorylation to induced SOD and catalase production in liver tissue	[73]
	High glucose-induced rat retinal ganglion cells	SA-β-Gal ↓ p53, p21, p16 ↓ Lamin B1 ↑	Restoration of mitochondrial function by promoting PGC-1α transcription via VDR/cAMP/PKA/CREB signaling axis	[74]
Astragaloside IV	Replicative senescent or LPS/MPP+-induced primary astrocytes	SA-β-Gal ↓ p16 ↓ Lamin B1 ↑ Il1a, Il1b, Il6, Cxcl1, Mmp3, Mmp9 ↓	Restoration of PINK1/Parkin to induce mitophagy in primary astrocytes	[75]
	MPTP-induced mice
	Bleomycin-induced VSMCs	SA-β-Gal ↓ p21, p16 ↓ DcR2 ↓	Activation of Parkin to induce mitophagy in both VSMCs and aorta tissue	[76]
	D-galactose-induced BALB/c mice
	UVA radiation-induced PC12 and primary neuronal cells	SA-β-Gal ↓ p21, RB ↓ CDK2 ↑	Activation of the ERK signaling pathway in both primary cortical neurons and cerebral cortex tissue	[77]
	UVA radiation-induced C57BL/6 mice
	Oligomerized Aβ-induced primary human astrocytes	SA-β-Gal ↓ p53, p21, p16 ↓	Inhibition of HSP90AA1 protein levels to disrupt stabilization of pro-survival molecules	[78]
	H2O2-induced RAW264.7 cells	SA-β-Gal ↓ p53, p21, p16 ↓ Il6, Tnf ↓	Inhibition of STING/NF-κB signaling pathway	[79]
	BMSCs treated with senescent macrophage conditioned medium
	NaIO3-induced ARPE-19 cells	SA-β-Gal ↓ p53, p21 ↓ γ-H2AX ↓ Il1b, Il6 ↓	Destabilization of IL-1β mRNA via FTO- mediated m6A modification in both ARPE-19 cells and retinal tissue	[80]
	NaIO3-induced C57BL/6J mice
	Isoproterenol-induced C57BL/6J mice
Celastrol	H2O2, Adriamycin, or HG-induced HUVECs and NIH3T3 cells	SA-β-Gal ↓ p21, p16 ↓	Inhibition of HSC70-Bim-CHIP complex to disrupt ubiquitination of pro-apoptotic Bim protein	[81]
	Bleomycin or CCl4-induced IPF C57BL/6 mice		Activation of caspase-3 to eliminate SnCs in lung and liver tissues
	Doxorubicin-induced 786-O and A498 cells	SA-β-Gal ↓ p53, p21, p16 ↓ IL-6, IL-8, CXCL12 ↓	Downregulation of caveolin-1 expression to suppress the p53/p21Waf1/Cip1 pathway in clear cell renal cell carcinoma	[82]
	Subcutaneous ccRCC xenograft C57BL/6J mice
	High glucose-induced HK-2 cells	SA-β-Gal ↓ CDKN1A, CDKN2A ↓ IL1B, CCL2, TNF ↓	Inhibition of the AKT/NF-κB/TNF-α signaling pathway in both HK-2 cells and kidney tissue	[83]
	Streptozotocin-induced SD rats
	Replicative senescent human primary astrocytes and MRC-5 cells	SA-β-Gal ↓ IL-6 ↓	Antagonization of p53 by elevating Δ133p53α protein levels	[84]
	Angiotensin II-induced primary rat VSMCs	SA-β-Gal ↓ p53, p21 ↓	Induction of autophagy through inhibition of the PI3K/AKT/mTOR signaling pathway	[85]
Ganoderic acid A	Replicative senescent IMR90 cells	SA-β-Gal ↓ p53, p21, p16, Cyclin D1 ↓ γ-H2AX ↓ IL-6 ↓	Maintenance of ribosomal homeostasis and biogenesis by stabilizing TCOF1 phosphorylation via direct binding	[86]
	H2O2, Etoposide, or CX-5461-induced HUVECs
	Naturally aged or IR-induced C57BL/6J mice		Upregulation of the ribosomal pathway in heart and lung tissues
	Aβ25-35-induced HT22 cells	SA-β-Gal ↓ p21, p16 ↓ HMGA1 ↓	Upregulation of PADI4 to suppress AKT/mTOR signaling and enhance autophagic flux	[87]
Ganoderic acid D	H2O2-induced hAMSCs	SA-β-Gal ↓ p21, p16 ↓	Modulation of CaM/CaMKII/NRF2 signaling through 14-3-3ε interaction	[88]
	D-galactose-induced ICR mice		Promotion of Nrf2 nuclear translocation by elevating 14-3-3ε expression in bone marrow stem cells
	H2O2-induced hAMSCs	SA-β-Gal ↓ p21, p16 ↓	Activation of the PERK/Nrf2 signaling pathway	[89]
Cycloastragenol	Etoposide-induced IMR90 cells	SA-β-Gal ↓ p53, p21, p16 ↓ Il6, Cxcl5, Cxcl10 ↓	Inhibition of BCL-2 family, PI3K/AKT/mTOR, p38 MAPK/NF-κB, and JAK/STAT3 signaling pathways in both IMR90 cells and inguinal adipose tissue	[90]
	Irradiation-induced C57BL/6 mice
	5xFAD-induced C57BL/6J mice	SA-β-Gal ↓ Cdkn1a, Cdkn2a ↓	Inhibition of PDE4B to activate CREB/BDNF signaling and promote microglial phagocytosis of SnCs	[91]
	High glucose-induced rat NPCs	SA-β-Gal ↓ p16 ↓	Upregulation of TERT expression	[92]
Oleanolic acid	5-Fluorouracil-induced HUVECs and NCM460 cells	SA-β-Gal ↓ TP53, CDKN1A ↓ p16 ↓ IL1B, IL6, IL8, IFNG, TNF ↓	Inhibition of mTOR signaling pathway in both NCM460 cells and colon tissue	[93]
	5-Fluorouracil-induced BALB/c mice
	Bleomycin-induced HDFs and MEFs	SA-β-Gal ↓ p16 ↓ IL-1β, IL-6, IL-8 ↓	Inhibition of IGF-1 expression and PI3K/AKT/mTOR signaling pathway	[94]
	oxLDL-induced fli1a::EGFP+ zebrafish	SA-β-Gal ↓	Inhibition of JNK/MAPK pathway in zebrafish endothelial cells	[95]
Betulinic acid	Replicative senescent or etoposide-induced HDFs	SA-β-Gal ↓ CDKN1A ↓	Suppression of IFN-inducible genes through downregulating IRF9 expression	[96]
	D-galactose-induced HK-2 cells	SA-β-Gal ↓ p53, p21 ↓ IL-6, TGF-β1 ↓	Inhibition of BCL-2 family, PI3K/AKT/mTOR, p38 MAPK/NF-κB, and JAK/STAT3 signaling pathways in both IMR90 cells and inguinal adipose tissue	[97]

↓ indicates a decrease in expression and ↑ indicates an increase in expression.

).

2.1. Monoterpenoids

2.1.1. Limonene

Limonene is a monocyclic monoterpenoid abundant in the essential oils of citrus fruits and other aromatic plants. Owing to its high-quality fragrance, limonene is widely used as an additive in food and cosmetic product formulations. In addition, it possesses diverse bioactive properties, including anti-inflammatory, antioxidant, antitumorigenic [98], and neuroprotective effects [39]. In particular, the robust radical-scavenging activity of D-limonene confers its potential as a preventive and therapeutic agent, particularly for skin aging.

Limonene protects the skin from UVB exposure by reducing reactive oxygen species (ROS) generation. Pretreatment with limonene in human keratinocyte HaCaT cells activated PI3K/AKT signaling and induced nuclear translocation of Nrf2, thereby enhancing the Nrf2-mediated antioxidant defense system (Figure 1). Limonene also inhibited p53 phosphorylation, suppressed α-MSH secretion, and protected the skin barrier against photodamage [39]. In addition, limonene treatment counteracts the initiation and progression of aging-associated skin damage [40]. Six weeks of limonene treatment in a D-galactose-induced skin aging mouse model enhanced antioxidant defense by restoring superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities, suppressed inflammation, and thereby attenuated epidermal thinning. The expression of pro-inflammatory cytokines, including TNF-α, IL-1β, and IL-6, was significantly reduced through the inhibition of NF-κB activation and p38 MAPK signaling [40]. Limonene also inhibited collagenase and elastase activities, which contribute to the loss of skin structural integrity and wrinkle formation, and suppressed MMP expression, thereby delaying skin aging [99].

Moreover, limonene has been reported to increase the lifespan of C. elegans. Limonene (5 μM) achieved maximum lifespan, increasing lifespan by 17.9%. It promoted longevity by scavenging ROS, activating DAF-16 (a FOXO ortholog), and upregulating stress resistance-related genes, such as sod-3, daf-2, and hsp-70 [100]. Given that the DAF-16/FOXO transcription factor is evolutionarily conserved, evaluating the effects of limonene in more complex animal models would be of considerable interest and may provide further insight into its potential to promote longevity across species.

2.1.2. Thymol, Carvacrol, Eugenol

Monoterpenoids exhibit a wide range of biological activities, particularly antioxidant and anticancer activities [101]. Among these, three essential oil–derived compounds, thymol, carvacrol, and eugenol, have recently emerged as potential senotherapeutics. Despite their structural differences, these compounds engage in somewhat similar mechanisms involving oxidative stress and apoptosis.

In H₂O₂-induced senescent human mesenchymal stromal cells (MSCs), thymol, carvacrol, and eugenol promoted senescent cell death without affecting healthy MSCs by triggering ROS-dependent mitochondrial apoptosis [35]. Thymol, carvacrol, and eugenol inhibited SRC signaling, which drives cell cycle progression from G1/G0 arrest to S phase and activates the G2/M transition, thereby shifting cell fate from senescence to cell death. In addition, these compounds increased the expression of pro-apoptotic factors, including BAX and cytochrome c, and enhanced intrinsic apoptotic signaling. Mechanistically, treatment with these compounds elevated intracellular ROS levels in SnCs beyond the level that can be effectively managed by the cellular antioxidant system, leading to destabilization of mitochondrial integrity [35]. Glutathione treatment attenuated this terpene-induced apoptosis, supporting the notion that oxidative stress is a key driver of SnCs elimination [35]. Although all three compounds achieve senolysis, they differ in the specific molecular mechanisms through which senescent cell death is induced. Carvacrol induces canonical caspase-dependent apoptosis, characterized by the activation of caspase-3, whereas thymol and eugenol rely on a caspase-independent pathway that induces nuclear translocation of apoptosis-inducing factor [35].

Beyond their senolytic activity, thymol exerts geroprotective effects. Thymol extended the healthspan of C. elegans and suppressed epigenetic aging in skeletal muscles [41]. Chronic treatment with thymol (20 mg/kg/day) for 12 weeks increased the myofiber cross-sectional area and improved physical performance in the SAMP8 mouse model, supporting its potential as a therapeutic candidate for preventing sarcopenia. Thymol also transiently reduced the mitochondrial membrane potential and induced a stress response, triggering a mitohormetic response through PINK-1 signaling [41]. In addition, thymol delays ovarian aging and preserves granulosa cell function by inhibiting JAK1/STAT3 signaling (Figure 1). Thymol inhibited JAK1 phosphorylation and reduced the expression of senescence markers p53, p21, and p16 in t-BHP-induced KGN cells. Moreover, thymol treatment increased estradiol levels and exerted beneficial effects on reproductive outcomes in aged mice [42]. Collectively, these findings position the herbal monoterpenes thymol, carvacrol, and eugenol as promising agents for mitigating cellular senescence.

2.2. Sesquiterpenoids

2.2.1. Dihydroartemisinin

Dihydroartemisinin, the primary active metabolite of artemisinin, exhibits enhanced bioavailability and potency compared with its parent compound and has been widely investigated for its antimalarial, antitumor [102], antioxidant [103], and anti-inflammatory properties. Earlier studies revealed that dihydroartemisinin induces cancer cell death through ferroptosis [104], and subsequent studies have shown that this ferroptosis-promoting ability is also observed in SnCs, indicating that dihydroartemisinin functions as a senolytic agent. Dihydroartemisinin treatment in H₂O₂-induced senescent (SA-β-gal–positive) NIH3T3 cells activates ferroptosis, thus inducing selective cell death [43]. Mechanistically, dihydroartemisinin activates AMPK and suppresses mTOR phosphorylation, thereby promoting autophagy (Figure 1). Enhanced autophagy accelerates ferritin degradation and increases intracellular Fe²⁺ levels while concurrently inhibiting the key ferroptosis-protective system, Gpx4. Pharmacological inhibition of either autophagy or ferroptosis attenuated dihydroartemisinin-mediated clearance of SnCs, supporting the notion that dihydroartemisinin eliminates SnCs via autophagy-dependent ferroptotic mechanisms. SnCs exhibit elevated intracellular iron levels due to impaired iron homeostasis, rendering them more sensitive to dihydroartemisinin-dependent ferroptosis. In addition, treatment with dihydroartemisinin (50 mg/kg) extended the lifespan of naturally aged mice by 15.8%, further verifying its anti-aging effects in vivo [43].

Dihydroartemisinin has also been reported to alleviate cellular senescence across multiple tissues and exert protective effects against diverse diseases [44,45,46,47]. Dihydroartemisinin reversed myeloid-derived suppressor cells senescence through the upregulation of the Nrf2/HO-1 pathway and suppressed the progression of systemic lupus erythematosus, a chronic autoimmune disease [44]. In addition, dihydroartemisinin ameliorated TNFα–induced senescence in nucleus pulposus cells and improved extracellular matrix metabolism [45], supporting its therapeutic potential in intervertebral disc degeneration (IDD). Likewise, dihydroartemisinin improved Pfirrmann grade, which is a standard classification system used to evaluate the severity of IDD and delayed degenerative changes in a puncture-induced rat IDD model. Intraperitoneal administration of dihydroartemisinin at 40 mg/kg every other day significantly lowered the Pfirrmann score and restored the interrupted boundary between annulus fibrosus and nucleus pulposus [45]. These protective effects on IDD were mediated through the suppression of PI3K/AKT and NF-κB signaling (Figure 1). Dihydroartemisinin directly binds to PI3K and inhibits downstream pathways, thus attenuating the progression of IDD.

In an ischemia/reperfusion-induced renal aging model, dihydroartemisinin reversed premature senescence of renal tubular epithelial cells through the enhancement of autophagic activity and improved renal histopathology [46]. Dihydroartemisinin treatment significantly reduced SASP factors and alleviated necrosis and fibrosis progression in the kidney. It also increased the expression of Klotho, an anti-aging protein that counteracts the accumulation of SnCs [105]. Furthermore, dihydroartemisinin attenuated chondrocyte senescence and associated arthropathy both in vitro and in vivo, with chondroprotective effects mediated by the activation of the Keap1–Nrf2 axis [47]. Dihydroartemisinin induced the ubiquitination and degradation of Keap1 and increased the expression of antioxidant genes, thereby regulating cellular senescence.

Collectively, dihydroartemisinin exhibits multifaceted senotherapeutic effects across different models. While dihydroartemisinin selectively induces autophagy-dependent ferroptosis in senescent NIH3T3 cells, it attenuates senescence-associated phenotypes in renal, cartilage, and intervertebral disc degeneration models, thereby mitigating the development of age-related diseases. Given that dihydroartemisinin is an FDA-approved drug with low toxicity in normal cells and exhibits selective vulnerability to SnCs, dihydroartemisinin holds strong potential as a senolytic agent.

2.2.2. Handelin

Handelin is a bioactive compound derived from Chrysanthemum indicum L. (wild chrysanthemum), which has traditionally been used to treat inflammatory diseases. A water extract of C. indicum L. was shown to attenuate UV irradiation-induced skin aging, and handelin was identified as one of the bioactive compounds mediating this protective effect. C. indicum L. extract significantly reduces ROS levels and protects HaCat cells from photoaging by inhibiting p38 MAPK activation (Figure 1) [48].

Handelin supplementation (50 μM) extended the lifespan of C. elegans by 19%, exhibiting longevity-promoting effects comparable to that of metformin [106]. It also improved motility and pharyngeal pumping, which are phenotypes for improving healthspan. These longevity effects are accompanied by a decline in intracellular ROS levels, and the gene expression of gst-5, gst-33, stdh-2 and F12E12.11 was markedly upregulated following 8 days of handelin feeding [106]. The gst-5 and gst-33 are known to encode glutathione S-transferases and are involved in ROS detoxification, while F12E12.11 is predicted to exhibit NAD-dependent oxidoreductase activity. In addition, handelin contributes to the reversal of mitochondrial dysfunction. Handelin supplementation increased mtDNA copy number, improved mitochondrial morphology, and enhanced mitochondrial biogenesis during aging in worms [106]. Similarly, in 23-month-old mice, intraperitoneal administration of handelin for one month increased muscle redness and upregulated mitochondrial biogenesis genes, including Pgc1α, Mfn1, Drp1, and Tfam1 [49].

Furthermore, handelin is effective in maintaining skeletal muscle integrity and preventing muscle atrophy. In TNF-α–treated C2C12 myotubes, handelin increased the expression of MyoD, myogenin, and myosin heavy chain, and directly enhanced myogenic differentiation by promoting the IGF-1/AKT pathway. Handelin also suppressed TNF-α-induced NF-κB activation, attenuated the inflammatory response, and consequently, mitigated muscle atrophy. These findings were further supported by in vivo evidence, as daily handelin administration increased skeletal muscle mass, downregulated Fbxo32, and restored the NAD level of tibialis anterior muscle in aged mice [49]. Notably, the protective effects of handelin against age-associated muscle dysfunctions were abolished by the Hsp70 inhibitor VER-155008, suggesting that Hsp70 mediates the beneficial effects of handelin on mitochondrial function and muscle health [49,107]. Combining these findings, Handelin delays aging through multiple mechanisms and may have therapeutic potential for aging-related conditions, including sarcopenia.

2.2.3. β-Caryophyllene

β-Caryophyllene is a naturally occurring sesquiterpene found in the essential oils of various plants, including cinnamon, oregano, and black pepper. As a phytocannabinoid, it selectively activates cannabinoid receptor type 2 and exerts diverse bioactive properties. Beyond its anti-inflammatory, antioxidant, and anticancer properties [108,109,110], β-Caryophyllene has recently emerged as a potential geroprotective agent.

β-Caryophyllene treatment increased the lifespan of C. elegans by 22% while reducing intracellular ROS levels [50]. Mechanistic analyses revealed that the pro-longevity effects of β-Caryophyllene are mediated by skn-1 and sir-2.1, corresponding to mammalian Nrf2 and SIRT1, respectively. Lifespan extension was abolished in skn-1 and sir-2.1 mutants but retained in daf-16 mutants, indicating that β-Caryophyllene primarily engages in detoxification and stress resistance pathways rather than the canonical insulin/IGF-1 signaling. In addition, β-Caryophyllene reduced lipofuscin accumulation, which increases with aging, and decreased the pharyngeal pumping rate in worms, thereby promoting longevity in a dietary restriction (DR)-like manner [50].

Additionally, β-Caryophyllene restrained SASP expression in both replicative and drug-induced senescent human umbilical vein endothelial cells, as well as in LPS-induced THP-1 monocytes. While β-Caryophyllene alone effectively reduced the gene expression of pro-inflammatory cytokines, including IL1B, IL6, and TNF, and restored SIRT1 levels, this effect is synergistically enhanced when combined with resveratrol and curcumin. Furthermore, β-caryophyllene modulated microRNA expressions, downregulating inflamma-miRs (miR-146a, miR-21) and upregulating miR-126, which plays a critical role in maintaining vascular homeostasis [51]. These findings suggest that β-Caryophyllene suppresses inflammaging, which is exacerbated by the spread of inflammation to the surrounding tissues, and exerts a protective effect against endothelial senescence.

2.3. Diterpenoids

2.3.1. Ginkgolide B

Ginkgolide B (GB), an active compound derived from Ginkgo biloba, is known to exert various health-promoting effects. GB has been reported to modulate inflammation and apoptosis and block oxidative stress [111], with accumulating evidence supporting its potential to promote longevity. Chronic oral administration (12 mg/kg) of GB prolonged the median lifespan of aged female mice (>20 months) by 8.5% and increased the maximal lifespan by approximately 50 days. In addition, GB markedly improved multiple healthspan parameters, including muscle strength, physical performance, frailty index, and metabolic indicators. At the molecular level, GB reduced the secretion of several SASP factors, including p16, p57, IL-6, and IFN-γ, in various tissues [52]. These findings suggest that Ginkgolide B exerts strong geroprotective effects.

Ginkgolide B also exerts a critical influence on muscle regeneration. In aged mice, GB treatment increased skeletal muscle mass and myosin heavy chain–positive area and reversed age-associated impairment of muscle function. Importantly, GB activated osteoblasts to restore osteocalcin levels to those observed in young mice and promoted muscle regeneration by stimulating the bone–muscle axis [53]. Endurance exercise in aged mice facilitates muscle repair by increasing IL-6 release from myocytes, which in turn enhances osteocalcin secretion. Similarly, GB enhanced osteocalcin–GPRC6A signaling and promoted myogenesis, supporting its potential role as an exercise mimetic [53]. Single-nucleus RNA sequencing analyses revealed that GB directly modulates aging-related pathways within the skeletal muscle and restores aging-associated transcriptional changes, including alterations in cell-type composition. GB downregulated Runx1, a factor that promotes cellular senescence through its interaction with p53, and reduced the formation of Runx1⁺ type 2B myonuclei, which accumulate with age [52]. Mechanistically, GB enhanced miR-27b-3p levels, thereby directly suppressing Runx1 and attenuating muscle degeneration.

These findings position Ginkgolide B as a promising senotherapeutic. GB effectively mitigates late-life aging and associated functional decline while preserving muscle integrity by restoring osteocalcin signaling. Given that musculoskeletal health is important for overall health and longevity in elderly individuals and is strongly associated with mortality, GB may provide a therapeutic avenue for promoting healthy aging.

2.3.2. Oridonin

Oridonin, an active diterpenoid isolated from the medicinal herb Rabdosia rubescens, has been widely studied for its anti-inflammatory, antitumor, and antioxidant activities [112,113,114]. Oridonin was then identified as a novel senolytic compound through a screening of 18 bioactive ingredients of the Traditional Chinese Medicine library [54]. Senolytic activity was evaluated by comparing the viability of senescent and non-senescent cells using cisplatin-induced senescent A549 cells, and oridonin exhibited the most potent activity, with a ratio of 0.54. Activity-based protein profiling further identified GSTK1 as a direct target of oridonin [54]. Oridonin inhibits GSTK1 and increases cellular susceptibility to oxidative stress, leading to a marked increase in intracellular ROS levels. This, in turn, activates p38 signaling and downstream apoptotic pathways, ultimately promoting senolysis.

Effects of oridonin were further validated in various aging models. Oridonin attenuated SASP expression in bleomycin-induced BJ cells by inhibiting p38 phosphorylation and NF-κB p65 activity [55]. In doxorubicin-induced senescent WI-38 cells, oridonin significantly reduced the proportion of SA-β-gal-positive cells and cell cycle markers, in addition to SASP suppression [56]. In addition, monthly administration of oridonin extended the average lifespan of aged mice by 9.8% and improved both performance and memory function. These anti-aging effects are mediated by the AKT/FOXO1 pathway, as oridonin inhibits AKT activation and reduces p21 expression [56]. Altogether, these findings highlight the potential of oridonin as a senotherapeutic compound capable of targeting SnCs and mitigating age-related decline.

2.3.3. Tanshinone IIA/Sodium Tanshinone IIA Sulfonate

Tanshinone IIA (TSA) is a diterpenoid quinone extracted from the medicinal herb Salvia miltiorrhiza, widely used to treat cardiovascular disorders. TSA is known to protect vascular function from inflammation and oxidative stress [115], and recent studies have demonstrated that TSA also exerts anti-senescent effects, particularly in hyperglycemic conditions. High glucose treatment accelerated senescence in human peritoneal mesothelial cells, whereas TSA counteracted this glucose-induced cellular aging, as evidenced by reduced SA-β-gal positivity and decreased p16 and p21 expression [57]. TSA has also been reported to alleviate H₂O₂-induced senescence in endothelial cells through the activation of SIRT1 [58].

Sodium tanshinone IIA sulfonate (STS), a water-soluble TSA derivative, was developed to improve its bioavailability and applicability. STS protects the vascular system from aging by targeting oxidative stress [59,60]. In high-glucose–treated endothelial cells and diabetic mouse models, STS markedly reduced intracellular ROS levels and decreased the number of SnCs [59]. In addition, STS reduced γ-H2AX and p21 expression while increasing CD31 and vWF levels in endothelial progenitor cells. These cellular effects are further translated into enhanced vascular repair and suppression of neointimal hyperplasia in diabetic mouse models [60]. The underlying mechanism of these effects involves the NF-κB–NLRP3 axis. STS inhibits the NLRP3 inflammasome by activating A20 and restores catalase activity, which is reduced under hyperglycemic conditions [59]. Taken together, TSA and its derivative STS attenuate cellular senescence induced by metabolic stress and provide a useful senotherapeutic strategy to counteract accelerated senescence associated with diabetes.

2.3.4. Andrographolide

Andrographolide, a bioactive diterpenoid derived from Andrographis paniculata, possesses anti-inflammatory [116] and antioxidant [117] properties. Andrographolide has also been reported to exert protective effects against diabetic nephropathy by suppressing NF-κB activation and reducing oxidative stress [117].

Recent studies elucidated their roles in modulating cellular senescence. Andrographolide alleviated lipotoxicity-mediated premature senescence and mitigated renal fibrosis in HFD-fed mice [61]. Six weeks of andrographolide administration downregulated senescence markers, including p16, p21, and p53, and reduced ROS production and consequent oxidative DNA damage. Mechanistically, andrographolide acts as an AMPK agonist, and its AMPK activation activity reduced renal lipid accumulation and SASP formation, both of which are known to promote fibrogenesis. Moreover, andrographolide suppressed paracrine fibroblast activation [61]. SnCs can exacerbate fibrosis by stimulating neighboring fibroblasts, and this paracrine effect was effectively inhibited by andrographolide.

Andrographolide also inhibits senescence and exerts protective effects in the musculoskeletal system. In dexamethasone-induced bone marrow mesenchymal stem cells, andrographolide reduced the SA-β-gal–positive area as well as p53 and p21 expression and promoted osteogenesis [62]. The expression of osteoblast marker genes RUNX2, COL1A1, and ALP was restored, along with osteocalcin levels. These cellular effects are translated into attenuation of bone loss in vivo, as andrographolide administration (50 mg/kg) increased femoral bone mass and trabecular number. Activation of the PI3K/AKT pathway was identified as a key mechanism underlying these protective effects, and the PI3K inhibitor LY294002 abolished the anti-senescence activity of andrographolide and bone formation [62].

2.4. Triterpenoids

2.4.1. Ginsenoside Rg1

Ginsenoside Rg1 (Rg1), a major dammarane-type triterpenoid saponin and active constituent of Panax ginseng, is one of the most frequently investigated terpenoids in phytomedical studies. Numerous review articles have summarized the biological activities of Rg1, highlighting its role in cardiovascular diseases [118], neurodegenerative disorders [119,120], ischemic stroke [121], diabetes [122], liver injury [123], and inflammatory diseases [124,125]. Indeed, the anti-aging effects of Rg1 have also been investigated [126], with growing attention focused on its capacity to modulate cellular senescence. The anti-senescence activities of Rg1 and its associated effects on age-related pathologies are outlined in Table 1.

Hematopoietic stem cell (HSC) aging, characterized by diminished self-renewal and skewed lymphoid differentiation, disrupts hematopoietic homeostasis and impairs immune surveillance, thereby driving the onset of age-related myeloproliferative and malignant pathologies [127]. Rg1 consistently improved pathological hematopoietic deterioration by attenuating cellular senescence. Rg1 reduced p16 and p21 expression and recovered the stem cell antigen-1 positive (Sca-1⁺) hematopoietic stem/progenitor cell (HSC/HPC) compartment, implying that Rg1 rejuvenates the pluripotency and self-renewal capacity of HSCs [128]. Moreover, Rg1 restored the mRNA expression of Cxcl12, Kitl, and Vcam1, which play pivotal roles in supporting HSC/HPC survival and differentiation. Conversely, Rg1 dampened the levels of Selp, Nupr1, and Mt1, which are recognized as markers of hematopoietic stem and progenitor cell senescence [63,129]. Mechanistically, transcriptomic analysis showed that TLR2 is a putative upstream target of Rg1. Rg1 reduced D-galactose-induced TLR2 protein expression, and molecular docking predicted an interaction between Rg1 and TLR2 involving the F266 and F284 residues. Consistent with the inhibition of TLR2 signaling, Rg1 suppressed MyD88 expression and decreased IκBα and NF-κB p65 phosphorylation, thereby reducing inflammatory signaling in senescent mesenchymal stromal cells [63].

The deterioration of MSCs through cellular senescence compromises their self-renewal, multilineage differentiation, and immunomodulatory functions, fundamentally undermining both tissue homeostasis and the efficacy of clinical regenerative applications [130]. Rg1 not only restored osteogenic and chondrogenic differentiation capacity but also enhanced the clonogenicity, proliferation, and antioxidant defense of MSCs [64,65]. By modulating GSK-3β phosphorylation, Rg1 prevented excessive WNT/β-catenin activity, which in turn lowered the downstream target T-cell factor/lymphoid enhancer factor (TCF/LEF) and rescued differentiation competence [64]. Moreover, Rg1 activated Nrf2 and its downstream targets, such as HO-1, GCLC, GCLM, and NQO1 [65]. These beneficial changes were attributed to the inhibitory effects of MSC senescence, which diminished p53, p21, and p16 levels and γ-H2AX signals [65,66,131].

Rg1 also exerts protective effects against neural stem cell (NSC) senescence. Chen et al. demonstrated that Rg1 ameliorates cognitive decline, motor dysfunction, and structural deterioration of the hippocampus [67]. Furthermore, Rg1 alleviated brain atrophy and improved the mitochondrial ultrastructure in hippocampal neurons [68]. D-galactose exposure increased the expression of p53, p16, p21, and RB, thereby inducing cell cycle arrest. Rg1 reversed these changes and potentiated the SIRT1/Nrf2/BDNF axis, which is required to restore mitochondrial energy metabolism and diminish ROS levels in NSCs [68]. Moreover, Rg1 suppressed AKT/mTOR phosphorylation and the expression of SASP-related genes [67], suggesting that Rg1 is a promising therapeutic strategy for cognitive health during aging.

In addition, the administration of Rg1 holds medicinal promise for mitigating pulmonary fibrosis, primarily by suppressing cellular senescence [69]. In paraquat-induced C57BL/6 mice, Rg1 reduced the lung wet-to-dry ratio, hydroxyproline content, and collagen deposition. These improvements were driven by reduced p16 and p21 expression, as well as lower levels of SASP factors, including Tnf, Il1b, Il6, Mmp3, Mmp9, and Mmp13. Functionally, Rg1 restored autophagic activity, characterized by the upregulation of the LC3B-II/I ratio and ATG12 and a decrease in p62 [69]. Moreover, Ding et al. revealed that Rg1 acts by inhibiting the cGAS/STING pathway in lung tissue, resulting in diminished chronic inflammation and expression of p16 and p21, which ultimately alleviates pulmonary hypertension [70].

Furthermore, Rg1 attenuates age-related functional impairment in the kidneys. Treatment with Rg1 in senescence-accelerated mouse prone 8 (SAMP8) mice notably restored glomerular pathology, as evidenced by reduced blood urea nitrogen, serum creatinine, and glomerular fibrosis markers, such as collagen IV and TGF-β1 [71]. Similarly, Rg1 ameliorated kidney injury and fibrosis while reducing SA-β-gal, p53, and p21 levels [72]. At the molecular level, Rg1 inhibited the NLRP3 inflammasome, leading to decreased IL-1β signaling [71]. Furthermore, network pharmacology identified caspase-1 as a candidate target, and experiments showed that Rg1 decreased caspase-1, ROS, malondialdehyde (MDA), and TNF-α levels in D-galactose-induced mouse kidneys [72]. Attenuation of cellular senescence also contributes to the improvement of age-related fatty liver disease [73]. By suppressing FOXO1 phosphorylation, Rg1 sustained FOXO1 activity, which in turn elevated superoxide dismutase and catalase activities while lowering SASP-associated cytokine levels, specifically IL-1β, IL-6, and CCL2 [73].

Collectively, the available evidence highlights ginsenoside Rg1 as a potent senomorphic agent that counteracts systemic aging by suppressing canonical senescence markers and coordinating multi-target signaling pathways (Figure 2). In hematopoietic and mesenchymal stem cell models, Rg1 primarily restored self-renewal and differentiation, whereas in neural stem cell models it improved mitochondrial function and cognitive phenotypes. In lung, kidney, and liver models, its effects were characterized by the attenuation of fibrotic and inflammatory responses. These model-specific outcomes likely reflect heterogeneity in senescent cell lineage, senescence-inducing stress, and tissue microenvironment.

2.4.2. Astragaloside IV

Astragaloside IV is a cycloartane-type triterpenoid saponin obtained from Astragalus membranaceus, a traditional medicinal herb widely used in East Asia. It has been reported to exhibit diverse therapeutic potential, including neuroprotective [132,133,134], cardioprotective [135,136,137], and anti-fibrotic activities [138]. Studies have demonstrated that astragaloside IV effectively attenuates cellular senescence in various cell types.

In neuronal models, astragaloside IV alleviates senescence by enhancing mitophagy and reducing oxidative stress [75,139]. Using both replicative senescent and MPP⁺/LPS-induced premature astrocytes, astragaloside IV significantly promoted mitophagy, as indicated by the recovery of LC3-II, PINK1, and Parkin, depletion of p62 and TOM20, and suppression of mitochondrial ROS accumulation [75]. A parallel role of mitophagy quality control has also been observed in bleomycin-induced vascular smooth muscle cells (VSMCs) [76]. Additionally, in amyloid-beta (Aβ)-induced human astrocytes, astragaloside IV inhibited the chaperone protein HSP90AA1 [78], which is linked to the apoptosis resistance of SnCs. Because HSP90 inhibition destabilizes pro-survival client proteins such as phosphorylated AKT and suppresses PI3K/AKT-dependent anti-apoptotic signaling, targeting HSP90AA1 may represent a relevant mechanism that sensitizes SnCs to apoptosis [20].

Consistent with these in vitro results, astragaloside IV has shown promising therapeutic outcomes in several in vivo age-related pathologies, including pulmonary fibrosis [140], myocardial fibrosis [141], osteoporosis [79], age-related macular degeneration [80], cognitive impairment [77], and Parkinson’s disease [75]. Astragaloside IV attenuated pulmonary and myocardial fibrotic injury, as indicated by improved histopathology, reduced collagen deposition, lower levels of fibrosis-associated markers (collagen I/III and α-SMA), and SASP expression, including IL-1β, IL-6, TNF-α, and TGF-β1 [140,141]. Integrated transcriptomic and proteomic profiling combined with KEGG enrichment analysis revealed that astragaloside IV targets pathways involving cellular senescence and p53 signaling [141], suggesting that the modulation of senescence and SASP signaling by astragaloside IV may represent a shared mechanism underlying its therapeutic potential in age-related fibrotic diseases [142].

Furthermore, astragaloside IV mitigated D-galactose-induced bone deterioration in C57BL/6J mice, improving trabecular microarchitecture and reducing senescent phenotypes in bone marrow mesenchymal stem cells (BMSCs) [79]. In particular, macrophage polarization shifted away from a pro-inflammatory M1-like state toward an anti-inflammatory M2-like phenotype. The suppression of the STING/NF-κB axis was identified as the underlying signaling pathway driving the rescue of macrophage senescence and, in turn, promoting the osteogenic differentiation of BMSCs [79,143].

Astragaloside IV also ameliorated NaIO₃-induced retinal pathology in mice by improving retinal structure and thickness while decreasing p53 expression and γ-H2AX signal levels [80]. Mechanistically, astragaloside IV directly interacts with the fat mass and obesity-associated (FTO) protein, which is required for m6A modification of Il1β mRNA to reduce its stability [80].

Taken together, these findings indicate that astragaloside IV exerts senotherapeutic and tissue-protective effects for several age-related disorders by suppressing canonical senescence and inflammatory phenotypes while restoring mitochondrial quality control and modulating key signaling nodes, including PINK1/Parkins, STING/NF-κB, and FTO-dependent post-transcriptional regulation (Figure 2).

2.4.3. Celastrol

Celastrol is a quinone methide pentacyclic triterpenoid originally isolated from Tripterygium wilfordii and other Celastraceae species, which are abundantly distributed across China and Southeast Asia. Celastrol exerts diverse bioactivities, including anticancer [144], antimicrobial [145], anti-inflammatory, metabolic regulatory, and neuroprotective effects [145].

Celastrol was identified as a novel senolytic compound that preferentially eliminates SnCs in stress-induced NIH-3T3 and human umbilical vein endothelial cells (HUVECs), as well as replicative senescent mouse embryonic fibroblasts (MEFs) [81]. Celastrol stabilized the pro-apoptotic protein Bim and disrupted the HSC70–Bim interaction, which normally facilitates Bim degradation through CHIP-dependent ubiquitination. Moreover, celastrol modestly extended lifespan in Drosophila and attenuated bleomycin-induced lung fibrosis and CCl₄-induced liver fibrosis in C57BL/6 mice, along with increased apoptosis of p16-positive cells [81].

Celastrol also exerts anti-senescent effects in renal cell carcinoma [82] and tubular epithelial cells [83]. Celastrol administration in clear cell renal cell carcinoma (ccRCC) effectively alleviated doxorubicin-induced senescence by downregulating caveolin-1, which promotes tumor senescence via the p53/p21^Waf1/Cip1 pathway [146]. This pharmacological intervention neutralized the deleterious paracrine effects of SnCs, including enhanced migration, invasion, epithelial–mesenchymal transition, and stemness [82]. Moreover, the protective action in renal tubular epithelial cells was associated with the suppression of AKT1 and NF-κB phosphorylation, suggesting that celastrol interrupts senescence-linked inflammatory responses [83].

Moreover, in a quantitative high-throughput screening assay using doxycycline-inducible eGFP-tagged Δ133p53α, cellular GFP fluorescence intensity was measured to identify compounds that increase Δ133p53α protein levels. As Δ133p53α is known to antagonize full-length p53 and block its function [147,148], it strongly suppresses the expression of p21 and SASP factors. Celastrol was selected based on its potency, absence of cytotoxicity, and reproducibility across Δ133p53α reporter systems. Subsequently, the effect of celastrol was validated to increase endogenous Δ133p53α levels in primary human astrocytes and MRC-5 fibroblasts, with a concomitant reduction in IL-6 secretion and SA-β-gal positivity [84]. Additionally, celastrol inhibited the PI3K/AKT/mTOR/p70S6K signaling axis, triggering an autophagic response that restored the cell cycle in rat VSMCs [85].

Altogether, these studies indicate that celastrol elicits heterogeneous senotherapeutic responses across experimental models. It promotes Bim-dependent apoptosis in senescent fibroblasts and endothelial cells, whereas in renal, astrocytic, and vascular models it mainly attenuates senescence-associated signaling through CAV1/p53/p21, AKT/NF-κB, Δ133p53α, or autophagy (Figure 2).

2.4.4. Ganoderic Acid A and D

Ganoderic acids are a class of tetracyclic triterpenoids predominantly isolated from the medicinal fungus Ganoderma lucidum, a traditional herbal medicine widely used in East Asia to promote health and longevity. Numerous ganoderic acid derivatives have been identified, and these compounds exhibit diverse biological activities, including antioxidant, immunomodulatory, and anticancer activities [149,150].

Studies have elucidated their roles in modulating cellular senescence and aging-related pathways. Using a high-content screening platform, Chen et al. screened 805 natural products in replicative senescent IMR90 cells using multiparametric senescence readouts, including SA-β-gal positivity, cell number, nuclear area, cell area, and morphology [86]. Subsequent validation across diverse models, including replication-, oxidative stress-, and genotoxicity-induced senescent HUVECs, identified ganoderic acid A as a lead senotherapeutic candidate. Notably, it consistently reduced the number of SA-β-gal-positive cells while demonstrating a wide effective concentration range and low cytotoxicity in senescent MEFs and L02 cells [86]. Ganoderic acid A significantly extended the healthspan of X-ray-irradiated prematurely aged, naturally aged, and Western diet-induced obese C57BL/6J mice. Systemic administration of ganoderic acid A mitigated the accumulation of SnCs and curtailed multi-organ physiological deterioration (creatine kinase-MB, creatinine, ALT, and AST), while notably enhancing physical capacity and preserving metabolic homeostasis without triggering abnormal cellular proliferation [86].

Mechanistic analysis revealed that ganoderic acid A directly binds to TCOF1, a nucleolar protein that regulates ribosomal RNA transcription and its biogenesis. Cellular senescence is frequently accompanied by nucleolar stress and impaired ribosomal production [151], leading to translational dysfunction and activation of stress signaling pathways by impairing MDM2-mediated ubiquitination of p53 [152,153]. By stabilizing the phosphorylated form of TCOF1, ganoderic acid A effectively maintained ribosomal protein production and global translation capacity, as evidenced by the restored O-propargyl puromycin (OPP) incorporation in SnCs. Furthermore, siRNA-mediated knockdown of TCOF1 completely abrogated the recovery of ribosomal function and its subsequent anti-senescent effects, confirming that the preservation of TCOF1-dependent ribosome biogenesis is indispensable for the senotherapeutic action of ganoderic acid A [86].

Also, treatment with ganoderic acid A in Alzheimer’s disease models significantly reduced senescence phenotypes by activating autophagic pathways, including ATG5 and Beclin-1. Specifically, PADI4 knockdown abrogated the protective effects of ganoderic acid A, indicating that PADI4 may play a significant role in mediating ganoderic acid A-induced autophagy activation [87].

In hydrogen peroxide–treated human amniotic mesenchymal stem cells (hAMSCs), ganoderic acid D prevented cell cycle arrest while enhancing antioxidant responses, such as HO-1 and NQO1 [88,89]. Ganoderic acid D activated Nrf2-dependent antioxidant signaling through PERK phosphorylation, promoting Nrf2 nuclear translocation and PRDX3 induction [89]. In parallel, ganoderic acid D stabilized 14-3-3ε interactions with CaM or phosphorylated CaMKII. This regulation of the Ca²⁺-sensing CaM/CaMKII module upstream of Nrf2 likely facilitated nuclear translocation of Nrf2 and restoration of calcium/redox homeostasis [88]. These molecular events translated to enhanced systemic antioxidative defense and improved physical endurance in D-galactose-induced in vivo models [88].

Additionally, G. lucidum demonstrates a clear capacity to mitigate cellular senescence when administered as a crude extract. Abdelmoaty et al. reported that G. lucidum extract, rich in ganodermanontriol, ganodermanondiol, ganoderiol A/B, and ganoderal A, possesses senolytic activity against adriamycin-induced hepatocellular carcinoma cells [154]. This complex triggered apoptosis via caspase-dependent and mitochondrial pathways, which is further supported by the downregulation of anti-apoptotic BCL-2 family members and the PI3K/AKT axis [154]. Also, G. lucidum extract induced the expression of antioxidant defense genes, including HMOX1, GCLM, and NQO1, to alleviate senescence in human dermal fibroblasts (HDFs) [155].

In summary, these studies suggest that ganoderic acids, particularly ganoderic acid A and D, confer substantial senescence-modulating effects by improving age-related physiological impairment and reducing multiple senescence markers by preserving nucleolar and ribosomal function, promoting autophagic flux, and strengthening Nrf2-driven cytoprotective antioxidant signaling (Figure 2). Furthermore, G. lucidum extracts exhibit broad anti-senescence potential across diverse cellular contexts, including both malignant and non-malignant proliferative cells.

2.4.5. Cycloastragenol

Cycloastragenol, a bioactive triterpene aglycone derived from Astragalus, has been shown to possess versatile properties, including telomerase activation [156], proteasome activity [157], circadian rhythm regulation [158], and anti-inflammatory responses [159]. Zhang et al. investigated the senolytic activity of cycloastragenol in etoposide-induced IMR90 fibroblasts. This study revealed the capacity of cycloastragenol to selectively eliminate SnCs by suppressing the PI3K/AKT/mTOR and anti-apoptotic BCL-2 family signaling pathways [90]. Additionally, cycloastragenol attenuated microglial senescence and cognitive deficits in 5xFAD mice by targeting PDE4B to enhance microglial phagocytosis and activate the CREB/BDNF signaling pathway [91]. In contrast to inducing apoptosis in SnCs, cycloastragenol preserved nucleus pulposus cell proliferation by reducing p16, cleaved caspase-3, and BAX [92]. Taken together, cycloastragenol exerts distinct senotherapeutic effects across different models, including direct senolysis in senescent IMR90 cells, attenuation of microglial senescence in 5xFAD mice, and preservation of nucleus pulposus cell proliferation under high-glucose conditions (Figure 2).

2.4.6. Oleanolic Acid

Oleanolic acid is a naturally occurring pentacyclic triterpenoid that is abundant in olive leaves (Olea europaea L.). Oleanolic acid exhibits broad pharmacological efficacy, including antidiabetic, anticancer, antihypertensive, hepatoprotective, and neuroprotective effects [160,161]. In an intestinal injury model induced by 5-fluorouracil, oleanolic acid attenuated senescence in HUVECs and NCM460 cells, reduced SASP gene expression (IL1B, IL6, IL8, IFNG, and TNF), and ameliorated diarrhea, colonic shortening, and crypt disruption in BALB/c mice [93]. Functionally, oleanolic acid suppressed mTOR signaling, p-p65, and p-p38 [93], consistent with a report that oleanolic acid blunted senescence in HDFs and MEFs by targeting the IGF-1-mediated PI3K/AKT/mTOR pathway [94]. In addition, it was demonstrated that inhibiting the JNK/MAPK pathway to suppress senescence is another mechanism of action of oleanolic acid by treating a zebrafish atherosclerosis model with oleanolic acid nanoparticles [95]. Collectively, these studies suggest that oleanolic acid functions as an anti-senescence compound by coordinating the inhibition of the PI3K/AKT/mTOR, p38/NF-κB, and JNK/MAPK signaling pathways, respectively (Figure 2).

2.4.7. Betulinic Acid

Betulinic acid, a lupane-type pentacyclic triterpenoid enriched in the bark of Betula and Ziziphus species, is well known for its antioxidant, anti-inflammatory, and anticancer activities [162,163,164]. Following reports of lifespan extension by betulinic acid in S. cerevisiae [165], C. elegans [166], and D. melanogaster [167], its potential senotherapeutic properties have also been explored. Odama et al. demonstrated that betulinic acid effectively mitigates replicative senescence in high-passage fibroblasts. Transcriptomic analysis revealed that betulinic acid suppresses type I interferon programs, including IFI6 and MX1, by downregulating IRF9 [96]. Moreover, a network pharmacology study suggested that betulinic acid may involve a broader multi-target mechanism, particularly p53 and SIRT1, as important interacting nodes. Indeed, it was experimentally confirmed that betulinic acid modulates the SIRT1-p53 signaling axis and promotes HK-2 cell proliferation, accompanied by downregulation of the expression of the inflammatory markers TGF-β and IL-6 [97]. Overall, these findings indicate that betulinic acid attenuates cellular senescence by modulating a wide range of inflammatory factors.

3. Conclusions

The aging population has increased rapidly on a global scale, posing a major socioeconomic burden. Life expectancy continues to increase, but the healthspan fails to keep pace with the lifespan [168]. This gap highlights the need for therapeutics that promote healthy aging. Cellular senescence is now recognized as an essential contributor to the fundamental aging process and etiology of age-related diseases [169]. Accordingly, targeting cellular senescence has emerged as a promising anti-aging strategy, and the development of safe and effective senotherapeutics has become increasingly important. Natural compounds, in particular, have garnered increasing attention for their potential to alleviate cellular aging. Although their potency may be lower than that of synthetic compounds, they are generally considered safe, and their lower toxicity makes them more favorable for clinical use. Among the various phytocompounds, this review focuses on terpenoids and comprehensively summarizes their senescence-modulating roles at the cellular, tissue, and organismal levels.

Plant-derived terpenoids are mainly obtained from aromatic and essential-oil-rich plants and from perennial medicinal herbs, shrubs, and trees distributed across temperate East Asia, tropical and subtropical Asia, the Mediterranean region, and temperate Eurasia. Numerous studies have shown that terpenoids exert senotherapeutic effects and mitigate the detrimental effects of aging. Notably, these compounds directly eliminate SnCs by apoptosis or ferroptosis and suppress the senescence-associated secretory phenotype (SASP), which fuels age-related degeneration [30]. These effects are mediated by multiple regulatory pathways rather than a single response. Specifically, terpenoids modulate key signaling pathways associated with cellular senescence, including inflammatory pathways such as NF-kB, JAK/STAT, PI3K/AKT/mTOR, and p38 MAPK signaling pathways. In addition, certain terpenoids regulate redox homeostasis through Nrf2 activation and modulate core cellular processes, such as mitochondrial function and autophagy. Taken together, terpenoids not only reduce the accumulation of SnCs but also modulate interconnected senescence-associated networks, thereby attenuating the initiation and progression of senescence.

Monoterpenoids and sesquiterpenoids predominantly exert senotherapeutic effects through SASP modulation (Figure 1). While thymol promotes senescent cell apoptosis and dihydroartemisinin induces ferroptosis-dependent senolysis through AMPK activation and autophagic ferritin degradation, most other compounds function as senomorphic agents. Limonene suppresses NF-κB inflammatory signaling, whereas thymol and carvacrol attenuate oxidative stress and inhibit JAK/STAT3-driven senescence pathways. β-Caryophyllene promotes longevity through SIRT1 induction, and handelin suppresses p38 MAPK activation and enhances AKT/mTORC1 signaling. Diterpenoids provide broader protection against age-related dysfunction. Oridonin displays senolytic activity via GSTK1 inhibition and p38-mediated apoptosis, whereas ginkgolide B and andrographolide alleviate frailty, age-associated muscle decline, and bone loss by suppressing SASP-associated inflammation. Tanshinone IIA further protects against vascular aging by inhibiting NF-kB/NLRP3 signaling. Meanwhile, triterpenoids provide multifaceted senotherapeutic regulation, acting through both senolytic and senomorphic mechanisms (Figure 2). In the senolytic context, celastrol and cycloastragenol exhibit senolytic activity by enhancing apoptotic susceptibility through Bim stabilization or inhibition of PI3K/AKT/mTOR and BCL-2 family signaling. On the other hand, ginsenoside Rg1, astragaloside IV, ganoderic acids, oleanolic acid, and betulinic acid mainly act as senomorphic agents. Rg1 and oleanolic acid suppress NF-κB, SASP, and mTOR-linked inflammatory pathways. Astragaloside IV restores PINK1/Parkin-mediated mitophagy and regulates STING/NF-κB signaling. Ganoderic acids reinforce ribosomal homeostasis, autophagy, and Nrf2-dependent antioxidant defense, while betulinic acid attenuates interferon-driven inflammation and modulates the SIRT1–p53 axis.

The aforementioned ability of terpenoids to improve cellular senescence at multiple levels highlights their potential as anti-senescence agents. However, several limitations remain. Most current studies are based on phenotypic observations and describe pathway alteration without a complete understanding of molecular targets or underlying mechanisms. Indeed, only a limited number of compounds have defined direct molecular targets, including oridonin (GSTK1), celastrol (HSC70), and ganoderic acid A (TCOF1). Target identification of the remaining compounds should be prioritized in future studies. In addition, much of the existing evidence is derived from preclinical studies and therefore may not fully capture the complexity of in vivo aging. Although a few candidate terpenoids and their derivative formulations have entered clinical evaluation for aging-associated phenotypes and dysfunction (NCT05578443, NCT05647473, NCT05598359), most of these trials are still in their nascent stages or remain ongoing, leaving publicly available efficacy data highly sparse. Further validation using diverse animal models and well-designed clinical trials should be conducted to confirm their effects on senescence.

Another important consideration is the heterogeneity of cellular senescence, posing a challenge to the generalization of existing findings. Senescent phenotypes and responses vary across cellular and tissue environments, and whether comparable effects occur in different models remains unclear. This variability necessitates context-dependent validation and careful optimization. Furthermore, a deeper understanding of pharmacokinetics and toxicology, along with ADME assessment, is required to facilitate the development of terpenoid-based senotherapeutics. While the terpenoids discussed in this review are naturally derived and generally considered to have favorable safety profiles, their long-term safety under aged conditions should be addressed.

In conclusion, this review provides a comprehensive analysis of the senotherapeutic potential of terpenoids, which have been relatively underexplored. Terpenoids combat cellular aging and suppress senescent phenotypes, thereby emerging as promising candidates for promoting healthy aging. Although terpenoid-based senothereapeutics remain at an early stage of development, accumulating findings support their promising senotherapeutic activities. We believe that terpenoids could possibly serve as a novel class of drugs for age-related diseases.