In general, the worldwide burden of HNSCC mortality and incidence is changing. This trend is influenced by the aging and expanding population, along with shifts in the spread and prevalence of key cancer risk factors, many of which are linked to socioeconomic development. The latest study on cancer prevalence is conducted in 2020 according to the GLOBOCAN estimates of cancer mortality and incidence which is created by the International Agency for Research on Cancer (1). As reported by this study, new cases of mouth and lips cancers as well as larynx, Nasopharynx, Oropharynx, Hypopharynx, and Salivary glands are detected as 377,713, 184,615, 133,354, 98,412, 84,254, and 53,583 cases were worldwide (1). According to the statistics of this study, oral cancer is the 8th most public cancer among men while it is the 15th most public among women (1). Region-Specific Incidence of oral and lips cancers shows that Melanesia, south central Asia, eastern Europe, New Zealand and Australia are the 5 top regions for this cancer. Lip and oral cavity cancers are very common in South Central Asia (such as Sri Lanka, India, and Pakistan) and in Melanesia which shows that chewing betel nut in these regions is a vital risk factor for oral cancer (1). Over the last ten years, laryngeal cancer cases have risen by 23%. In developed countries, there has been a significant increase in cases among younger women, possibly due to evolving cultural norms regarding tobacco and alcohol use, along with a heightened burden of HPV (2). In Japan, the rates of tumors in the oral cavity, oropharynx, and salivary glands have increased further in women than in men, while the incidence of nasopharyngeal and laryngeal tumors has declined, particularly in association with certain factors (2).

The main risk factors typically related to HHNSCC include alcohol and tobacco use, chewing areca nut, human papillomavirus (HPV) infection, and Epstein–Barr virus (EBV) infection (particularly for nasopharyngeal cancers) (all risk factors are summarized in Figure 2).

The treatment of HNSCC involves using surgery, radiation, and chemotherapy in different combinations, depending on the TNM (node, tumor, and metastasis) stage and the primary location of the cancer (also summarized in Figure 4).

Trismus is a condition where individuals experience limited movement in the jaw muscles, making it difficult to open their mouths wider than 35 mm. This complication is observed after conventional treatments for HNCs including surgery. The current literature indicates that rehabilitation strategies designed to prevent trismus include both passive and active stretching exercises for the jaw, and may utilize jaw mobilization tools (all studies are summarized in Table 1). For instance, a group of researchers tried two different tools on HNC patients (77). Their study aimed to evaluate the efficiency of two extending devices for improving maximal mouth opening (MMO). A target sample of 30 patients per group was set and during the initial visit, patients received a stretching device. Results showed no noteworthy difference in MMO improvement between the two devices, with gains of 3.0 mm for TheraBite users and 1.5 mm for DTS users. Only one patient achieved full recovery from trismus (77). They also reported that patients found it difficult to use either stretching device because of the demanding exercise regimen, pain experienced during workouts, issues with properly using the stretching equipment, and their overall declining health (77).

Sandler et al. (78) examined Jaw variety of motion exercise therapy on patients with oropharyngeal and/or oral tumors who were scheduled to undergo surgery and did not use any tools in their study. They measured jaw ROM, pain numeric rating scales (NRS), patient-rated QoL and performance status scale-head and neck (PSS-HN) in their subjects and found out that the degree of jaw opening was significantly linked to several QoL assessments, such as the ability to eat normally and the comfort of eating in public. Moreover, it was seen the relationship between MDADI global and jaw MIO was stronger 1 month after the operation compared to 2–3 months or 6 months’ post-surgery. However, this relationship weakens in the months after the surgery (78). However, this study did not assess the start of exercise at 1, 2–3, and 6 months after surgery. Although the changes between the results of the two exercise intervention protocols were not statistically significant, this study provides a valuable basis for future research into the potential advantages of starting jaw exercises early versus later. The preliminary results, along with the nearly significant correlation between maximum interincisal opening (MIO) and MDADI Global scores. However, the small sample size and other limitations highlight the need for a follow-up study with a larger participant group, an extended time frame between interventions, and a well-defined control group to better assess the ideal timing and effectiveness of postoperative jaw exercise interventions (78).

Another study on oral cancer patients also confirms the impact of exercise in decreasing trismus and improving mandibular function in subjects undergoing curative surgery for oral cancer (79). In study, people who were admitted for oral cancer surgery at a general hospital were recruited and divided into either the active control group or the experimental group. Both groups participated in a 12-week intervention program that included warm compresses, massages for the masticatory muscles, and jaw exercises (79). These subjects were assessed at the beginning of the study, at week 4, and week 12. The results indicated that after 12 weeks of intervention, the experimental group engaged in 299.67 min more practice time than the active control group. The increase in maximum interincisal opening was 10.30 mm higher in the experimental group compared with the active control group. Additionally, the change in the mandibular function impairment score was −0.36 more favorable in the experimental group than in the active control group (79). Despite the promising findings of the mentioned studies, another investigation showed paradoxical results. In a study involving subjects with HNCs receiving radiotherapy, participants were assigned to either a group that engaged in supervised exercises 5–6 times a week for 45 min, in addition to standard care, or a control group that received only standard care. The main goal was to assess changes in maximal interincisor distance (MID) at 5 and 12 months, while secondary outcomes included cervical range of motion, tissue tightness, and QoL (80). At 12 months’ post-radiotherapy, the mean difference in MID for the exercise group compared to the control group was 0.83 mm, indicating no significant improvement. After adjusting for surgery and tumor size, the adjusted mean difference was 5.92 mm, still not statistically significant (80). Notably, cervical rotation significantly worsened in the exercise group compared to controls, while other secondary outcomes showed no significant changes. They concluded that early supervised exercises do not appear to offer additional benefits over standard care in reducing trismus for patients with oral cavity or oropharyngeal cancer during radiotherapy (80). In summary, current research evaluates rehabilitation strategies, including the use of devices like TheraBite^® and Dynasplint Trismus System^®, to improve maximal mouth opening (MMO). One study found no noteworthy change in MMO improvement between the devices, with minimal gains reported and challenges faced by participants. Another study examined jaw range of motion exercises without tools for patients undergoing surgery for oral and oropharyngeal tumors. It highlighted a correlation between jaw mobility and QoL measures, suggesting that early exercise initiation post-surgery could enhance QoL. However, the small sample sizes and other limitations designate the requirement for further research to better understand the impact of postoperative jaw exercises.

Dysphagia, or difficulty swallowing, is a common and often distressing complication faced by subjects who have experienced treatment for HNCs. This condition can arise as a result of numerous treatment modalities, including radiation therapy, surgery, and chemotherapy, which can lead to functional and structural changes in the pharynx, oral cavity, and esophagus. After surgical intervention, patients may experience alterations in anatomy, such as the removal of tumors or surrounding tissues, which can impact the swallowing mechanism. Radiation therapy can cause inflammation and fibrosis in the tissues of the throat, leading to decreased mobility and sensitivity in the swallowing structures. Chemotherapy may further exacerbate these issues by causing mucositis, which can make swallowing painful and difficult. The consequences of dysphagia extend beyond the physical act of swallowing; they can significantly affect a patient’s nutritional status, hydration levels, and overall QoL. Given the importance of dysphagia, a great body of research has tried to overcome this side effects through a diversity of interventional methods. The most recent investigation in this field is conducted in 2024 which is a case report on a 72-year-old subject who was diagnosed with larynx carcinoma and underwent SCPL with cricohyoidoepiglottopexy (CHEP) (81). In the fiberoptic endoscopic evaluation of swallowing assessments, the patient consistently showed signs of laryngeal penetration and potential tracheal aspiration, which were corroborated by videofluoroscopic swallowing study results. Furthermore, a narrowing of the upper segment of the cervical esophagus was noted, attributed to a large bone spur in the front part of the C5 vertebra. This narrowing hindered the movement of the bolus, causing it to accumulate above the upper esophageal sphincter and subsequently enter the airway (81). This patient received rehabilitation for 3 months and the data exhibited that the buildup of the bolus above the cervical osteophyte of patient was cleared with several swallows, showing no signs of penetration or aspiration in him. This case report highlights the need for a coordinated assessment that includes a variety of specialists such as otorhinolaryngologists, speech therapists, and radiologists to investigate dysphagia in patients receiving conservative laryngeal surgeries, so that rehabilitation can be tailored to their individual needs (81).

Expiratory muscle strength training (EMST) is one of methods in which patients are instructed to exhale vigorously using a device equipped with a one-way spring-loaded valve. This adjustable valve prevents airflow until enough expiratory pressure is generated, at which point it opens to let the air flow through. The valve can be modified to accommodate different maximum expiratory pressure (MEP) levels, enabling the control of airflow resistance tailored to each individual, which can be progressively heightened as needed (82). Palmer et al. (82) used this method for six patients who had undergone supracricoid partial laryngectomy. Their results shown that the average MEP raised during follow-up, which was not statistically significant. Since EMST focuses on expiration rather than inspiration, an increase in maximum inspiratory pressure from baseline to follow-up was not anticipated, and this expectation was confirmed (82). Overall, patients were able to undergo a 4-week treatment program of EMST following SCPL with very few side effects. The main advantages seemed to center around breathing and coughing, rather than voice and swallowing. Nonetheless, these benefits are significant, considering how vital these functions are for respiratory health, especially in individuals who are prone to aspiration (82). Another similar study worked on patients who underwent supracricoid laryngectomy with CHEP and detected an enhancement in the overall level of deviations concerning vocal quality, roughness, and breathiness of the patients. They concluded that the extended vocal exercise involving the prolonged /b/ sound along with the vowel /e/, paired with chest and arm-pushing exercises, showed positive effects on the overall vocal quality, specifically in reducing roughness, deviation, and breathiness. These improvements began to be noticeable from the fourth minute in subjects who had experienced supracricoid laryngectomy with CHEP reconstruction (83).

Another study probed the condition of patients with total laryngotomy (TL) and tried to enhance their swallowing problems through a guided self-help exercise intervention which contained flexibility exercises for head, neck, jaw, tongue, and lips. They used the swallowing QoL questionnaire (SWAL-QoL) foe assessing the problems of patients and observed that the total swallowing problems improved significantly over time in the intervention group compared with the control group. The data revealed that, at the 6-month follow-up, subjects in the intervention group had a significantly lower score than those in the control group (84). There were seven subdomains in SWAL-QoL score including fear of eating, eating duration, food selection, general burden, mental health, eating desire, and social function. These subdomains did not exhibit a significant change over time separately; nevertheless, the intervention group had meaningfully improved (lower) scores at the 6-month follow-up for eating duration and fear of eating (84). Social Functioning and mental health had also notable differences which was significant (84). In prophylaxis point of view, research evaluated the efficiency of preventive swallowing exercises on the swallowing abilities of patients who were having a total laryngectomy (TL). They included 92 patients who had a TL due to stages III and IV laryngeal cancer to their study and practiced them for five specific swallowing exercises for the duration of 3 months following their surgery, beginning 2 weeks after the procedure. Weekly therapy sessions were also conducted with the patients. The results shown that there were no significant differences in the swallowing function, eating in public subscale, and normalcy of diet subscale scores between the intervention and control groups; at months 3, 6, 9, and 12, the scores for the intervention subjects were significantly improved across all measures (85).

A study compared a resistance-based chin-to-chest (CtC) exercise with a head-lift exercise for achieving better measures of hyolaryngeal muscle activation in healthy participants (86). A decrease in the opening of the upper esophageal sphincter (UES) during swallowing is a key factor in dysphagia, which can be caused by both neurological and cancer-related issues. The UES normally opens due to factors like relaxation controlled by the central nervous system, pressure from the bolus at the UES, and the movement of the hyoid and thyroid bones (hyolaryngeal excursion). This movement is driven by muscles like the mylohyoid and thyrohyoid. When hyolaryngeal excursion is reduced, the UES does not open enough, which can prevent the bolus from entering the esophagus and increase the risk of aspiration, potentially leading to serious health issues. If untreated with swallowing therapy, this may require feeding tubes for proper nutrition. Participants lifted and held their heads from a lying position for 10 s. The activation of the hyolaryngeal muscles, as assessed through surface electromyography (sEMG), was notably higher during the CtC exercise than the other exercise (86). However, this study was done on healthy individuals and further investigations are needed for using CtC on HNC patients.

Chronic vocal dysfunction is a common and often debilitating consequence of treating HNCs, which can involve surgery, radiation therapy, and chemotherapy. These treatments can lead to various vocal issues, including hoarseness, breathiness, reduced vocal range, and difficulty with projection. The underlying causes of these dysfunctions may include damage to the laryngeal structures, changes in vocal fold elasticity, and alterations in the surrounding musculature and nerves. Research indicates that the incidence of chronic vocal dysfunction may significantly affect patients’ QoL, impacting their ability to communicate effectively and engage socially. Voice therapy, which may include exercises to strengthen vocal muscles and improve technique, is often recommended as part of rehabilitation. Additionally, interventions such as surgical procedures or the use of voice prostheses may be considered for more severe cases. Ongoing studies aim to better understand the long-term impacts of cancer treatments on vocal function and to develop effective strategies for prevention and rehabilitation. Early intervention and tailored therapeutic approaches are crucial for improving outcomes and elevating the overall QoL for survivors of HNCs experiencing chronic vocal dysfunction (87).

In this point of view, there are plenty of studies which have focused on solving this problem by vocal exercises. Angadi et al. (88) tried to increase the voice-related QoL of laryngeal cancer patients and used a combination of vocal hygiene counseling (VH) and vocal function exercises (VFEs). Their research showed that both groups demonstrated an overall enhancement in acoustic parameters. The VFE + VH group showed significant improvements in maximum phonation time and pitch range. However, the VH group did not show significance in any of the mentioned parameters. In contrast, the VH group did not exhibit any changes in these stroboscopic parameters from pre- to post-treatment. Additionally, high-speed imaging showed notable pre- to post-treatment changes in the amplitude of vibration for the VFE + VH group, while the VH group did not demonstrate any significant alterations in high-speed parameters (88). A multicenter study in Netherlands worked on HNC patients who had a total laryngotomy surgery (84). They used several exercises for these patients including eight range-of-motion exercises for the lips, tongue, and jaw which were taught by speech therapist to patients. In this study, after a 6-months follow up, no notable main effect was observed on the speech issues. Nevertheless, moderation analyses indicated positive impacts on the SHI for a small group of subjects within 6 months following TL surgery (84).

TL combined with ND is a fundamental treatment for subjects with advanced-stage laryngeal cancer. While this surgical intervention can significantly improve survival rates, it is associated with various postoperative complications. One common and well-documented complication is shoulder dysfunction, which can negatively influence a patient’s QoL. This dysfunction typically results from the disruption of the spinal accessory nerve during the neck dissection procedure, leading to limitations in shoulder mobility and strength. Recognizing the impact of shoulder dysfunction on recovery, healthcare providers have begun exploring early rehabilitation strategies to mitigate these effects. Prophylactic rehabilitation, implemented shortly after surgery, aims to prevent or reduce the severity of shoulder dysfunction and enhance recovery. In this regard, a study on 76 people who underwent TL with ND tried to answer the questions about the impacts of exercise on shoulder dysfunction (89). The control group underwent the usual standard care without any structured shoulder exercises, whereas the intervention group participated in a preventive rehabilitation program that lasted 12 weeks. Participants were evaluated at the beginning of the study, as well as 3- and 6-months after surgery (89). The results indicated that there was a significant improvement in shoulder function and QoL reported by patients over time. However, there was no notable change between the intervention and control groups, which suggests that the preventative intervention had little to no impact on shoulder function outcomes (89). Another study also worked on shoulder problems in patients who underwent TL from 5 different HNC centers in the Netherlands (84). This research was consisting of two treatment groups: intervention and control. Patients in the intervention group received both a self-care education program and a guided self-help exercise program, while the control group only received the self-care education program (84). Strengthening exercises were excluded from this intervention despite their recognized significance in rehabilitation, as their focus was solely on incorporating simple exercises. Their results shown that there were no notable changes in shoulder issues over time in the intervention group compared with the control group. While statistically significant differences in shoulder problems were observed at the 3- and 6-months follow-up, these differences lost their statistical significance after adjusting for the baseline scores (84). Also some differences in health-related QoL (HRQoL) of intervention group at 3 and 6-months follow-up were detected but they were not statistically significant (84).

The safety and efficacy of exercise during different phases of HNC treatment depend on treatment intensity, symptom burden, and individual capacity. Prehabilitation, initiated after diagnosis but before treatment, is generally safe and improves post-surgical outcomes, physical function, and mental resilience. During active treatment, such as radiotherapy or chemotherapy, moderate-intensity aerobic or resistance exercise has been shown to mitigate fatigue, preserve muscle mass, and enhance quality of life (90, 91). However, high-intensity exercise (e.g., HIIT) should be used cautiously, particularly during radiotherapy, when mucosal inflammation, dysphagia, and fatigue are common. In such cases, aggressive exercise may exacerbate tissue injury, delay healing, or worsen symptoms. Thus, exercise interventions should be individualized, closely monitored, and preferably supervised by exercise physiologists or oncology rehabilitation specialists. Post-treatment exercise plays a crucial role in recovery and rehabilitation, aiding in the restoration of physical capacity, speech and swallowing function, and psychological well-being (90, 91).

A recent study investigated the combined effects of AE and crocin supplementation on learning, memory, and hippocampal gene expression of neurotrophins and tau in an Alzheimer’s disease (AD)-like rat model. Forty male Sprague Dawley rats were assigned to five groups: healthy control, endurance training (ET), crocin treatment, Alzheimer’s control, and combined ET plus crocin. Alzheimer’s was induced in all groups except the healthy control via intraperitoneal injection of trimethyltin chloride (TMT). ET involved treadmill running three times a week, while crocin was administered daily at 25 mg/kg. TMT-induced Alzheimer’s significantly impaired memory and learning and downregulated NGF, TrkB, and BDNF gene expression, while upregulating tau gene expression. Both ET and crocin independently improved cognitive functions and neurotrophin gene expression while decreasing tau expression. Notably, the combination of ET and crocin produced the most substantial improvements, highlighting a synergistic effect on neuroprotection and cognitive function in the AD model (92) (Table 4). Another study investigated the combined effects of ET and crocin on aerobic power and anxiety-like behaviors in AD model rats. Forty rats were distributed into five groups: control, ET, ET plus crocin (ETCR), crocin, and sham. Over 8 weeks, rats in ET and ETCR groups performed treadmill running three times per week, while the ETCR and crocin groups also received daily crocin injections (25 mg/kg). The data showed that ET alone meaningfully reduced anxiety-like behaviors and body weight, and improved aerobic capacity. Crocin administration also significantly enhanced aerobic power and reduced anxiety-like behaviors. However, combining ET with crocin did not show additional synergistic benefits beyond the effects of each treatment alone (93).

A study explored the effects of ET combined with crocin intake on glycogen and IGF-1 expression in the hippocampus of rats with TMT-induced AD. Thirty rats were allocated into five groups: Alzheimer’s control, healthy control, ET, crocin, and ET with crocin. AD was induced in groups 2–5 using 8 mg/kg TMT. Over 8 weeks, rats in the training groups ran on a treadmill three times per week, and crocin-treated groups received daily 25 mg/kg crocin. The results showed that TMT significantly reduced glycogen and IGF-1 gene. ET alone significantly increased IGF-1 and glycogen, while crocin alone had no significant effect. However, combining ET with crocin led to significant improvements in IGF-1 expression and glycogen levels, suggesting that endurance exercise, with or without crocin, plays a key role in counteracting TMT-induced deficits (94). Another study investigated the effects of ET combined with saffron (Sa) intake on calmodulin kinase 2 and cytochrome C expression in the heart tissue of AD model rats. Forty rats with TMT-induced AD were allocated into five groups: ET, AD control, Sa, ET + Sa, and sham. Over 8 weeks, rats in the ET and ET + Sa groups performed treadmill running (15–20 m/min, three sessions per week), and the Sa and ET + Sa groups received 25 mg/kg of Sa extract daily. The findings showed that Sa, ET, and ET + Sa treatments each significantly decreased calmodulin kinase 2 and cytochrome C levels. Moreover, the combination of ET and Sa led to a greater reduction in calmodulin kinase 2 compared to ET alone (95).

It should be noted that the referenced crocin studies were conducted in male rats to reduce variability linked to hormonal cycles, which can affect behavioral and biochemical outcomes. However, future research should incorporate both sexes to fully elucidate potential sex-specific effects of crocin treatment.

A study investigated the synergistic influences of quercetin and exercise on memory and learning impairments in a streptozotocin (STZ)-induced AD rat model. Fifty-six Wistar rats were distributed into eight groups, including sham, control, AD, quercetin-treated, quercetin vehicle, exercise pretreatment, off-treadmill, and exercise + quercetin groups. Quercetin (80 mg/kg) was consumed intraperitoneally for 21 days post-STZ injection, while exercise involved treadmill running (1 h/day, 20–22 m/min) for 60 days. STZ administration led to spatial memory deficits and elevated hippocampal oxidative stress. Both exercise pretreatment and quercetin treatment individually improved memory and oxidative stress. Notably, their combination produced the most significant improvements, suggesting a synergistic effect on enhancing antioxidant defense and cognitive function (96).

A study assessed cardiovascular function in 7-month-old male 3xTg AD mice and age-matched wild-type (WT) mice. While interventricular septal dimensions and aortic root were similar, 3xTg mice showed reduced systolic function and impaired diastolic function compared with WT mice. RES supplementation and treadmill exercise training for 5 months normalized diastolic deceleration time and improved systolic function. Although pulse wave velocity was ~33% higher and elastin fragmentation greater in 3xTg mice, exercise and RES improved aortic structure without significantly altering pulse wave velocity (97). Another study evaluated the effects of 5 months of ET, RES treatment, or their combination on Aβ toxic species and markers of apoptosis, inflammation, neuroprotection, and endolysosomal degradation in 3xTg-AD mice. RES treatment significantly reduced neuroinflammation and Aβ oligomer accumulation, enhanced neurotrophin and synaptic marker levels, increased silent information regulator expression, and decreased markers of apoptosis, autophagy, endolysosomal degradation, and ubiquitination. Exercise training alone improved some neuroprotective markers, but combining ET with Resv did not provide additional benefits beyond those achieved by Resv alone (98).

A study investigated whether RES and exercise could improve bone fracture resistance in a 3xTg-AD mouse model. 3-month-old male 3xTg-AD mice were treated for 4 months with RES, exercise, or both, and compared with WT mice. Exercise involved treadmill running (15 m/min, 45 min/day, 5 days/week), while RES was provided at 4 g/kg diet. The data revealed that 3xTg mice had weaker bone quality compared with WT mice. However, combined RES and exercise treatment meaningfully improved bone strength and quality, restoring them to WT levels (99). Another work examined the impacts of RES and aerobic training (AT) on the AMPK/PGC-1α/SIRT1 pathway in the hippocampus of AD rats. Wistar rats were distributed into 5 groups: Normal, AD, AD with training (ADT), AD with RES (ADRES), and AD with training plus RES (ADTRES). The RES groups received 20 mg/kg orally, and the exercise program involved treadmill running 5 days per week for 8 weeks. The data showed that AD meaningfully reduced AMPK/PGC-1α/SIRT1 expression, while both RSV and exercise treatment increased their expression. The combination of exercise and RES (ADTRES group) led to greater increases than either treatment alone (100).

A study explored the influences of AT and combined RES and fisetin (Fis) treatment on brain neurogenesis signaling pathways in AD mice. Twenty-five mice were divided into five groups: AD, AD+RES + Fis, control, AD + AT, and AD+AT+RES + Fis. AD was induced by injecting amyloid-beta into the hippocampus. AT was performed 5 days/week for 8 weeks, and RES (25 mg/kg) plus Fis (20 mg/kg) were administered. Results showed that AD reduced hippocampal BDNF, VEGF, and FGF7 gene expression, while AT and RES + Fis treatments significantly increased these neurogenesis-related markers (101).

A study assessed the effects of GJ consumption combined with aquatic exercise on cognitive function and oxidative stress in people with Parkinson’s disease (PD). Participants were allocated into a grape juice group (GJG) and a control group, both undergoing 4 weeks of aquatic exercise. The GJG additionally consumed 400 mL of GJ daily. No cognitive improvements were seen in either group. Both groups showed reductions in TBARS, antioxidant enzymes, and uric acid, but only the GJG had a significant reduction in protein oxidation levels (102). Another work evaluated the effects of aquatic exercise combined with GJ consumption on BDNF, functional outcomes, and histone H4 acetylation in people with PD. Nineteen participants underwent 4 weeks of aquatic training, with one group also consuming GJ daily. Aquatic exercise improved mobility, functional capacity, BDNF levels, and histone H4 acetylation, but GJ did not further enhance these effects, as no significant differences were found between the groups (103).

The study assessed the effects of red GJ combined with treadmill running on a PD animal model using 30 male Wistar rats. The rats were allocated into five groups: PD, Sham, PD treated with exercise (PD-Ex), PD treated with GJ (PD-GJ), and PD treated with both GJ and exercise (PD-GJ-Ex), with six rats per group. The data showed a significant change in the number of rotations between the Sham and PD groups. At the end of the experiment, the number of rotations reduced meaningfully in both the PD-GJ-Ex and PD-GJ groups. Exercise alone did not significantly affect the number of rotations (104). Another study compared the neuroprotective effects of red GJ and exercise on PD in male rats. Two weeks after surgery, the rats were treated with red GJ and exercise for 1 month. The extent of the lesion was assessed using intraperitoneal apomorphine injections, and the number of rotations within 1 h after injection was used as the main evaluation parameter for PD. The results exhibited that red GJ meaningfully reduced the signs of PD compared with other groups. Rats with PD that did not receive red GJ had the highest number of rotations. Both red GJ and exercise reduced rotations, but red GJ was more effective in reducing PD symptoms than exercise alone (105).

A work examined the impacts of combined training and red GJ intake on memory improvement in women with multiple sclerosis. Forty-eight women aged 20–40 were distributed into four groups: supplement, training, training + supplement, and control. The combined training, consisting of 60-min sessions 3 times per week for 8 weeks, was performed at an intensity of 10–12 on the Rate of Perceived Exertion scale. Red GJ supplementation was also administrated 3 times/week for 8 weeks. Memory was assessed before and after the intervention using daily, prospective, and retrospective memory questionnaires. The findings exhibited significant improvements in daily, retrospective, and prospective memory in the training, supplement, and training + supplement groups compared with the control group (106). Another work aimed to compare the influences of different long-term exercise modalities on cognitive performance and antioxidants in PD patients. Sixty-one participants were allocated to either the AE, Tai Chi exercise (TCE), or control group. The results showed no significant changes in cognitive performance or oxidative markers in the TCE and AE groups. However, after 12 weeks of AE, there was a significant increase in catalase and GSH levels, alongside a decrease in uric acid (UA) levels. The TCE group showed a substantial rise in GSH levels. In contrast, the control group experienced a significant decrease in superoxide dismutase activity and Mini-Mental State Examination (MMSE) scores. Associations between changes in MMSE and changes in UA and GSH levels were significant in the AE group. The findings proposed that long-term AE and TCE may help preserve cognitive function and reduce oxidative damage in PD, with AE providing greater benefits than TCE (107).

A study explored the neuroprotective influences of curcumin and regular AE in PD. Rats were treated for 8 weeks with curcumin (50 mL/kg) alone or in combination with AE. PD was induced by 6-OHDA, resulting in increased α-synuclein protein levels, higher malondialdehyde levels, decreased substantia nigra neurons, total antioxidant capacity, and glutathione peroxidase activity in brain tissue. These alterations were reversed by the combined treatment of curcumin and AE. Behavioral tests confirmed these results, showing increased rod test time and rotations due to apomorphine injection. Histopathological assays supported the antioxidant and behavioral improvements observed (108). Another study investigated the effect of moderate-intensity interval training combined with curcumin consumption on LRP1 (a key carrier of Aβ) and Aβ levels in the plasma and brain of AD induced rats. Fifty Wistar rats were allocated into 5 groups: AD + exercise, AD + exercise + curcumin, AD, AD + curcumin, and control. After a 3-day recovery, the training groups underwent moderate-intensity interval training for 4 weeks, while the other groups continued their normal routine. Curcumin was injected three times a week into the curcumin groups. The results showed significant differences in hippocampal Aβ, plasma Aβ, and plasma LRP1 levels between the groups. The AD + exercise + curcumin group showed the highest improvements in plasma Aβ and LRP1 levels compared to both the healthy control and AD control groups (109).

Despite the growing body of evidence supporting the synergistic effects of polyphenols and exercise on neuroprotection, tumor suppression, and metabolic regulation, several critical limitations hinder the clinical translation of these findings. Most notably, the majority of supporting studies are based on preclinical animal models, which do not fully capture the complexity of human physiology, lifestyle variability, or disease heterogeneity. Small sample sizes, short follow-up durations, and the absence of multicenter trials further weaken the strength of existing evidence. These limitations restrict our ability to generalize findings or draw firm conclusions about long-term clinical outcomes. A major barrier to clinical translation lies in the lack of standardized protocols for both polyphenol supplementation and exercise interventions. Doses, durations, and delivery mechanisms vary widely across studies, making comparisons difficult and impeding replication in clinical settings. Furthermore, polyphenol bioavailability in humans is often low and inconsistent, influenced by individual differences in metabolism, gut microbiota, and dietary context.

Another challenge is the limited integration of personalized medicine approaches. Most clinical studies do not stratify patients by genetic background, metabolic profiles, or pre-existing conditions—factors that significantly influence response to both diet and exercise. This heterogeneity dilutes statistical power and limits the development of targeted interventions. To overcome these barriers, future research should prioritize large-scale, multicenter trials with standardized intervention protocols and long-term follow-up. Incorporating multi-omics profiling and systems biology tools will also be essential to identify predictive biomarkers and personalize interventions. Addressing these gaps is critical to translating the promising synergistic effects of polyphenols and exercise into safe, effective, and accessible clinical therapies. Despite promising findings, current research on the combined effects of polyphenols and exercise in brain function, HNC therapy, and metabolic regulation is hindered by several methodological shortcomings. First, there is a notable scarcity of large-scale, randomized controlled trials in human populations. Most available studies are preclinical or small pilot trials, limiting the generalizability and clinical translation of the findings. Furthermore, interindividual variability in dietary habits, physical fitness, and genetic predispositions is rarely accounted for, underscoring the need for personalized and stratified study designs. Second, many animal studies rely on short-term or acute interventions, which may not accurately reflect chronic disease processes such as neurodegeneration or cancer progression. Longitudinal animal studies with extended follow-up periods and functional outcome measures are needed to better understand long-term therapeutic effects and safety profiles. Third, in vitro studies often utilize simplified monoculture systems that fail to mimic the complexity of human physiology, including the tumor microenvironment or neurovascular units. These limitations restrict mechanistic insight and translational potential. Advanced models such as organoids, co-culture systems, and microfluidic platforms offer more physiologically relevant alternatives and should be prioritized in future studies. Finally, there is limited integration of systems biology approaches. The application of multi-omics techniques, including genomics, transcriptomics, proteomics, metabolomics, and microbiome analysis, could help identify biomarkers of response and elucidate the molecular basis of exercise-polyphenol synergy. These tools are also essential for developing personalized intervention strategies based on individual molecular profiles. Addressing these methodological limitations through interdisciplinary, long-term, and large-scale studies will be critical for advancing our understanding and optimizing the therapeutic application of combined polyphenol and exercise interventions.