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Review

Natural Products Acting as Senolytics and Senomorphics Alleviate Cardiovascular Diseases by Targeting Senescent Cells

by
Hejing Tang
1,†,
Xu Zhang
1,†,
Senyang Hu
1,
Yuhan Song
2,
Wenhua Jin
1,
Jianmin Zou
1,
Yan Zhang
3,
Jiayue Guo
1,
Peng An
1,
Junjie Luo
1,
Pengjie Wang
1,
Yongting Luo
1,* and
Yinhua Zhu
1,*
1
Beijing Advanced Innovation Center for Food Nutrition and Human Health, Department of Nutrition and Health, China Agricultural University, Beijing 100193, China
2
Ministry of Agriculture and Rural Affairs Key Laboratory of Veterinary Biological Products and Chemicals, Beijing Engineering Technology Center for Design and Preparation of Veterinary Polypeptide Vaccine, Beijing 100095, China
3
College of Food Science and Engineering, Gansu Agricultural University, Lanzhou 730070, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Targets 2025, 3(3), 23; https://doi.org/10.3390/targets3030023
Submission received: 3 April 2025 / Revised: 27 May 2025 / Accepted: 19 June 2025 / Published: 25 June 2025
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Abstract

Taken together, cardiovascular diseases (CVDs) have become one of the prime causes of the global disease burden. Aging is closely related to CVDs and is considered to be one of the crucial factors in the incidence of CVDs. In the process of aging, cellular senescence is an important cause of CVDs such as atherosclerosis and atrial fibrillation. The treatment for CVDs by targeting senescent cells has been carried out in cellular models, animal experiments, and anti-aging clinical trials. Chemical approaches to regulate the fate of senescent cells by senolytics and senomorphics, which could selectively eliminate senescent cells or inhibit their senescence-associated secretory phenotype (SASP) secretion, have been increasingly explored. Importantly, many natural products with promising biological activity extracted from food or medicine–food homology have the above-mentioned effects. Furthermore, the identification of the target cells or target proteins of these natural products is of great significance for the indication of their mechanism of action, and it also lays a scientific foundation for the realization of precision nutrition intervention in the future. This review details how senescent cells affect CVDs, how natural products target senescent cells through nutritional intervention, and research methods for natural products in cardiovascular aging.

1. Introduction

Aging is an inevitable natural law, and individual aging involves multiple levels of changes, among which senescent cell accumulation increases the risk of accelerating individual senescence and age-related diseases, such as osteoporosis [1], idiopathic pulmonary fibrosis [2], type 2 diabetes, and non-alcoholic fatty liver disease/non-alcoholic steatohepatitis [3]. Furthermore, cellular senescence is a fundamental driving force for age-related diseases. It is mainly characterized by cell cycle arrest, DNA damage, and high expression of senescence-associated secretory phenotype (SASP), including inflammatory cytokines and chemokines [4]. Senescent cells also exist and accumulate in organs that have a weak ability to divide and proliferate, such as the brain or heart [5]. Among these harmful effects of age-related diseases, the accumulation of senescent cells has become one of the dominating factors in CVD. For example, senescent endothelial cells commonly found in atherosclerotic plaques in geriatrics could reduce the secretion of nitric oxide (NO), easily form thromboses, and increase the expression of pro-inflammatory molecules such as IL-6, thereby aggravating inflammation and aging [6]. Furthermore, senescent vascular smooth muscle cells (VSMCs) can lead to atherosclerotic plaque calcification [7]. The geroscience hypothesis also mentions that targeting “hallmarks of aging”, such as cellular senescence, may delay, prevent, alleviate, or treat chronic diseases [8]. Currently, senescent cell-targeting strategies mainly fall into two categories: senolytic therapy, which selectively kills senescent cells, and senomorphic therapy, which reduces the secretion of SASP. Therefore, addressing age-related chronic diseases by targeting senescent cells and SASP secreted from senescent cells is one of the major research topics at present.
Natural products are physiologically active compounds extracted from food or natural organisms. Their potential in regulating senescent cells to alleviate age-related diseases in the form of nutritional interventions has been widely explored in recent years. More specifically, natural products can selectively kill senescent cells or inhibit the production of SASP through senolytic or senomorphic mechanisms. Numerous natural products, such as flavonoids, anthocyanins, and other polyphenols or sterols can kill senescent cells or inhibit oxidative stress, reduce ROS levels, and inhibit SASP, including IL-6, IL-8, tumor necrosis factor-alpha (TNF-α), improving the microenvironment to achieve the purpose of treating CVDs, which has great development potential [9,10,11,12,13].
This review mainly focuses on vital CVDs, including atherosclerosis (the main cause of many other CVDs), ischemic heart disease (heart failure and myocardial infarction), and stroke. It highlights natural products that target senescent cells and discusses the potential applications of these interventions in cardiovascular therapy.

2. Aging and CVDs

CVDs are a group of disorders affecting the heart and blood vessels, including coronary heart disease, cerebrovascular disease, and peripheral arterial disease [14]. CVDs pose an enormous challenge to healthcare systems worldwide [15]. In 2020, the overall prevalence of CVDs in adults (≥20 years old) was 48.6%, and the prevalence increases with age [16]. CVDs contribute to about 19.91 million deaths globally [16]. Aging has been regarded as one of the main factors in the incidence of CVDs for a long time. An analysis of age-specific mortality data from the global burden of disease database showed that the CVD mortality rate increased exponentially with age in people aged 25 to ≥95 years, and based on this analysis, the average doubling time of CVD mortality was 7.2 years in men and 6.5 years in women. Additionally, the observed CVD mortality rate showed that compared to adults aged 25–29 years, the mortality rate in those aged 65–69 years was 61 times higher in men and 67 times higher in women [17]. A lifetime study of stroke in China focused on individuals aged 40 or older also found a slight increase in morbidity among the population with optimal levels of all risk factors with age, which provides solid evidence that aging is a key independent predictor of CVD [18].
Degenerative changes in the structures and functions of the aging heart and arteries are important potential risks for various CVDs [19]. Even normal aging is accompanied by a continuous decline in cardiac systolic function, a decline in left ventricular diastolic function, an increase in myocardial fibrosis, and other structural function deteriorations, contributing to the increased susceptibility to heart failure in the elderly population [19,20]. At the same time, the lipid metabolism of aging individuals is prone to disturbances, such as increases in cholesterol, low-density lipoprotein, triglycerides, and other indicators, which lead to atherosclerosis and aggravate the burden of CVDs [21]. Cardiovascular aging is closely related to the aging of senescent cells. Cell senescence refers to a state of cell cycle arrest [22]. DNA damage, telomere dysfunction, oncogene activation, and innate immunity can lead to cell aging [23]. Cellular senescence results in an elevation of senescence markers and disruptions in cellular functions, such as proliferation, migration, homing, and differentiation. In addition, senescent cells produce SASP, which affects the tissue microenvironment and surrounding cells by secreting proinflammatory cytokines, chemokines, growth factors, and extracellular matrix degradation proteins. Figure 1 illustrates cellular senescence associated with age-related CVDs. Different senescent cells are involved in different age-related CVDs, making cellular senescence a main cause of the pathophysiology of CVDs [24].
Therefore, investigating how different types of senescent cells promote the development of CVDs is of great significance for facilitating intervention and treatment.

3. The Role of Senescent Cells in CVDs

Senescent cells, specifically endothelial cells, VSMCs, and immune cells, in blood vessels and myocardial cells, are closely related to the occurrence of age-related CVDs [25]. Some pathways, such as the p53/p21WAF1CIP1 and p16INK4A/pRB tumor suppressor pathways, are responsible the senescence in various cell types (PMID: 33855023). Epithelial cells, SMCs, immune cells, and certain cells have specific aging pathways due to their different functions. This section discusses how senescent cells in the cardiovascular system regulate atherosclerosis, ischemic heart disease, stroke, and other CVDs.

3.1. Endothelial Cell Senescence and CVDs

Endothelial cells are at the interface between the circulating blood and blood vessels. Therefore, endothelial cells are prone to aging due to vascular shear, oxidative stress, inflammation, and activation of tumor suppression pathways. Endothelial cell senescence has been identified as an important predisposing factor for various CVDs.
Senescent endothelial cells undergo structural and functional alterations that contribute to cardiovascular pathologies. With aging, these cells adopt an enlarged and flattened morphology, reducing their responsiveness to shear stress [26]. A hallmark of senescence is the diminished synthesis of NO, a critical mediator of vasodilation and platelet inhibition. This NO deficiency compromises vascular relaxation and exacerbates diastolic dysfunction [27].
Furthermore, senescent endothelial cells secrete aging-related SASP factors, which impair vascular repair by suppressing neighboring cell proliferation and migration. Concurrently, increased vascular stiffness caused by endothelial senescence disrupts hemodynamics, ultimately diminishing cardiac perfusion [27].
Senescent endothelial cells are prominently observed within atherosclerotic plaques in elderly patients, underscoring their role in age-related vascular pathology [28]. These cells exhibit upregulated expression of proinflammatory mediators, including cytokines, chemokines, adhesion molecules, and vascular cell adhesion protein 1, culminating in endothelial dysfunction.
Beyond well-characterized senescence mechanisms, epithelial cells may exhibit epithelial–mesenchymal transition (EMT)-related pathways during senescence. For instance, the TGF-β/Smad pathway can induce EMT and affect cell adhesion and mobility, which contribute to the senescent phenotype (PMID: 37327791, PMID: 30654892).
Moreover, epithelial cells’ high secretory activity drives the release of inflammatory factors and ROS, which propagate senescence to adjacent healthy cells through paracrine effects. The SASP factor, secreted by aging endothelial cells, establishes an inflammatory microenvironment [29], exacerbating endothelial impairment and accelerating atherosclerotic progression. Additionally, microvesicles derived from senescent endothelial cells promote VSMC calcification [30]. Aging endothelial cells reduce NO production, leading to impaired vasodilation function, while increases the release of endothelin 1, promoting vasoconstriction and thrombosis [31].
Senescent endothelial cells are also observed in heart failure. The risk of heart failure with ejection fraction preservation increases with age and is associated with endothelial cell senescence [32]. Cerebral capillary endothelial cells are important blood–brain barrier components. The permeability of the blood–brain barrier increases gradually during aging. BBB dysfunction is closely related to a series of cerebrovascular diseases and central nervous system diseases, including ischemic stroke [33].

3.2. Smooth Muscle Cell Senescence and CVDs

VSMCs are mainly responsible for regulating vascular tone, blood pressure, and vascular homeostasis. Inflammatory factors, such as TNF-α, can induce the senescence of SMCs [34]. Elevated levels of Prelamin A, arising due to mutations in the LMNA gene (encoding Lamin A/C) or as a side effect of HIV protease inhibitors, induce senescence in VSMCs by reducing the expression of ZMPSTE24, a metalloprotease responsible for processing Prelamin A (PMID: 26724531).
Smooth muscle cell (SMC) aging promotes arterial intima thickening and extracellular matrix deposition, which leads to decreased arterial function and increases arterial stiffness [35]. Senescent VSMCs can form various SASPs, which promote monocyte chemotaxis and stimulate adjacent non-senescent VSMCs and endothelial cells to express increased adhesion molecules and decreased inflammatory factors [36].
Aging VSMCs can degrade the matrix through protease secretion, which leads to the proliferation of VSMCs, promotes the thinning of fiber caps, and affects the stability of plaque. At the same time, aging VSMCs produce less collagen than normal VSMCs, which further affects plaque stability [7]. In addition, senescent VSMCs exhibit osteoblast secretion phenotype and activate several osteoblastic pathways, enhancing their susceptibility to calcification [7], thereby leading to plaque calcification. Although the relationship between vascular calcification and plaque vulnerability is not well established, calcification is strongly associated with a high incidence of adverse cardiovascular events [37]. In addition, aging VSMCs contribute to the occurrence of pulmonary hypertension through SASP [24].

3.3. Immune Cell Senescence and CVDs

Immune cells play an important role in maintaining cardiovascular system homeostasis. The outer layer of blood vessels is rich in extracellular matrix, which forms a natural basic network, accommodating and supporting a variety of immune cells [38]. In addition, some immune cells (for example, macrophages) reside in myocardial tissue and interact with cardiomyocytes and fibroblasts to participate in myocardial damage repair [39].
Immunological aging is associated with a decline in the phagocytic capacity of immune cells. The phagocytic function of immune cells relies on various receptors, including Fcγ receptors, scavenger receptors, and complement receptors. With advancing age, the expression levels of these receptors decrease (PMID: 31201918). Furthermore, impaired autophagy, which is closely linked to phagocytosis, is associated with numerous cardiovascular diseases (PMID: 37193857).
Senescent immune cells secrete abundant proinflammatory factors that contribute to CVDs, with evidence particularly well documented in T cells [40] and macrophages (PMID: 40148467). For example, senescent T cells exhibit heightened secretion of TNF, interferon-gamma (IFN-γ), and osteopontin, which directly exacerbate vascular inflammation [40]. Transferring senescent T cells into middle-aged mice aggravates angiotensin-induced cardiovascular damage [41]. Memory T cells have been found in atherosclerotic plaques, and senescent memory T cells can produce excessive levels of IL-6, TNF-α, and other cellular inflammatory factors and increase plaque instability [42].
During the formation of atherosclerotic plaque, macrophages can take up low-density lipoprotein particles and form senescent foam cells, which increase plaque instability. A senescent macrophage can induce “paracrine senescence” of the surrounding cells via SASP [43]. This SASP causes an increased inflammatory response during atherosclerosis. p16Ink4a-induced cell aging promotes the differentiation of macrophages into proinflammatory phenotype M1 macrophages, which can further secrete inflammatory factors and chemokines [44]. While there is no direct evidence linking senescent B cells to atherosclerosis, G-protein-coupled receptor 55 deficiency in B cells promotes atherosclerosis progression [45], indicating a potential connection.
In addition, age-induced atypical neutrophils exacerbate the pathological changes in ischemic stroke [46].

3.4. Myocardial Cell Senescence and CVDs

Cardiomyocytes constitute about 30% of the cells in adult mammalian hearts [47]. During aging, cardiomyocytes undergo a variety of physiological alterations that directly impair their functional and structural integrity [48]. For example, in ischemic hearts, the main source of energy production is transformed from aerobic respiration into anaerobic glycolysis, known as cardiomyocyte metabolic remodeling. This pathological adaptation substantially diminishes ATP synthesis efficiency in the heart, leading to myocardial aging and impaired heart function in ischemic heart disease [49].
Senescent cardiomyocytes can secrete SASP factors to induce senescence in neighboring cells, including fibroblasts [50]. Mitochondrial dysfunction and increased ROS levels are present in aging cardiomyocytes, triggering inflammation in cardiomyocytes [51,52,53,54]. The inflammatory cytokines further maintain SASP and promote CVD progression [24].
Aging signals can be transmitted from non-cardiomyocytes to cardiomyocytes, leading to myofibroblast activation, fibrosis, collagen synthesis, calcification, hypertrophy, and inflammation, all of which contribute to the progression of CVD [24]. The mechanisms of CVD regulation by different senescent cells are summarized in Figure 2.

4. Natural Products That Target Senescent Cells

The accumulation of senescent cells may contribute to the incidence of CVDs. Instead of drugs or surgical treatment, addressing CVDs through the administration of nutrients targeting senescent cells is a critical method. Regulating senescent cells to treat diseases is one of the major research focuses at present. The senescent cell-targeting method is called senotherapeutics, divided into senolytic and senomorphic, both of which are being increasingly explored. Among the anti-aging compounds, synthetic compounds have high efficiency in targeting senescent cells. However, they are associated with potential side effects such as strong toxicity, slow metabolism, and even cancer induction [55]. Unlike chemically synthesized compounds, natural products extracted from food or other natural organisms have been confirmed to be anti-aging, with their mechanisms and applications in this field being deeply explored. For example, most flavonoids, sterols, and terpenoids can delay the process of aging and age-related diseases, such as atherosclerosis and endothelial dysfunction, by clearing ROS and inhibiting oxidative stress [56]. In addition, many natural products downregulate the expression of TNF-α, IL-6, IL-β, and other inflammatory factors, thereby reducing the risk of age-related CVDs from an anti-inflammatory perspective. It is also worth noting that some natural products have been found to extend lifespan by regulating age-related pathways such as IIS/FoxO [57]. Compared to synthetic compounds, natural products may not be as effective, but their advantages—such as low toxicity and extensive source—provide an opportunity for their application in clinical treatments for age-related diseases or for the realization of precision nutrition intervention [58]. Therefore, we mainly focus on natural products that can regulate senescent cells and summarize their potential applications in cardiovascular interventions. Table 1 lists the different natural products and the senescent cells and diseases they target.

4.1. Senolytic

Senolytics were first proposed in 2015 by James L. Kirkland and his team [59]. The use of senolytics is an anti-senescence strategy that can target anti-apoptotic pathways to promote senescent cell apoptosis in vitro and result in systemic senescent cell reduction [60]. In contrast to medicine that is taken continuously, senolytics can be used intermittently to reduce off-target or other side effects because many of them are able to work independently of their age-clearing properties when administered continuously [8,61,62]. In addition, tissue-damaging senescent cells do not reaccumulate until 1–6 weeks after removal [63]. In recent years, many other compounds with senolytic activity have been discovered or created. For example, ABT-263 is the most widely used senolytic compound, which currently acts as a Bcl-2 inhibitor to selectively kill senescent cells by inducing apoptosis. The study of senolytics has become one of the most popular topics in the field of anti-aging.

4.1.1. Dasatinib and Quercetin

Dasatinib and Quercetin (D + Q) was the first proposed drug combination to selectively eliminate senescent cells instead of proliferating non-senescent cells. Dasatinib, a chemotherapeutic agent, selectively targets senescent preadipocytes, while quercetin, a plant extract, kills senescent HUVECs. The combination of D + Q showed better senolytic activity than either alone.
Cardiac progenitor cells in patients with CVD exhibit obvious aging markers such as cell cycle arrest, positive SA-β-gal staining, and increased secretion of SASP. The highly efficient senolytic activity of the combination of D + Q also plays a significant role in the treatment for CVDs. In vivo experiments on aging INK-ATTAC transgenic and wild-type mice confirmed that p16Ink4a expression was significantly decreased and the number of smaller ventricular myocytes was increased after D + Q treatment. In addition, the self-repair ability of myocardial cells was increased, and the cardiac progenitor cell (Sca-1+/c-kit+/CD45-/CD31-/CD34-) numbers were higher than those in untreated aged mice. D + Q treatment also helped alleviate the level of left ventricular fibrosis to relieve heart failure and myocardial infarction [12]. In addition, it has been reported that a single dose of the drugs (D: 5 mg/kg body weight and Q: 50 mg/kg by oral gavage) on 24-month-old mice improved left ventricular ejection fraction, contributing to the treatment for ischemic heart disease [59].
Further experiments have also demonstrated that D + Q exerts senolytic activity in age-dependent intervertebral disc degeneration and intestinal senescence. Mice aged 6 months and 14 months were administered intraperitoneally with 5 mg/kg dasatinib and 50 mg/kg quercetin weekly until 23 months of age. The tissue morphology of the lumbar intervertebral discs was better preserved. Additionally, in 18-month-old mice, oral gavage of 5 mg/kg dasatinib and 50 mg/kg quercetin reduced the expression of p16 and p21 in ileum, cecum, and colon tissue, and significantly decreased the secretion of SASP, including IL-1β and IL-6 [64,65]. Moreover, another clinical trial showed that subjects with diabetic kidney disease who took 100 mg/d and Q 1000 mg/d orally for three days exhibited reduced p16 and p21 expression in adipose tissue and decreased SASP levels in blood [66].

4.1.2. Fisetin

Fisetin is a natural flavonol, which can be found in a variety of vegetables, fruits, and nuts [67]. Fisetin has been confirmed to be a highly effective senolytic compound. As a BCL2 inhibitor, it can induce apoptosis [68]. Fisetin can selectively eliminate more than 50% of senescent mouse embryonic fibroblasts at a concentration of 5 μM, and its remarkable senolytic activity in IMR90 cells kept well at a concentration of 7.5 μM [69]. Furthermore, intervention with fisetin in aged wild-type mice can prolong longevity. Feeding food containing 500 mg/kg of fisetin can also reduce the number of senescent cells in progeroid Ercc1−/∆ mice, which confirms its senolytic activity [69].
Fisetin has also been shown to relieve myocardial infarction and reduce the damage caused by myocardial ischemia. A pretreatment with 10 mg/kg and 20 mg/kg fisetin in rats can decrease the expression of IL-6 and TNF-α levels, which are important components of SASP. Fisetin can also reverse ISO-induced detrimental effects on left ventricular dysfunction, such as decreased contractility (+LVdP/dtmax) and relaxation (−LVdP/dtmax), and increased LVEDP. Furthermore, it has been well demonstrated that RAGE can be activated during ischemic injury with upregulated NF-κB expression, modulating involvement in myocardial infarction [13]. Fisetin significantly reduced the expression of RAGE and NF-κB p65 in the myocardium, and mitigated injury. In addition, fisetin could increase the expression of key proteins such as p-IGF1R, p-PI3K, and p-AKT in the IGF-IR-dependent PI3K/Akt cell survival pathway in H9c2 cardiomyoblasts, which further proved its protective effect on cardiac cells [70]. Nevertheless, low oral bioavailability, primarily due to poor absorption and rapid metabolism, remains a major challenge for its clinical application [71].

4.1.3. Curcumin

Curcumin is a natural polyphenol mainly extracted from turmeric, which has been consumed in Asia for centuries. It exhibits anti-inflammatory, antioxidant, and anti-obesity properties [72,73]. Curcumin is one of the world’s largest-selling natural food colorings and is approved for use by the World Health Organization and the United States Food and Drug Administration. Abundant studies have shown that curcumin prolonged the lifespan of Drosophila melanogaster and C. elegans, proving its powerful anti-aging capacity [74].
Thrombosis is the cause of fatal heart attacks like strokes and heart attacks. Curcumin can inhibit arachidonic acid-induced aggregation by reducing thromboxane formation, which contributes to antithrombosis and cardiovascular protection [75]. In vitro studies have shown that curcumin protects against collagen–epinephrine-induced thromboembolism in mice [76].
Furthermore, it was reported that endothelial cells and SMCs are potential targets for curcumin against atherosclerosis [77]. TNF-α can promote the expression of genes related to adhesion, such as vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 [78], while curcumin inhibits the expression of these adhesion molecules by downregulating signaling pathways like NF-κB to inhibit the adhesion of monocytes on human endothelial cells and improve endothelial dysfunction. An in vitro experiment showed that the pre-exposure of endothelial cells to curcumin (0.5–1 μM) for 3 h reduced the adhesion of monocytes and endothelial permeability, reflecting a potential benefit for the vascular endothelial function barrier [79]. Another in vitro study indicated that curcumin reduced the proliferation and migration of SMCs and collagen synthesis by blocking the binding of platelet-derived growth factor to its receptor. This has been confirmed in another experiment in rats with carotid balloon injury [80]. Curcumin can also be an inhibitor of NF-κB, which is a vital signaling pathway for inflammation and senescence, inhibiting the expression of SASP to treat CVDs [81].
However, curcumin has poor water solubility and fast degradation, leading to poor oral administration effects [82]. How to overcome the above shortcomings is an important measure to improve the biological and pharmacological activities of curcumin.

4.1.4. Cardiac Glycoside

Cardiac glycoside is a type of steroid glycoside existing in the natural world, which is formed by the combination of an aglycone fragment and a sugar fragment. It has been approved for the treatment of heart diseases such as congestive heart failure and arrhythmia [83]. In the cardiac glycosides family, many compounds have been proven to have strong senolytic activity.
Digoxin, derived from digitalis plants, is a widely used cardiac glycoside that reduces hospitalizations in heart failure patients but carries risks, like arrhythmias [84]. The researchers found that digoxin could inhibit the alpha subunit of the Na+/K+ ATPase pump, resulting in the depolarizing effect of senescent cells, cell acidification, and induced senescent cell death [85]. Cardiac glycoside is broad spectrum senolytic, besides digoxin, proscillaridin A, k-Strophanthin, and strophanthidin also proved to be senolytic in senescent IMR90 cells, senescent A549 cells, and SK-Hep1 cells [84]. Besides the senolytic activity, digoxin can also act as a senomorphic, increasing T reg cells and reducing their transformation into Th17 cells that produce SASP, such as TNF-α and IL-6 [86]. The results of animal experiments showed that taking digoxin for 12 weeks can significantly reduce the levels of IL-6, IL-17A, TNF-α, and other SASPs in atherosclerotic mice fed with high-fat food, increasing the levels of anti-inflammatory IL-10 to reduce atherosclerotic plaques [87].

4.2. Senomorphics

Senescent cells are characterized by prolonged and usually irreversible cell cycle arrest, DNA, and other types of macromolecular damage [88]. Furthermore, senescent cells exhibit molecular features such as the secretion of multiple bioactive factors, including inflammatory cytokines, chemokines, growth factors, and matrix metalloproteinases, known as SASP [89]. SASP can recruit immune cells to clear senescent cells; however, too much SASP (TGF-β family members, VEGF, and so on) may increase inflammation and accelerate aging via paracrine [90]. A treatment that does not lead to cell death by inhibiting SASP secretion from senescent cells to delay the process of aging is called senomorphic. Rapamycin is one of the earliest identified senomorphics. As an mTOR inhibitor, numerous studies have clearly demonstrated that rapamycin can reduce cell senescence and inhibit the secretion of SASP markers in mouse, rat, and human cell lines to extend lifespan [91,92,93,94]. Since its discovery, more natural products with senomorphic activity have been identified.

4.2.1. Resveratrol

Resveratrol is a natural phenolic substance originally extracted from Veratrum grandiflorum and also found in grapes, peanuts, and other plants. Known for its antioxidant and anti-inflammatory activity, resveratrol can reduce ROS and holds great potential in the field of cardiovascular protection [95]. The protective effect of resveratrol on ischemic brain injury was well supported in pre-clinical studies [96,97]. Resveratrol is an activator of silent information regulator Sirtuin 1 (SIRT1) [98]. Numerous studies have demonstrated that SIRT1 acts as a crucial anti-aging molecule regulating signaling molecules related to DNA damage repair [99,100,101,102]. Studies have shown that resveratrol enhances SIRT1 expression and inhibits NF-κB activation to exert an anti-inflammatory effect [103]. The administration of 25 mg/kg/d of resveratrol for three days protected cerebral vascular endothelial cells in stroke model rats, alleviated brain damage, reduced inflammation, and prevented recurrent ischemic stroke [104], which was associated with activation of SIRT1. A 10 mg/kg pretreatment of resveratrol in LPS-induced myocardially injured mice reduced the expression of SASPs such as TNF-α and IL-1β [105]. In addition, a 30 mg/kg intraperitoneal injection of resveratrol lasting for seven days provided neuroprotection in rats with ischemic brain injury, reflected in the significant reduction in ischemic infarction size, which is mediated by the regulation of PI3K/AKT/mTOR signaling pathway [106].
Numerous clinical trials have explored the potential benefits of resveratrol for the prevention or treatment of CVD. In a double-blind trial comprising 40 post-infarction Caucasian patients, a daily dose of 10 mg resveratrol supplementation for 3 months improved left ventricular diastolic function and increased flow-mediated vasodilatation compared to the placebo group [107]. In another randomized clinical trial, 500 mg resveratrol taken daily for 30 days could increase circulating SIRT1 and decrease plasma noradrenaline, suggesting benefits in inhibiting inflammation and improving endothelial dysfunction [108]. Moreover, a meta-analysis of randomized controlled trials showed that resveratrol can reduce the levels of TNF-α in patients with CVDs [109].
However, the validity of existing human studies has been challenged by some researchers. Visioli [110] argued that small sample sizes of patients and short-term studies led to inconclusive results in human studies.

4.2.2. Kaempferol

Kaempferol, the most common flavonoid, plays an active role in antibacterial and anticancer [111]. Kaempferol is also an inhibitor of SASP by inhibiting NF-κB p65 activity and IκBζ expression via the IRAK1/IκBα signaling pathway. In particular, blocking IκBζ expression decreased the expression of IL-1α, IL-1β, and other SASP in senescent BJ cells, and significantly decreased the mRNA levels of SASP and IκBζ in the kidneys of aging rats [112].
Similarly, due to its powerful antioxidant properties, kaempferol can inhibit inflammation and oxidative stress to alleviate endothelial dysfunction mediated by endothelial injury. Kaempferol can significantly attenuate the expression levels of inflammatory factors TNF-α and IL-6 in H2O2-stimulated HUVECs. In vivo experiments in mice also proved that the expressions of GSH-Px and SOD in paraquat-induced model mice treated with kaempferol at 50 mg/kg/d for 10 days were significantly increased compared with the model group, and the expression levels of TNF-α and IL-6 in the abdominal aorta of mice treated with kaempferol were decreased, which may be related to the activation of the Nrf2/HO-1 signaling pathway [113]. Another study also reported the therapeutic effect of kaempferol on atherosclerosis. Ovariectomized female rats fed a high-fat diet had increased lipid deposition in the aorta, and the treatment with kaempferol at 50 mg/kg or 100 mg/kg inhibited the progression of the lesions, which showed a significant reduction in area and lipid deposition in a concentration-dependent manner. The serum TNF-α and IL-6 expression levels were also significantly decreased after the treatment, which was probably because the kaempferol upregulated the expression of GPER, which has been considered to be involved in the progression of AS and the activation of the PI3K/AKT/Nrf2 pathway, revealing its anti-inflammation and anti-oxidation capacity [114]. These findings provided new guidance for the treatment of atherosclerosis in postmenopausal women.

4.2.3. Colchicine

The formation of atherosclerotic plaque is one of the common causes of ischemic heart disease. In recent years, a growing number of studies have indicated that powerful lipid-lowering drugs, such as statins and PCSK9, can reduce lipid deposition in arteries, reverse atherosclerotic plaque, and restore arterial elasticity [115,116]. Colchicine, a natural alkaloid from the flower Colchicum autumnale, offers an anti-inflammatory approach to plaque regression. A prospective, open-label, single-center study demonstrated a significant reduction (15.9 mm3 vs. 6.6 mm3; p < 0.05) in low-attenuation plaque volume in ACS patients who took colchicine 0.5 mg/day for 12 months, and although the total volume of the atherosclerotic plaque was not statistically significant, the trend of significant decrease in the colchicine treatment group was instructive. Moreover, other Coronary CTA evaluation indexes, such as Dense Calcified Plaques Volume, Noncalcified Plaque Volume, and LDL, were all decreased after the treatment with colchicine [117]. Although colchicine’s mechanism of action is not completely understood, several pathways and targets involved in inflammation have been demonstrated to be closely related to the reduction in or reversal of atherosclerotic plaques. IL-1β, IL-18, and IL-6 expressed in the downstream are key inflammatory factors for plaque formation and progression. Colchicine can inhibit the activation of caspase-1 by downregulating the expression of the TNF-α receptor on the surfaces of macrophages, thereby inhibiting the secretion of IL-1β and IL-18, and the production of other inflammatory mediators (IL-6, TNF-α, etc.) and TGF-β [117]. However, a meta-analysis of randomized controlled clinical trials indicated that taking colchicine would increase the risk of gastrointestinal and diarrhea events [118]. Overall, the inhibition of these SASP provides great support to reversing plaque and restoring arterial elasticity.
Table 1. Natural products targeting senescent cells and disease interventions.
Table 1. Natural products targeting senescent cells and disease interventions.
Natural ProductsCell/Tissue TypesMechanismsDiseasesReferences
FisetinH9c2 cardiomyoblastsincrease the expression of p-IGF1R,
p-PI3K, and p-AKT		hypertension[70]
myocardiumreduce the expression of RAGE and NF-κB p65relieve myocardial infarction[13]
Curcuminmonocytesinhibit the adhesion of monocytes by down-regulating NF-κB pathwayrelieve vascular endothelial
dysfunction		[79]
SMCsreduce proliferation and migration[80]
Digoxinaortareduce the levels of IL-6, IL-17A, and TNF-α and other SASPs, increase the levels of anti-inflammatory IL-10reduce atherosclerotic plaques[87]
Resveratrolcerebral vascular endothelial cellsreduce ROS and inflammationrecurrent ischemic stroke[104]
brainregulate PI3K/AKT/mTOR signaling pathwayreduce the size of ischemic infarction[106]
Kaempferolabdominal aortadecrease the expression of IL-1α, IL-1β and other SASPrelieve vascular
injury		[113]
aortadecrease serum TNF-α and IL-6 expression levels, activate the PI3K/AKT/Nrf2 pathwayrelieve
atherosclerosis		[114]
Colchicineaortainhibitor of TNF-α receptorreversal of atherosclerotic plaque[117]

5. Research Methods for Natural Products in CVDs

Different types of senescent cells independently or jointly promote the occurrence and deterioration of different CVDs. The use of natural products in the treatment of CVDs is a major research direction at present. Natural products with clear target proteins or target cells will help not only to clarify the targeted cell types of specific diseases but also further explore their pathways and mechanisms of action. Exploring and applying different types of research methods have a profound impact on promoting the application of natural products.

5.1. Single-Cell RNA Sequencing

In previous studies, traditional RNA sequencing was analyzed by extracting RNA from unclassified cell populations or treated homogenate tissue, determining RNA sequence information and expression levels to provide a theoretical basis for further mechanism exploration [119]. However, it is impossible to precisely identify cell types expressing specific genes via redundant data. In contrast, single-cell RNA sequencing can evaluate gene expression at the single-cell level and characterize cardiovascular cell heterogeneity [120], contributing to discovering potential targets for CVD and facilitating the implementation of precise intervention therapy for natural products. The overview of identifying target proteins via single-cell RNA sequencing is summarized in fig 3. Wenhui et al. performed 10×scRNA-seq on aortic tissues of mice of different weeks of age, finding endothelial cells 1 (EC 1) that highly expressed Cd36, Rgcc, and Gpihbp1 exhibited higher senescent activity and participated in the aging process of aorta in aged mice (86 weeks old). EC 1 was significantly enriched in leukocyte trans-endothelial migration and the platelet activation pathway, indicating its high susceptibility to vascular inflammation during aging. Furthermore, the analysis of SRNA-SEQ and the KEGG pathway indicated that the expression of TNF-α, NF-κB, and TGF-β was upregulated in the aortic fibroblasts of 26-week-old mice, which promoted aortic inflammation–aging [121]. Accordingly, the precise targeting of EC 1 and fibroblasts by natural products may achieve the therapeutic purpose of treating aortic dissection. Moreover, using single-cell RNA sequencing analysis, Luo et al. [122] identified a substantially increased proportion of synthetic SMCs in the aortic cell population of patients with aortic dissection compared to the control group. By constructing the potential developmental trajectories of cell type transformation, it was concluded that synthetic SMCs were switched to Fibromyocyte, LipoSCM, and Fibro-like SMC, which were developed from partial systolic SCMs. A subsequent series of experiments on the mechanism suggested that the AP-1 transcriptional complex mediated the transition of contractile SMCs, which worked via the TNF-OXPHOS-AP-1 axis. Therefore, finding compounds such as OXPHOS activators or AP-1 inhibitors targeting the TNF-OXPHOS-AP-1 axis to intervene in AD may be an emerging approach for the non-surgical treatment of aortic dissection in the future.
Natural products have shown potential in targeting specific cardiovascular cells. It has been reported that Phloretinis, a flavonoid compound that can activate AMPK, inhibits the EndMT pathway in HUVECs and improves endothelial damage [123]. Additionally, as a flavonoid, Nobiletin can inhibit NF-κB mediated TF expression in endothelial cells and inhibit thrombosis [124]. Nevertheless, current studies on natural products for the treatment of CVDs focus more on the macro mechanism at the tissue or individual level, and the specific target cell subsets of natural products identified by single-cell RNA sequencing have not yet been further elaborated, so this deserves further exploration in the future.

5.2. Activity-Based Protein Profiling

Activity-Based Protein Profiling (ABPP) is a small-molecule compound target protein screening technique developed based on click chemistry and LC-MS, it is a part of chemical proteomics, and it has broad application prospects. The reaction group on one side of the activity-based probes (ABPs) can bind to the target protein and the other side can add fluorophore or biotin by click reaction for tracer and separation. The binding target protein can be quickly and directly screened by LC-MS [125]. The overview of identifying target proteins via ABPP is summarized in Figure 3. Using ABPP technology, Su et al. revealed that N-Cinnamoylpyrrole-derived alkaloids from the genus Piper can regulate NF-κB and NRF2 signaling pathways by targeting the eEF1A1 protein, relieve inflammation and oxidative stress, and treat ischemic stroke [126]. Additionally, it is reported that Seventy Flavors Pearl Pill, which is a traditional Tibetan medicine, stabilized energy metabolism by regulating key proteins such as ATP5PD, NDUFB4, and COX15 in the OXPHOS pathway to treat ischemic stroke [127]. This suggests that ABPP technology, as a new method of modern pharmacological research, can help us find target proteins and analyze the mechanism of natural products in treating CVDs through nutritional intervention.

6. Conclusions and Future Direction

Much evidence shows that the presence and accumulation of senescent cells in age-related diseases, such as CVD, contribute to and exacerbate the progression of these diseases, making senescent cells important therapeutic targets. Natural products extracted from fruits, vegetables, grains, and so on have gradually been adopted as new potential therapies for the treatment of many CVDs due to their high safety profile over long-term use and their ability to act on a variety of cell signaling pathways. Some nature-based drugs are now being used in clinics due to their pleiotropic properties and synergistic outcomes, as well as their reduction in the side effects associated with current drug treatments [75]. In particular, some natural products, especially polyphenols and flavonoids, exhibit significant antioxidant and anti-inflammatory activity [128] while having the potential to selectively kill senescent cells and/or inhibit SASP.
The review by Chaib [8] et al. discussed the general characteristics of cellular senescence, including the mechanisms and pathways of cellular senescence, and comprehensively summarized advances in small-molecule compounds with senolytic/senomorphic activities across preclinical models. In contrast, our review focuses on the specific mechanisms and pathways of senescent cardiovascular cells, including endothelial cells, smooth muscle cells, immune cells, cardiomyocytes, and cell subsets like SMCs, in regulating CVDs, which are not fully summarized in prior reviews. Moreover, natural products with senolytic or senomorphic activity targeting cardiovascular senescent cells or proteins and research methods on natural products in cardiovascular aging are summarized innovatively in our review. The comparative information of current review and our review is in Table 2. Despite advances in natural product research for cardiovascular diseases (CVDs), most studies focus on tissue- or organism-level mechanisms, with limited exploration of cell subsets specifically targeted by natural products. Single-cell RNA sequencing can evaluate gene expression at the single-cell level and characterize cardiovascular cell heterogeneity, contributing to discovering potential targets for CVD and facilitating the implementation of precise intervention therapy for natural products. In addition, it can also be combined with ABPP technology for further enhancing target discovery. After binding to the target proteins of specific cell subsets, small-molecule probes can be rapidly and directly screened through LC-MS, which is conducive to analyze the mechanism of natural products treating CVD through nutritional intervention.
As valuable resources for human beings, natural products are still being deeply explored for their anti-senescence effects. Therapies targeting senescent cells with different natural products are advancing in cell and animal tests, but many compounds have not yet been tested or have shown limited effectiveness in clinical trials. This highlights the need for further research to fully explore the potential of these natural therapies in anti-aging usages and treating CVDs.

Author Contributions

Conceptualization, Y.Z. (Yinhua Zhu) and Y.L.; methodology, Y.Z. (Yinhua Zhu), Y.L., H.T., and X.Z.; validation, H.T. and X.Z.; formal analysis, H.T. and S.H.; investigation, H.T., X.Z., S.H., Y.S., W.J., and J.Z.; writing—original draft preparation, H.T. and X.Z.; writing—review and editing, Y.Z. (Yan Zhang), J.G., P.A., J.L., P.W., Y.L., and Y.Z. (Yinhua Zhu); visualization, Y.S.; project administration, Y.L. and Y.Z.; funding acquisition, Y.L. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by National Natural Science Foundation of China, grant number 82470442, 82170429; the State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, Chinese Academy of Medical Sciences, grant number 2024GZkf-05.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Data will be provided upon request.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:
CVD(s)Cardiovascular Disease(s)
SASPSenescence-Associated Secretory Phenotype
VSMCsVascular Smooth Muscle Cells
EMTEpithelial-Mesenchymal Transition
SMCsSmooth Muscle Cells
TNFTumor Necrosis Factor
NONitric Oxide
INF-γInterferon-Gamma
SIRT1Sirtuin 1
EC 1Endothelial Cells 1
D + QDasatinib and Quercetin
ABPPActivity-Based Protein Profiling
ABPsActivity-Based Probes

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Figure 1. Cellular senescence associated with age-related CVDs.
Figure 1. Cellular senescence associated with age-related CVDs.
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Figure 2. Mechanisms of different types of senescent cells regulating CVDs.
Figure 2. Mechanisms of different types of senescent cells regulating CVDs.
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Figure 3. Overview of identifying target proteins via single-cell RNA sequencing (A) or ABPP (B). Circles of different colors represent different types of cells or cell subsets (A).
Figure 3. Overview of identifying target proteins via single-cell RNA sequencing (A) or ABPP (B). Circles of different colors represent different types of cells or cell subsets (A).
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Table 2. Comparative table of this review article vs. others.
Table 2. Comparative table of this review article vs. others.
Current ReviewKey Points of Current ReviewThe Novel Points of Our Review
Chaib et al. [8]The general mechanisms and pathways of cellular senescenceThe specific mechanisms and pathways of senescent cardiovascular cells and cell subsets in regulating CVDs
Small-molecule compounds with senolytic/senomorphic
activities in cell senescence
Advantages and disadvantages of senolytics and senomorphics
Grootaert et al. [127]The general characteristics of cellular senescenceDifferent targets of senescent cardiovascular cells and target proteins of natural products
The role of senescent cells in cardiometabolic diseases
Small-molecule compounds with senolytic/senomorphic
activities in cell senescence
Zhang et al. [128]Small-molecule compounds with senolytic/senomorphic
activities and their mechanisms of action		Research methods on natural products in cardiovascular aging
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Tang, H.; Zhang, X.; Hu, S.; Song, Y.; Jin, W.; Zou, J.; Zhang, Y.; Guo, J.; An, P.; Luo, J.; et al. Natural Products Acting as Senolytics and Senomorphics Alleviate Cardiovascular Diseases by Targeting Senescent Cells. Targets 2025, 3, 23. https://doi.org/10.3390/targets3030023

AMA Style

Tang H, Zhang X, Hu S, Song Y, Jin W, Zou J, Zhang Y, Guo J, An P, Luo J, et al. Natural Products Acting as Senolytics and Senomorphics Alleviate Cardiovascular Diseases by Targeting Senescent Cells. Targets. 2025; 3(3):23. https://doi.org/10.3390/targets3030023

Chicago/Turabian Style

Tang, Hejing, Xu Zhang, Senyang Hu, Yuhan Song, Wenhua Jin, Jianmin Zou, Yan Zhang, Jiayue Guo, Peng An, Junjie Luo, and et al. 2025. "Natural Products Acting as Senolytics and Senomorphics Alleviate Cardiovascular Diseases by Targeting Senescent Cells" Targets 3, no. 3: 23. https://doi.org/10.3390/targets3030023

APA Style

Tang, H., Zhang, X., Hu, S., Song, Y., Jin, W., Zou, J., Zhang, Y., Guo, J., An, P., Luo, J., Wang, P., Luo, Y., & Zhu, Y. (2025). Natural Products Acting as Senolytics and Senomorphics Alleviate Cardiovascular Diseases by Targeting Senescent Cells. Targets, 3(3), 23. https://doi.org/10.3390/targets3030023

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