Age-Related Decline in Cognitive Flexibility


Aging is a complex biological process that impacts various aspects of cognition. One notable area of decline is in learning, memory, and executive function, which are crucial for maintaining daily life activities and independence [Salthouse, 2009; Samson and Barnes, 2013; Nyberg and Pudas, 2019; McQuail et al., 2020].

In addition to these cognitive changes, aging is also associated with a reduction in cognitive flexibility – the ability to adapt to new environments, switch between mental tasks, and adjust strategies in response to changing circumstances.

Cognitive flexibility is a fundamental component of executive function, and its decline may contribute to age-related cognitive impairment [Nyberg and Pudas, 2019; McQuail et al., 2020].

However, not all cognitive functions decline with age. Aspects like procedural, automatic, and verbal memory tend to be preserved during normal aging [Nyberg and Pudas, 2019; McQuail et al., 2020]. Moreover, cognitive decline can be partially mitigated through increased learning and cognitive training.

While specialized tests can detect subtle age-related cognitive changes in humans, animal models, particularly rodents, face limitations in assessing such nuanced features due to the lower resolution of behavioral tasks designed for them.

Another hallmark of aging is the reduction in neurogenesis, the process of generating new neurons, in the dentate gyrus (DG) of the hippocampus. The hippocampus supports neurogenesis throughout an individual’s life [Kuhn et al., 1996; Encinas et al., 2011].

Adult-born hippocampal neurons have been linked to various functions, including pattern separation, behavioral flexibility, and active forgetting [Saxe et al., 2006; Clelland et al., 2009; Arruda-Carvalho et al., 2011; Sahay et al., 2011b].

Decreased hippocampal neurogenesis has been associated with impaired performance in learning and memory tasks, while experimental enhancement of neurogenesis can improve cognitive performance [Hernandez-Mercado and Zepeda, 2021].

This study aimed to investigate the effects of aging on cognitive flexibility using a novel set of tasks developed for mice. We found that aging in mice is associated with the adoption of inefficient and spatially imprecise search strategies, leading to impaired learning. However, extended training can partially overcome these deficiencies. Additionally, we explored the relationship between age-related changes in neurogenesis and cognitive flexibility.


Our findings revealed a decline in cognitive flexibility during the adult-middle age period in mice. This decline manifested as a reduced ability to adapt previous experiences to solve tasks involving new combinations of familiar cues and contexts. Notably, the impairment of cognitive flexibility in older mice could be partially mitigated through extended training.

Moreover, our results indicated a correlation between the decline in cognitive flexibility within individual mice and a decrease in the number of recently generated mature neurons or immature neuronal precursors in their hippocampi.

We focused on the mature adult-middle age period of mice to reduce confounding factors associated with younger and older age groups. This period is characterized by minimal changes in various behavioral tests related to learning, memory, anxiety, and pain sensitivity.

Importantly, we did not observe significant learning or memory deficits in the older mice compared to the younger group in conventional spatial versions of the Morris Water Maze (sMWM). However, differences emerged when older mice were tested in a reversal version of the Morris Water Maze (rMWM), which requires cognitive flexibility. Older mice exhibited longer escape latencies, spatially imprecise search strategies, and increased initial pattern errors compared to younger mice.

A more pronounced difference was observed when mice were tested in a complex cognitive flexibility task, the contextual discrimination Morris Water Maze (cdMWM). Older mice showed impaired performance in learning compared to younger mice, evident across various metrics, including escape latency, inefficient search strategies, odds ratio for efficient strategies, initial pattern errors, and time spent in the correct quadrant during memory tests. Importantly, these age-related differences diminished with extended training.

Furthermore, our study revealed a strong correlation between the levels of neurogenesis in the hippocampus and cognitive flexibility. This correlation was particularly evident in older mice. Notably, the number of immature neurons correlated with individual animals’ performance in the cdMWM task, while the number of mature neurons correlated with performance in all three tasks.

The Role of Physical Activity and Exercise in Preventing Cognitive Decline and Dementia.

With the global population aging, the prevalence of dementia has surged exponentially. Currently, over 55 million individuals worldwide are living with dementia, and projections indicate that this number will reach 78 million by 2030 and a staggering 139 million by 2050. This demographic shift presents a significant challenge for healthcare systems and societies as dementia negatively impacts individuals physically, psychologically, socially, and economically. This article delves into the pressing issue of dementia, exploring its causes, prevalence, and the role of physical activity and exercise in its prevention.

Understanding Dementia

Dementia is a multifaceted condition caused by various diseases and injuries primarily or secondarily affecting the brain. Alzheimer’s disease (AD) is the most common cause of dementia, accounting for 60-80% of clinical cases. Additionally, mild cognitive impairment (MCI) serves as the prodromal stage of dementia, with amnestic MCI often preceding clinical AD. The global population with MCI is growing faster than that with AD. Given the current absence of effective disease-modifying treatments for dementia, there is an urgent need for non-pharmaceutical interventions to prevent MCI development and its progression to dementia.

Modifiable Risk Factors for Dementia

Remarkably, research has identified twelve modifiable risk factors for dementia. These factors include low levels of education, hearing loss, traumatic brain injury, hypertension, alcohol consumption, obesity, smoking, depression, social isolation, physical inactivity, air pollution, and diabetes. Modifying these risk factors could prevent or delay up to 40% of dementia cases. Notably, physical inactivity stands out as a late-life risk factor for dementia, particularly AD, and has the potential to influence cognitive reserve and initiate neuropathological development.

The Power of Physical Activity and Exercise

Physical activity and exercise have emerged as low-cost, accessible, and highly effective non-pharmaceutical interventions for the primary and secondary prevention of dementia. Numerous studies have demonstrated that physical activity and exercise can stave off cognitive decline in both healthy older adults and patients with MCI. The World Health Organization (WHO) guidelines endorse physical activity, particularly aerobic exercise, for reducing the risk of cognitive decline. Consequently, physical activity and exercise interventions represent an ideal preventive strategy, particularly in developing countries.

Aerobic OSE vs. CSE

Recent scientific attention has turned to the differential effects of open-skill exercise (OSE) and closed-skill exercise (CSE) on cognitive function. OSE, which includes activities like table tennis, tennis, and badminton, takes place in dynamic, externally paced, and unpredictable environments. In contrast, CSE, such as running and cycling, occurs in relatively consistent, self-adjustable, and more predictable environments. Research has suggested that OSE may offer greater cognitive benefits than CSE, particularly in healthy older adults.

Effects of Physical Activity and Exercise Interventions

Observational studies with decades of follow-up have consistently shown that physically active individuals are less likely to develop cognitive decline, all-cause dementia, AD, and vascular dementia compared to their inactive counterparts. A recent systematic review and meta-analysis classified older adults into three groups based on the duration of physical activity. It revealed that both moderately and highly active groups had significantly lower risks of developing all-cause dementia, AD, and vascular dementia compared to physically inactive individuals.

Furthermore, meta-analyses of aerobic exercise interventions have demonstrated improvements in cognitive functions, particularly executive function. These improvements include enhanced attention, processing speed, executive function, and memory. Additionally, aerobic exercise interventions have shown promise in improving the memory of patients with MCI, particularly those with amnestic MCI. However, evidence regarding the effects of physical activity on cognition in patients with dementia is inconsistent, with some studies reporting positive effects and others finding limited or no benefits.

Possible Mechanisms Underlying the Effects

The positive impact of physical activity on cognitive function is mediated by several brain mechanisms, including improvements in cardiovascular risk factors, increased expression of neurotrophic factors, enhanced amyloid-β turnover, increased cerebral blood flow (CBF), and decreased inflammatory responses. Cardiovascular risk factors, which can lead to cognitive decline, are mitigated through regular physical activity, reducing the risk of neurodegeneration. Physical activity also increases the expression of neurotrophic factors like brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF). These factors are essential for neuroplasticity, neurogenesis, and cognitive function. Physical activity is also believed to promote amyloid-β turnover, potentially contributing to the prevention of cognitive decline. Furthermore, CBF decreases with age, and physical activity has been shown to increase it, potentially helping to maintain cerebral perfusion and prevent atrophy. Finally, physical activity reduces neuroinflammation in the elderly, decreasing the levels of inflammatory markers associated with better cognitive performance.

Differential Effects of OSE and CSE

OSE and CSE represent distinct categories of physical exercise, with OSE demanding more cognitive engagement and adaptability in unpredictable environments. Recent systematic reviews and meta-analyses have consistently favored OSE over CSE in improving cognitive functions, particularly executive functions such as inhibitory control and cognitive flexibility, across various age groups. OSE’s cognitive benefits may stem from its higher cognitive demands and greater social interaction compared to CSE. However, further research is needed to confirm the causal relations between OSE, cognitive health, and physical well-being, particularly in older adults with cognitive impairments.


Physical activity and exercise, especially aerobic OSE, offer a promising approach to preventing cognitive decline and dementia in aging populations. The differential effects of OSE and CSE underscore the importance of considering the type of exercise in cognitive interventions. While many mechanisms underlie the cognitive benefits of physical activity, further research is needed to solidify our understanding of the relationships between exercise, cognitive function, and dementia prevention. Nonetheless, promoting a physically active lifestyle is a valuable strategy for maintaining brain health and reducing the burden of dementia on individuals, caregivers, families, and society as a whole.

This study highlights age-related impairments in cognitive flexibility in mice, particularly during the transition from middle to old age. While these impairments were evident in tasks that required the reevaluation of previously acquired knowledge and adaptation to new environments, they were not apparent in tasks focused solely on efficient learning and memory. Extended training partially mitigated these deficits, suggesting that cognitive flexibility can be improved with practice, even in aging individuals.

Our findings also support the notion that adult hippocampal neurogenesis plays a critical role in cognitive flexibility, particularly in older animals. The correlation between neurogenesis and performance suggests that new neurons are essential when adapting to changing circumstances and modifying previously acquired experiences. The correlation was more pronounced in older mice, indicating the significance of neurogenesis in maintaining cognitive flexibility during aging.

In conclusion, our study provides valuable insights into age-related cognitive changes and the role of neurogenesis in cognitive flexibility.

These findings have implications for understanding the mechanisms underlying cognitive decline in aging and potential strategies for ameliorating these changes. Additionally, our study underscores the importance of comprehensive behavioral assessments and the development of animal models to better capture nuanced features of cognitive aging.

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