Integrated effects of a 12-week intermittent combined exercise on cognitive function, physical performance, and neurophysiological biomarkers in older women
Article information
Abstract
Aging is associated with a progressive decline in both cognitive and physical function, and neuroinflammation and metabolic dysregulation often exacerbate this decline, particularly in older women. This study investigated the effects of a 12-week intermittent combined exercise program on cognitive function, physical performance, and neurophysiological biomarkers in community-dwelling women aged 75 years and older. Forty participants were recruited from a local welfare center and randomly assigned to an exercise group (n=20) or a control group (n=20). The exercise group participated in three supervised sessions per week that integrated aerobic exercise, resistance exercise, functional exercise, and cognitive exercise. Cognitive domains (attention, language, and memory) were assessed using the Seoul Neuropsychological Screening Test-II. Physical function was assessed using the Geriatric Physical Fitness Test (chair stand, arm flexion, grip strength, and 6-min walk). Blood samples were analyzed to measure serum brain-derived neurotrophic factor (BDNF), interleukin (IL-6), tumor necrosis factor (TNF)-α, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). Paired and independent t-tests were performed to evaluate pre- and posttest differences (α=0.05). After 12 weeks, the exercise group significantly improved memory (P<0.05), lower upper-body muscle strength, grip strength, and walking endurance. Serum BDNF significantly increased (P<0.01), and IL-6, TNF-α, LDL-C, and TG decreased (P<0.05). HDL-C levels also significantly increased (P<0.05). Intermittent combined exercise significantly improved cognitive and physical function and favorably modulated neurotrophic, inflammatory, and metabolic biomarkers in very elderly women.
INTRODUCTION
As the global population ages, cognitive decline and increased risk of dementia in older adults are emerging as major public health concerns. Women aged 75 years and older are particularly vulnerable, often experiencing concurrent impairments in cognition, gait, metabolism, and cardiovascular health associated with increased life expectancy (Northey et al., 2018). These functional declines impair daily activities and quality of life, and increase long-term care needs. Therefore, safe and sustainable non-pharmacological interventions are urgently needed to prevent age-related cognitive decline. Regular physical activity is widely recognized to preserve and enhance cognitive function in older adults, providing important preventive and therapeutic benefits (Northey et al., 2018).
Randomized clinical trials and meta-analyses have shown that aerobic exercise, resistance exercise, and multicomponent exercise significantly improve overall cognitive function as well as specific domains such as memory, attention, and executive function in adults aged 50 years and older (Han et al., 2025; Luo et al., 2024). Resistance exercise combined with cognitive or functional tasks further improves verbal fluency, working memory, and frontal lobe-related functions, highlighting the value of a multidimensional approach to cognitive health in older adults (Coelho-Junior et al., 2022). While research in women aged 75 years and older is limited, existing studies consistently demonstrate that regular multicomponent exercise improves attention, language, and memory. In both middle-aged and older adults, combining aerobic and strength training increases brain-derived neurotrophic factor (BDNF) expression, promoting neuroplasticity and improving attention, concentration, and memory (Coelho-Junior et al., 2022). Experimental studies have shown that regular aerobic exercise, high-intensity interval training, and combined training significantly increase peripheral BDNF levels, which are associated with improved cognitive function and reduced risk of neurodegeneration (Nilsson et al., 2020). Furthermore, combining physical exercise and cognitive training has been shown to simultaneously increase BDNF levels and improve executive function and verbal fluency, suggesting synergistic neurocognitive benefits in older adults (Castaño et al., 2022).
Increased levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α), are associated with cognitive decline and dementia, and regular exercise has been shown to significantly reduce these markers in older adults (Tomeleri et al., 2018). Furthermore, aerobic and combined exercise improve metabolic and cardiovascular health by increasing high-density lipoprotein cholesterol (HDL-C) and decreasing low-density lipoprotein cholesterol (LDL-C) and triglycerides (TG). These positive lipid changes may indirectly support cerebrovascular health and cognitive function (Leitão et al., 2021). Multicomponent and concurrent exercise programs have been shown to improve muscle strength, gait, and balance, as well as memory, selective attention, processing speed, and executive function in older adults (Kaushal et al., 2018). Sustained engagement and appropriate doses of multicomponent training appear essential to maximize these effects. However, few studies have investigated whether intermittent combined exercise can simultaneously improve domain-specific cognitive functions (attention, language, and memory), standardized physical performance indices, and key biochemical markers such as BDNF, IL-6, TNF-α, HDL-C, LDL-C, and TG in older women.
Therefore, this study aimed to evaluate the effects of a 12-week intermittent combined exercise program on cognitive function, physical performance, and blood biomarkers in community-dwelling women aged 75 years and older, with a particular focus on the potential for cognitive health promotion and metabolic and inflammatory response modulation.
MATERIALS AND METHODS
Participants
In this study, 40 community-dwelling elderly women aged 75 years or older were recruited from a welfare facility in Suwon, South Korea, and assigned to either an exercise group (EG; n=20) or a control group (CG; n=20). The mean age was 77.2±5.4 years. Inclusion criteria were as follows: (a) age ≥75 years, (b) ability to walk independently without assistive devices, (c) ability to provide written informed consent, and (d) ability to complete a physical assessment. Exclusion criteria included clinically diagnosed dementia or severe cognitive impairment, severe cardiovascular disease, musculoskeletal disease affecting gait, or inability to comply with the gait assessment. All participants provided written informed consent, and the study was approved by the Kyung Hee University Institutional Review Board (approval number: KHU 2022-08-039) in accordance with the Declaration of Helsinki.
Intermittent combined exercise program
The exercise program was developed based on a multicomponent intervention protocol previously established by Castaño et al. (2022). Participants participated in supervised sessions 3 times a week on nonconsecutive days for 12 weeks. Each session lasted approximately 50 min and consisted of a warm-up, intermittent aerobic exercise, strength training and functional training, and a cool-down exercise involving a cognitive task. The exercise intensity was maintained at mild to moderate intensity to ensure safety in this elderly population. Specifically, Borg’s rating of perceived exertion (RPE) was initially 11–13 and then increased to 12–14. During the warm-up (approximately 10 min), participants performed light flexibility and joint mobility exercises while engaging in simple orientation and attention tasks (e.g., naming the days of the week, identifying colors, or counting in order). The aerobic exercise phase (15–20 min) alternated between 1 min of brisk walking (RPE 13–14) and 1–2 min of recovery walking (RPE 10–11), incorporating simple dual-task elements such as counting backwards or word recall to stimulate working memory and attention. The resistance and functional segment (approximately 20 min) targeted major muscle groups using elastic bands and bodyweight exercises (e.g., chair stands, wall push-ups, heel raises). Exercises were performed in two sets of 10–12 repetitions, with resistance gradually increasing as tolerated. The cognitive component included semantic and phonemic fluency tasks and short-term memory recall, following the protocol described by Castaño et al. (2022).
Brain function assessment
The cognitive assessment protocol was developed based on an established neuropsychological testing framework based on the Seoul Neuropsychological Screening Battery-II (SNSB-II) (Ryu and Yang, 2023). Cognitive function was assessed at baseline (Pre) and posttest (Post) across attention, language, and memory domains by trained examiners blinded to group assignment. Attention was measured using the Digit Span Test (forward and backward) and the Korean Trail Making Test Part A, as specified in the validated SNSB-II protocol. Raw scores were converted to percentiles adjusted for age and education level and averaged to produce a composite score. Language ability was assessed using the Boston Naming Test (short form) and the Controlled Oral Word Association Test for semantic and phonemic fluency, as per the SNSB-II standardization. Scores were standardized to normed percentiles adjusted for age, gender, and education level and averaged to produce a language score. Memory was assessed using the Seoul Verbal Learning Test-Elderly version, including immediate recall, delayed recall, and recognition tasks. All subscale scores were standardized and averaged to produce a composite memory score. Higher scores indicate better cognitive abilities. Pre- and posttest differences were analyzed to determine the effectiveness of the exercise intervention.
Physical function tests
The physical function assessment protocol was developed based on the standardized Senior Fitness Test (SFT) battery (Rikli and Jones, 1999), which was developed for older adults. Assessments were conducted before and after the intervention using standardized procedures by trained assessors who were blinded to group assignment. Low-body strength was assessed using the 30-sec chair stand test. Participants stood up as far as possible from a 43-cm chair with their arms crossed in 30 sec. Upper-body strength was assessed using a 30-sec push-up test using dumbbells (2.3 kg for women and 3.6 kg for men), with the number of valid repetitions calculated. Handgrip strength was measured using a Jamar dynamometer with the elbows flexed 90°, the wrists slightly extended, and the forearms in a neutral position. Participants performed three maximal attempts per hand after 60 sec of rest, with the highest value used. Walking endurance was assessed using the 6-min walk test (6MWT), which records the total distance traveled on a 30-m course. The tests were performed in a fixed order (handgrip→chair standing→arm flexion→6MWT), with 3–5 min of rest between each test. The primary outcomes were the number of repetitions (chair standing, arm flexion), maximum grip strength (kg), and 6-min walking distance (m).
Blood sampling and biochemical analyses
Blood collection and biochemical analyses followed previously established protocols for exercise-related neurotrophic and inflammatory biomarkers (Ruscheweyh et al., 2011). To minimize acute exercise effects, fasting venous blood samples were collected at baseline and 48–72 hr after the last session. Participants fasted for 10–12 hr (water intake was permitted) and avoided alcohol and strenuous activity for 24–48 hr. Blood samples were collected from the antecubital vein in a sitting position after 10–15 min of rest. After clotting for 20–30 min at room temperature, serum was collected and centrifuged (1,500–3,000 rpm for 10–15 min). Plasma collected in ethylenediaminetetraacetic acid tubes was processed similarly. All aliquots were stored at -80°C until analysis. Lipid profiles (HDL-C, LDL-C, and TG) were assessed using an enzymatic colorimetric assay using an automated analyzer. Inflammatory cytokines (IL-6, TNF-α) and serum BDNF were measured using highly sensitive enzyme-linked immunosorbent assay kits, and the assays were performed repeatedly with intra- and interassay variability of less than 10%–12%. The primary outcomes were serum BDNF, plasma or serum IL-6 and TNF-α, and serum HDL-C, LDL-C, and TG. To evaluate the effects of intermittent combined exercise on neurotrophic, inflammatory, and lipid markers, pre- and postexercise changes were compared between groups.
Data analysis
Data were analyzed using IBM SPSS Statistics ver. 26.0 (IBM Co., USA). Descriptive statistics, including the mean and standard deviation, were calculated to summarize all study variables. To assess the intervention effect, a paired-samples t-test was applied to compare pre- and postintervention values within each group, and an independent-samples t-test was used to examine the difference in change scores between the exercise and CGs. In all analyses, the statistical significance level was set at P<0.05.
RESULTS
The change in brain function assessment
Fig. 1 summarizes changes in brain performance across regions between the control (CON) and exercise (EX) groups before and after the 12-week intervention. No significant interactions or main effects were observed for attention. Both the CON and EX groups showed similar percentile scores before and after the intervention, indicating that the exercise program did not induce measurable changes in attention (P>0.05). Verbal performance showed no significant group×time interaction or within-group changes. Percentile scores remained relatively stable in both the CON and EX groups after the intervention (P>0.05). A significant group×time interaction was observed for memory function (P<0.05). Post hoc analysis revealed that the EX group showed significant improvement from baseline to postintervention (P<0.05), whereas no significant change was observed in the CON group. The postintervention memory percentile in the EX group was significantly higher than that in the CON group both before and after the intervention. Although the spatiotemporal scores tended to improve in the EG, the difference was not statistically significant. No significant difference was observed in the CG, and no interaction effect was observed (P>0.05).
Changes in cognitive function following 12 weeks of intermittent combined exercise in community-dwelling older women. (A) Attention. (B) Language. (C) Memory. (D) Visuospatial function. Data are expressed as the mean±standard error of the mean. Pre, before the 12-week intervention; Post, after the 12-week intervention; CON, control; EX, exercise. *P<0.05 compared to the control group.
The change in physical function
The results of the physical performance test are shown in Fig. 2. After the exercise intervention, the EG showed significant gains in all measures of strength and endurance, while no significant changes were observed in the CG. Specifically, performance in the 30-second push-up and 30-sec chair stand tests significantly improved, indicating increased upper and lower body strength and endurance (P<0.05). Furthermore, grip strength values significantly increased compared to baseline, indicating improved overall physical fitness. Aerobic endurance, measured by the 6MWT, showed a significant increase in walking distance in the EG (P< 0.05), but no significant change in the CG (P>0.05). Between-group comparisons confirmed that the posttest scores for all physical function parameters were significantly higher in the EG than in the CG (P<0.05). These findings demonstrate that intermittent combined exercise positively impacts multiple aspects of physical function in older participants, particularly those related to strength and endurance.
Effects of intermittent combined exercise on physical performance in older women. (A) 6-Min walk test. (B) 30-Sec chair stand. (C) Arm curl. (D) Grip strength. Data are expressed as the mean±standard error of the mean. Pre, before the 12-week intervention; Post, after the 12-week intervention; CON, control; EX, exercise. *P<0.05 compared to the control group.
The change in blood biomarkers
Fig. 3 shows the changes in blood biomarkers observed before and after the intervention. EG exhibited significant physiological adaptations, characterized by increased neurotrophic activity, decreased inflammation, and improved lipid metabolism, whereas CG showed no significant changes. In EG, serum BDNF levels significantly increased compared to preintervention levels (P<0.05), suggesting exercise-related upregulation of neurotrophic function.
Changes in blood biochemical markers following 12 weeks of intermittent combined exercise. (A) Serum brain-derived neurotrophic factor (BDNF). (B) High-density lipoprotein. (C) Low-density lipoprotein. (D) Triglyceride. (E) Serum tumor necrosis factor (TNF)-α. (F) Serum interleukin (IL)-6. Data are expressed as the mean±standard error of the mean. Pre, before the 12-week intervention; Post, after the 12-week intervention; CON, control; EX, exercise. *P<0.05 compared to the control group.
Meanwhile, two major inflammatory cytokines, IL-6 and TNF-α, significantly decreased after training in EG (P<0.05), indicating reduced systemic inflammation. Lipid profiles also significantly improved. HDL-C levels increased, while LDL-C and TG levels significantly decreased (P<0.05). CG showed no significant differences in any blood parameters between pre- and postintervention (P>0.05). Between-group comparisons revealed that BDNF and HDL-C levels were significantly higher after the intervention, while IL-6, TNF-α, LDL-C, and TG levels were significantly lower in the EG group than in the CG group (P<0.05). These results demonstrate that intermittent combined exercise intervention brought about positive changes in both the neurotrophic and metabolic profiles of older women.
DISCUSSION
The cognitive benefits observed in this study are consistent with evidence that multicomponent or concurrent exercise improves memory in older adults (Rondão et al., 2022; Suzuki et al., 2013). Chen et al. (2025) and Liao et al. (2025) further demonstrated that combining aerobic and resistance exercise improved cognitive flexibility and processing speed in adults aged 65 years and older. In this study, integrating dual-task components such as verbal recall and semantic fluency likely activated prefrontal and hippocampal regions, as shown in functional imaging studies of cognitively rich exercise (Kumfu et al., 2025). Attention and language did not show significant improvements in this study, which may be due to the relatively short intervention period or the low cognitive demands of the task. Previous studies (Coelho-Junior et al., 2022; Suzuki et al., 2013) suggest that longer or more cognitively intensive interventions may be necessary to elicit measurable changes in these domains. Postexercise serum BDNF increases suggest enhanced neuroplasticity, consistent with the well-established role of exercise-induced BDNF in supporting synaptic growth and hippocampal neurogenesis (Behrendt et al., 2021). Castaño et al. (2022) found that resistance training combined with a cognitive task increased circulating BDNF and improved working memory in older adults, supporting the dual-mechanism hypothesis underlying this intervention. Boidin et al. (2024) further demonstrated that BDNF responsiveness varied with training load, suggesting that the intermittent structure of this program may have optimized neurotrophic activation while minimizing fatigue. Additionally, Martín-Rodríguez et al. (2025) highlighted the link between physical activity, BDNF-mediated neuroplasticity, and recognition memory, providing a biological basis for the memory improvements observed in our study participants.
The decreases in IL-6 and TNF-α observed in this study are consistent with previous evidence that exercise attenuates chronic low-grade inflammation, a major driver of neurological and vascular deterioration with age (Ibrahim et al., 2023). Previous studies have shown that moderate physical activity reduces the risk of neurodegeneration by lowering inflammatory cytokines and enhancing antioxidant defenses (Tsai et al., 2019). These anti-inflammatory effects likely indirectly contributed to the cognitive improvements observed in the participants. Simultaneously, the improvements in lipid metabolism (upper HDL-C, lower LDL-C, lower TG) are consistent with the findings of Wang et al. (2014) and Kim and Song (2017), who reported that endurance and resistance training were associated with improved cardiovascular profiles and cognitive function in postmenopausal women.
Physical function assessed using the SFT also showed significant improvements across several domains. Improved performance in the chair lean, push-ups, grip strength, and 6MWTs reflected improvements in upper and lower body muscle strength, muscular endurance, and aerobic capacity. These results are consistent with previous studies showing that SFT-based protocols improve functional fitness and reduce frailty in older adults (Aibar-Almazán et al., 2020). Notably, increases in grip strength, a known indicator of overall vitality and cognitive resilience, strengthen the bidirectional relationship between muscle health and neurological health (Aibar-Almazán et al., 2020; Imaoka et al., 2019). The improvements in walking endurance and balance observed in this study are consistent with the results of a multicomponent intervention emphasizing mobility and coordination (Chen et al., 2025; Rondão et al., 2022). Therefore, these findings support the conclusion that intermittent combined exercise promotes systemic and neurocognitive adaptations essential for maintaining independence and cognitive longevity in older women.
From a mechanistic perspective, exercise can improve cognitive function through multiple complementary pathways, including neurotrophic activation, enhanced cerebrovascular function, metabolic regulation, and reduced neuroinflammation (Behrendt et al., 2021; Rubin et al., 2024). These interrelated mechanisms suggest that intermittent combined exercise not only strengthens the musculoskeletal and cardiovascular systems, but also enhances neural efficiency through sustained BDNF signaling and cytokine regulation. Indeed, supervised exercise performed 3 times per week in a community welfare center is safe, feasible, and well-tolerated, consistent with findings from existing real-world intervention studies (Liao et al., 2025). Given the increased risk of cognitive and functional decline in women aged 75 years and older, this model offers a realistic and scalable strategy for community-based cognitive health promotion.
Nonetheless, several limitations should be acknowledged. The sample size was relatively small, and the intervention period was limited to 12 weeks. Future studies should employ large-scale randomized controlled designs with extended follow-up periods and include additional biomarkers, such as insulin-like growth factor-1, vascular endothelial growth factor, and amyloid beta, to better understand the underlying neurobiological mechanisms (Martín-Rodríguez et al., 2025; Tsai et al., 2018). Despite these limitations, the results of this study contribute to the growing evidence that systematic multicomponent exercise, including cognitive components, can improve both physical and mental vitality in the oldest-old.
In conclusion, intermittent combined exercise appears to be a safe, effective, and sustainable approach to improving cognitive function, physical performance, and metabolic-inflammatory balance in very old women, and may have promising implications for geriatric rehabilitation and community health initiatives.
Notes
CONFLICT OF INTEREST
No potential conflict of interest relevant to this article was reported.
ACKNOWLEDGMENTS
This work was supported by the National Research Foundation of Korea (Grant No. NRF2020R1I1A1A01072455).