Cellular senescence represents a permanent arrest of cell cycle, which may be produced by a category of events, both intrinsic and extrinsic. DNA damage, shortening of telomeres, replication stress, and ROS [Figure 3) are the four basic categories that may be used to classify the triggers (Lopez-Otin et al., 2013).

A process known as DNA damage-induced senescence (DIS) is set in motion when double-stranded DNA breaks (DSBs) or other forms of DNA damage occur (Campisi, 2005). The presence of double-strand breaks triggers the DNA damage response (DDR), which then activates the ataxia-telangiectasia mutated (ATM) and Rad3-related (ATR) kinases (Campisi, 2005). The activation of these kinases results in a halt in the cell cycle and the senescence initiation, leading to the phosphorylation of p53 and other downstream effectors. Increasing evidence suggests that DIS plays a pivotal role in the progression of various age-related diseases, including cancer and neurodegenerative diseases (Childs et al., 2015).

Telomere shortening, a process characterized by the continuous reduction in the length of repeating DNA sequences located at the chromosome ends, is responsible for the occurrence of telomere shortening-induced senescence (TSIS) (Babizhayev and Yegorov, 2015). The normal process of telomere shortening happens whenever a cell divides; however, this natural process may be balanced out by the action of telomerase (Babizhayev and Yegorov, 2015; Shay, 2018). Telomeres naturally become shorter when cells divide (Shay, 2018). Eventually, the telomeres of cells that do not produce telomerase, such as somatic cells, become dangerously short, resulting in activation of DNA damage response and senescence (Razgonova et al., 2020; Lansdorp, 2022). There is evidence that TSIS has a role in both ageing and the illnesses that are associated with aging (Razgonova et al., 2020; Lansdorp, 2022).

The buildup of stalled or collapsed replication forks is what causes replication stress-induced senescence (RSIS), which may be caused by several different circumstances, including replication mistakes, DNA damage, and nucleotide depletion. The activation of DDR pathways in response to replication stress leads to the inhibition of the cell cycle and the initiation of senescence (Pedroza-Garcia et al., 2022). The RSIS gene has been demonstrated to play a role in the development of age-related illnesses and cancer pathogenesis (Pedroza-Garcia et al., 2022; Dhama et al., 2019).

The buildup of ROS, which are byproducts of cellular metabolism, is the fundamental trigger for ROS-induced senescence (ROSIS), also known as senescence induced by ROS (Fakouri et al., 2019). The oxidative injury inflicted by ROS on cellular elements such as DNA, proteins, and lipids can ultimately initiate the activation of DDR and senescence pathways (Fakouri et al., 2019; Reddy et al., 2017). ROSIS has been demonstrated to actively contribute to the etiology of aging and age-related disorders, such as neurodegenerative diseases (Reddy et al., 2017).

In summary, cellular aging can be initiated by a diverse array of internal and external factors, involving DNA damage, shortened telomeres, replication stress, and ROS (Reddy et al., 2017). It is necessary to have a solid understanding of the causes of senescence to be able to devise methods that may postpone or prevent illnesses associated with aging [Figure 4).

This figure illustrates the various stimuli and consequences of cellular senescence. Triggers such as DNA damage occurs due to events like double-stranded DNA breaks (DSBs), which activate the DNA damage response (DDR) and lead to the phosphorylation of p53 and other downstream effectors, initiating DNA damage-induced senescence (DIS). Telomere Shortening results from repeated cell divisions, leading to critically short telomeres that activate DDR and promote telomere shortening-induced senescence (TSIS). Replication Stress arises from stalled replication forks caused by replication errors, DNA damage, or nucleotide depletion, resulting in replication stress-induced senescence (RSIS) through DDR activation and cell cycle inhibition. Lastly, Reactive Oxygen Species (ROS), byproducts of cellular metabolism, induce oxidative damage to DNA, proteins, and lipids, triggering ROS-induced senescence (ROSIS) by activating DDR pathways. To sum up, these senescence pathways contribute to the progression of age-related diseases, including cancer and neurodegenerative disorders.

Several neurodegenerative disorders have been linked to the existence of senescent cells. Senescent cells are observed in neurons, microglia, and astrocytes of individuals with AD (Reddy et al., 2017; Slanzi et al., 2020). It has been reported that senescent astrocytes are a contributing factor in amyloid-beta plaques production in the brain (Reddy et al., 2017).

AD is a neurodegenerative condition described by the buildup of beta-amyloid plaques and neurofibrillary tangles within the brain (Reddy et al., 2017). This accumulation eventually causes the death of neurons and cognitive decline. The progression of AD has been linked to the senescence process observed in neurons, microglia, and astrocytes (Swerdlow and Khan, 2004).

p16 and p21, the senescence markers have been detected in the brains of individuals diagnosed with Alzheimer’s disease (Swerdlow and Khan, 2004). These markers related to tau pathology and neuronal loss are found in neurons (Bussian et al., 2018; Heneka et al., 2013). In addition, an accumulation of damaged DNA and oxidative stress may promote senescence in neurons, which results in a decline in mitochondrial function, synaptic dysfunction, and upregulated production of pro-inflammatory cytokines (Selvarasu et al., 2023). Senescence can also cause the death of neurons (Bussian et al., 2018; Heneka et al., 2013). When the brain is injured or infected, the resident immune cells known as microglia play a key role in both the maintenance of homeostasis and the response to the condition (Bussian et al., 2018; Nicaise et al., 2019). Microglia become persistently activated and create a proinflammatory phenotype in AD, which contributes to the neuroinflammation seen in this condition (Nicaise et al., 2019). Senescence in microglia has been connected to SASP factors development, which may make neuroinflammation and neurodegeneration worse (Nicaise et al., 2019; Freund et al., 2010).

Astrocytes, the predominant form of glial cells in the brain, offer structural and metabolic support to neurons (Freund et al., 2010). Evidence of enhanced expression of p16 and p21 in the brains of AD patients suggests that senescence in astrocytes may perform a vital role in the development of the disease (Sahu et al., 2022; Li et al., 2021). The ageing of astrocytes may result in a reduction in neurotrophic support, an impairment of glucose metabolism, and upregulated inflammation (Sahu et al., 2022; Regen et al., 2017). Some evidence suggests that blocking senescence in neurons, microglia, and astrocytes could be an effective therapy for AD (Sahu et al., 2022; Regen et al., 2017). Studies have shown that senolytic drugs, targeting senescent cells selectively, hold promise in enhancing cognitive abilities and mitigating neuroinflammation in mouse models of AD (Regen et al., 2017; Beraud and Maguire-Zeiss, 2012; Kang, 2019).

Parkinson’s Disease (PD) impacts dopaminergic neurons located in the substantia nigra region of the brain, which deteriorates over time (Beraud and Maguire-Zeiss, 2012). Many investigations have led researchers to the conclusion that cellular senescence is a critical factor in the development of PD (Beraud and Maguire-Zeiss, 2012).

Markers of senescence-like p16, p21, and p53 present in dopaminergic neurons, astrocytes, and microglia in the substantia nigra are affected by PD (Tian et al., 2021; Hohn et al., 2017). In addition, DNA damage indicators, including gamma-H2AX and 8-hydroxydeoxyguanosine (8-OHdG) were discovered in these cells (Hohn et al., 2017). According to these indicators, DNA damage-induced senescence could perform a vital role in the development of PD (Kang, 2019; Hohn et al., 2017). In addition, previous research has shown that oxidative stress caused by dysfunction of mitochondrial may bring about cellular senescence in PD patients (Kang, 2019; Schrauwen et al., 2010). Senescence can result from mitochondrial dysfunction, along with oxidative stress, which is correlated with the buildup of damaged proteins, impaired autophagy, and compromised mitochondrial quality control (Hohn et al., 2017; Schrauwen et al., 2010).

In summary, cellular aging, initiated by DNA damage and oxidative stress, could potentially play a role in the development of PD by instigating senescence in dopaminergic neurons, astrocytes, and microglia (Hohn et al., 2017). This may be the case because cellular senescence causes dopaminergic neurons to die off (Hohn et al., 2017). Advancing the discovery of markers for senescence and uncovering the underlying processes in PD could enhance the identification of novel therapeutic targets for treating the condition (Kang, 2019).

ALS, a neurodegenerative condition, is characterized by the gradual degeneration of motor neurons in both the brain and spinal cord (Pandya and Patani, 2020). The process of cellular senescence has been linked to the onset of ALS (Pandya and Patani, 2020). Postmortem examination of the spinal cords of ALS patients has shown higher levels of senescence markers such as p16 and p21 in the motor neurons, astrocytes, and microglia of these tissues (Ziff and Patani, 2019). Studies in individuals with ALS have demonstrated that aging cells display a pro-inflammatory SASP, contributing to the advancement of the disease (Oh et al., 2016). The SASP is distinguished by increased production and release of pro-inflammatory cytokines, chemokines, and matrix metalloproteinases in individuals with ALS, potentially resulting in chronic inflammation and tissue damage if not addressed (Pandya and Patani, 2020; Oh et al., 2016).

In ALS, senescent cells exhibit compromised autophagy and lysosomal function, which may result in the aggregation of dysfunctional organelles and protein aggregates (Pandya and Patani, 2020). This is in addition to SASP, a known risk factor for the disease. This buildup may make inflammation and neurodegeneration in ALS patients even worse (Liddelow and Barres, 2017). In the treatment of ALS, one possible therapeutic technique is to target cellular senescence. Recent studies demonstrated that treatment utilizing senolytics, compounds designed to induce apoptosis specifically in senescent cells, improved motor function and prolonged lifespan in a mouse model of ALS (Maximova et al., 2021). Considering the evidence linking senescent cells to the development of ALS, targeting these cells in treatment could offer a promising therapeutic approach for this debilitating illness (Maximova et al., 2021).

The neurodegenerative condition known as HD is passed down through families and is brought on by a change in the huntingtin gene (Jiang et al., 2011). The gradual degeneration of the striatum, which is the part of the brain that is important for both motor control and cognition, is the defining characteristic of HD (Jiang et al., 2011; Cohen and Torres, 2019). The concept of cellular senescence has been proposed as a potential factor in the onset of HD. Several studies have revealed indications of the existence of senescent cells in the brains of individuals with HD (Jiang et al., 2011; Cohen and Torres, 2019). Based on previous research, individuals with HD exhibit a buildup of senescent astrocytes in their brains, potentially resulting in neuroinflammation and the subsequent death of neurons in the neighboring regions (Liddelow and Barres, 2017; Cohen and Torres, 2019). Another research in HD animal models found senescent microglia in the striatum, which may be a factor in the progression of neuroinflammation and synaptic dysfunction (Liddelow and Barres, 2017; Jiang et al., 2011; Cohen and Torres, 2019).

It is possible that several other factors such as oxidative stress, damage to DNA, and shortening of telomeres, are to blame for the increase of senescent cells in HD (Acosta et al., 2013). Moreover, the mutant huntingtin protein can directly promote cellular senescence by activating the p53 pathway (Tian et al., 2021). As a potential treatment for HD, one strategy that shows promise targets cellular senescence (Tian et al., 2021; Jiang et al., 2011). Research findings demonstrated that inhibiting the p53 pathway enhanced motor function in a rat model of HD by lowering the number of senescent astrocytes that accumulated in the brain (Tian et al., 2021; Jiang et al., 2011; Cohen and Torres, 2019). In summary, it appears that cellular aging is significantly associated in the development of HD. Targeting senescent cells could emerge as a promising therapeutic approach for addressing this severe neurodegenerative condition (Jiang et al., 2011).

Senolytics are a group of drugs or plant chemicals that target and kill senescent cells in a specific way (Kang, 2019; Xu et al., 2018). In recent years, these compounds have gained a lot of attention because they might be able to treat age-related diseases (Kang, 2019; Xu et al., 2018; Zhu et al., 2015).

Senolytic drugs target specific molecular markers of cellular senescence, primarily p16Ink4a and p21Cip1/Waf1, which play crucial roles in neurodegenerative conditions. Senescence is characterized by cell cycle arrest mediated by these markers, with p21 acting downstream of the p53 pathway and p16 upstream of the RB pathway. This interaction leads to irreversible cell cycle arrest and contributes to the SASP, which exacerbates neurodegenerative diseases by promoting inflammation and tissue dysfunction (Kudlova et al., 2022; Wagner and Wagner, 2022; Chaib et al., 2022). Different senolytic agents, such as dasatinib and quercetin (D + Q), selectively eliminate senescent cells expressing high levels of p16 or p21. Their efficacy varies across neurodegenerative conditions due to the heterogeneous nature of senescent cells influenced by various stressors like oxidative damage or DNA damage responses (Chaib et al., 2022; Gasek et al., 2021). For instance, in AD models, targeting p21 may alleviate cognitive decline by reducing SASP factors that promote neuroinflammation (Kumari and Jat, 2021; Fan et al., 2024). Apparently, in models of PD, p16-targeting strategies may be more effective due to distinct cellular responses to stressors (Wagner and Wagner, 2022; Gasek et al., 2021). Thus, understanding these interactions is vital for optimizing senolytic therapies tailored to specific neurodegenerative conditions.

Dasatinib and quercetin form a well-established senolytic combination proven to eliminate aged cells across various tissues, resulting in improved functionality in aging mice (Kang, 2019; Zhu et al., 2015). In preclinical studies, other senolytic compounds [Figure 5), such as fisetin, have also shown promise (Zhu et al., 2015; Kirkland and Tchkonia, 2020). These substances function by inducing the death of senescent cells through various mechanisms, including the inhibition of anti-apoptotic pathways and promoting the initiation of apoptosis in senescent cells (Kirkland and Tchkonia, 2020). Senolytics show a lot of promise to treat diseases related to aging by stopping or reversing cellular senescence (Xu et al., 2018; Zhu et al., 2015).

Cellular senescence contributes to aging as senescent cells accumulate due to increased survival signals and reduced cell death, leading to tissue damage caused by inflammatory SASP factors. Treatments include senolytics, which remove these harmful cells, and senomorphics, reduce their damaging secretions, with effects on ageing and neurodegenerative diseases.

This figure illustrates the role of cellular senescence in aging, showing how the accumulation of senescent cells contributes to age-related diseases. Cellular senescence leads to reduced tissue function and the progression of aging-related pathology. The figure also outlines therapeutic strategies using senolytics and senomorphics that aim to enhance healthspan and reduce the effects of cellular senescence on aging and neurodegenerative diseases.

Dasatinib and Quercetin: Dasatinib is a tyrosine kinase inhibitor, while quercetin is a flavonoid molecule found in a wide range of fruits and vegetables.

Neurodegenerative diseases are characterized by a gradual deterioration in neuronal function, leading to eventual cell death, resulting in impaired cognitive and motor processes (Regen et al., 2017). With aging, there is a buildup of senescent cells that release pro-inflammatory and toxic substances, potentially leading to impaired neuronal function and the promotion of neuroinflammation (Baker et al., 2011; Freund et al., 2010; Regen et al., 2017).

The buildup of senescent cells has been recognized as a potential contributor to the onset of neurodegenerative diseases, underscoring the involvement of cellular senescence in their development (Baker et al., 2011; Freund et al., 2010). In preclinical investigations, usage of senolytics, has shown significant promise as a possible therapy for neurodegenerative illnesses (Maximova et al., 2021; Cohen and Torres, 2019).

In preclinical models of AD and PD, senolytics (Table 3) have been confirmed to be efficient in several trials in improving cognitive and motor impairments (Baker et al., 2011; Bussian et al., 2018; Maximova et al., 2021; Xu et al., 2018). Dasatinib, a senolytic medication, plus quercetin, an antioxidant, enhanced cognitive function in a mouse model of AD by lowering the number of senescent cells present in the brain (Baker et al., 2011; Bussian et al., 2018; Xu et al., 2018). Senolytic medication ABT-263 enhanced motor function and decreased the growth of aging cells in a mouse model of PD (Zhu et al., 2017; Tse et al., 2008). Similarly, ALS mouse model administered with senolytic medication navitoclax resulted in an enhancement in motor function and a reduction in neuroinflammation (Zhu et al., 2017; Liu et al., 2022).

MitoQ is a mitochondria-specific antioxidant that effectively inhibits oxidative damage to mitochondria (Wani et al., 2011). Recent study indicate that MitoQ can enhance mitochondrial activity, reduce oxidative stress-related aging, and lower reactive oxygen species (ROS) generation (Braakhuis et al., 2018). Using cellular models of prion disease, we examined MitoQ’s neuroprotective properties. Wu et al. (2025) demonstrate that MitoQ significantly reduces oxidative stress, mitochondrial dysfunction, and apoptosis caused by PrP106-126 by modifying DRP1- and OPA1-mediated mitochondrial dynamics. These results highlight MitoQ’s potential as a treatment for prion-induced neurodegeneration. In the 6-OHDA cell model of Parkinson’s disease, the mitochondria-targeted scavenger MitoQ decreases certain features of mitochondrial fission. Additionally, MitoQ prevented the pro-apoptotic protein Bax from moving to the mitochondria (Solesio et al., 2013). Furthermore, SS31 is a cell-permeable antioxidant peptide that targets mitochondria, reducing the formation of mitochondrial ROS, protecting mitochondrial structure, and alleviating mitochondrial dysfunction (Reddy et al., 2017). In APP/PS1 transgenic mice, increased levels of Aβ40/Aβ42 and the mitochondrial fission protein DLP1 were observed, along with decreased levels of SYN and PSD95, and elevated neuronal death and ROS production in the hippocampus (Jia et al., 2023). Long-term treatment with SS31 reversed these effects. Additionally, SS31 therapy corrected the cognitive deficits found in APP/PS1 transgenic mice. This study found that SS31 reduces ROS and Aβ levels, protects mitochondrial homeostasis and synaptic integrity, and improves behavioral impairments in early-stage AD. These findings suggest that SS31 may serve as a potential pharmacological treatment for managing or reducing the progression of Alzheimer’s disease. Melatonin is a methoxyindole that transmits circadian information about light and darkness (Claustrat and Leston, 2015). It also induces autophagy by decreasing methamphetamine toxicity, which protects against neuronal cell death in the AD brain (Hossain et al., 2021; Nopparat et al., 2023). Furthermore, depending on the phase of autophagy, melatonin can act as either a pro-autophagic signal or an anti-autophagic regulator (Hossain et al., 2019). Additionally, melatonin possesses antioxidant properties that help prevent mitochondrial damage, oxidative stress, and apoptosis. In a Parkinson’s disease model, melatonin can reduce oxidative stress, thereby decreasing mitochondrial breakdown and neuronal loss (Chuang et al., 2016).

There have been many hypotheses that put forth on the possible processes by which senolytics treat neurodegenerative illnesses (Zhu et al., 2017). Nevertheless, it is still not entirely clear how these treatments work (Campisi et al., 2019). Elimination of senescent cells is one strategy that may be used; these cells can cause neuroinflammation and neurodegeneration by the production of proinflammatory cytokines, chemokines, and matrix metalloproteinases. This can be prevented by the removal of these cells (Zhang et al., 2019; Campisi et al., 2019). Restoring the equilibrium between autophagy and apoptosis is another strategy that may be used; this can facilitate the removal of damaged proteins and organelles and stop the formation of hazardous aggregates (Zhang et al., 2019; Wong et al., 2020; Baar et al., 2017). Senescent cells may impede synaptic plasticity and neuronal activity by the production of toxic substances, which can be reversed by senolytics, which have the potential to have direct impacts on neuronal function (Wong et al., 2020; Baar et al., 2017).

In the context of clinical application, the development of senolytic drugs faces several limitations and hurdles. Key concerns include ensuring specificity toward senescent cells to avoid off-target effects, which is crucial for safety and efficacy. Additionally, competition from existing therapies for age-related conditions may hinder market acceptance. High costs associated with novel senolytic treatments could limit patient accessibility (Wong et al., 2023). Furthermore, the heterogeneity of the SASP complicates the identification of effective therapeutic targets (Chaib et al., 2022). Eventually, the need for extensive clinical trials to establish safety and efficacy remains a significant barrier to successful translation into clinical practice (Lelarge et al., 2024).

Senolytics have emerged as a promising approach for treating age-related diseases, including neurodegenerative conditions. Even though preclinical and clinical trials of the current senolytic drugs have shown promising results, their possible side effects are still a worry. Henceforth, assessing the senolytic activity of phytochemicals and exploring novel targets for senolysis will be crucial. Phytochemicals are compounds that come from plants and have been shown to have different pharmacological effects, such as slowing the aging process (Iyaswamy et al., 2023; Krishnamoorthi et al., 2023). Several studies have shown that phytochemicals like fisetin, quercetin, and curcumin can slow the aging process (Guan et al., 2024). It has been shown that these phytochemicals can selectively kill off old cells and make mice live longer and healthier. So, testing phytochemicals for their ability to slow the aging process could lead to the discovery of new compounds that could be used as senolytic drugs.

Notably, c current screening techniques include high-throughput library screenings and bioinformatics approaches to identify compounds targeting senescent cell anti-apoptotic pathways (SCAPs) (Zhang et al., 2021). For instance, prodrug strategies can enhance specificity for senescent cells by linking active compounds to moieties that activate in the presence of senescence markers (Zhang et al., 2021). Additionally, machine learning models have been successfully employed to predict senolytic activity from existing data, streamlining the identification process (Smer-Barreto et al., 2023). Future research should focus on integrating these methodologies, emphasizing robust validation in preclinical models to ensure efficacy and safety before clinical application (Chaib et al., 2022; Lelarge et al., 2024). By expanding on these techniques, researchers can better navigate the complexities of senolytic drug discovery and optimize the therapeutic potential of phytochemicals in combating age-related diseases.

Further, besides exploring novel senolytic compounds, identifying new targets for senolysis will be crucial. Current senolytic drugs primarily target the anti-apoptosis pathways activated in senescent cells. Recent studies, on the other hand, have found that senescent cells are also overactive in the inflammasome pathway and the mTOR pathway. Because of this, finding new senolysis targets could lead to the creation of more effective senolysis drugs. Developing methods to detect senescent cells without causing harm to the body is another key goal for the future. Currently, markers like p16INK4a and SA-β-Gal) are used to identify senescent cells. However, these methods are invasive and require a tissue biopsy. Developing non-invasive techniques to detect senescent cells could simplify the diagnosis and treatment of age-related diseases.

Overall, the future of senolytics appears promising, especially with the potential discovery of new compounds and targets for senolysis. Additionally, developing non-invasive methods to detect senescent cells could improve the diagnosis and treatment of age-related diseases.