The Potential of 1,5-Anhydro-D-Fructose in Mitigating Aging-Associated Brain Diseases


5′-Adenosine monophosphate-activated protein kinase (AMPK) stands as a pivotal serine/threonine kinase, evolutionarily conserved to maintain cellular energy homeostasis. Its regulatory role spans across various physiological and metabolic processes, making it a crucial determinant in aging and longevity.

The dysregulation of AMPK has been associated with major chronic diseases, particularly in the context of brain aging. This article delves into the intricate molecular mechanisms of AMPK, its implications in brain aging, and a groundbreaking exploration of the potential therapeutic effects of 1,5-Anhydro-D-fructose (1,5-AF) on aging-associated brain diseases.

AMPK and Brain Aging

As the focus of brain aging research intensifies, the intricate changes occurring in the aging brain remain a subject of considerable complexity. The aging process affects cognition and behavior at various levels, leading to increased susceptibility to conditions such as stroke and Alzheimer’s disease (AD). AMPK regulation emerges as a key player in the pathophysiology of brain aging, with implications for conditions like stroke and AD. Activating AMPK has shown promise in reducing blood pressure, enhancing fatty acid oxidation, and protecting against ischemic stimuli, thereby potentially preventing aging-associated brain diseases.

Aging-Related Pathways and Interventions

Aging-related pathways, including AMPK, are primary targets for anti-aging interventions. Exercise and metformin, both indirect AMPK activators, have exhibited neuroprotective effects in animal models of aging-associated brain diseases. Current clinical trials aim to ascertain their impact on human aging, emphasizing tissue homeostasis and metabolic dysfunction. Amidst these interventions, the role of 1,5-AF, an AMPK activator with diverse bioactive properties, emerges as a novel avenue for exploration.

1,5-Anhydro-D-Fructose and AMPK Activation

1,5-AF, derived from the degradation of starch and glycogen, has recently been identified as an activator of AMPK in PC12 neuron-like cells. With antioxidant, anti-inflammatory, antimicrobial, antidiabetic, and anticancer properties, 1,5-AF presents a multifaceted approach to potential therapeutic applications. The hypothesis that 1,5-AF administration could prevent aging-associated brain diseases is a groundbreaking initiative, prompting an in-depth investigation in multiple animal models.

Animal Models and Experimental Design

Recognizing the heterogeneity and complexity of brain aging in humans, the study employed two prominent animal models—stroke-prone spontaneously hypertensive rats (SHRSPs) and spontaneous senescence-accelerated mouse-prone (SAMP) mice. The SHRSP model, mimicking the human risk of aging-related stroke, and the SAMP8 mouse model, reflecting AD-related pathomorphologies, provided a comprehensive platform to examine the effects of 1,5-AF on aging-associated brain diseases.

Molecular Mechanisms and Pathways

The study explored the molecular mechanisms underlying the effects of 1,5-AF, focusing on the AMPK/PGC-1α/BDNF pathway. The exercise-induced enhancement of AMPK activity and the subsequent upregulation of PGC-1α and BDNF have been linked to beneficial effects on amyloid-β-induced impairments of learning and memory. Recent findings revealed that 1,5-AF activates PGC-1α via AMPK, suggesting potential mitochondrial biogenesis and cytoprotective effects. Mitochondrial dysfunction, a recognized contributor to aging-related diseases, is intricately regulated by PGC-1α, emphasizing the significance of this pathway in the context of brain aging.

Discussion: Unraveling the Therapeutic Potential of 1,5-Anhydro-D-Fructose in Aging-Associated Brain Diseases

1,5-AF Activation of AMPK and Downstream Pathways

In this comprehensive investigation into the behavioral and molecular effects of 1,5-Anhydro-D-Fructose (1,5-AF) across multiple animal models of human aging-associated brain diseases, a noteworthy discovery emerges. The activation of 5′-Adenosine monophosphate-activated protein kinase (AMPK) by 1,5-AF unveils a potential avenue for inducing brain damage tolerance. The subsequent activation of the PGC-1α/BDNF pathway emerges as a crucial downstream mechanism (Figure 7), implicating neurovascular protection, plasticity, and ischemic tolerance in the observed improvements [27, 28].

Insights from Animal Models

a. Acute Ischemic Stroke (AIS) Model

In the AIS model, the reduction in cerebral infarct volume and the consequent improvement in neurological function in response to 1,5-AF treatment are attributed to the enhancement of the fibrinolytic system by Brain-Derived Neurotrophic Factor (BDNF). Previous reports on BDNF’s dose- and time-dependent effects on tissue plasminogen activator/plasminogen expression align with our findings. The interplay of neurovascular protection, neurovascular plasticity, and ischemic tolerance potentially underpins the observed benefits in this model.

b. Stroke-Prone Spontaneously Hypertensive Rats (SHRSPs)

In the SHRSP model, 1,5-AF treatment not only reduced the incidence of stroke but also exhibited a blood pressure-lowering effect. The preservation of muscle mass in these rats suggests a multifaceted impact on longevity. The observed weight loss, attributed to fat loss rather than the typical physical decline associated with increased blood pressure, underscores the potential benefits of 1,5-AF. However, the contrasting potential of BDNF to increase blood pressure prompts further exploration into alternative AMPK signaling pathways activated by 1,5-AF in SHRSPs.

c. Spontaneous Senescence-Accelerated Mouse-Prone (SAMP8) Model

In SAMP8 mice, 1,5-AF treatment demonstrated increased spontaneous locomotor activity and reduced memory impairment. The prevention of aging-related decline in locomotor activity and the reversal of cognitive deficits are attributed to increased PGC-1α and BDNF expression, particularly in the hippocampus (CA3). While the Morris Water Maze (MWM) behavior remained unaffected, the Novel Object Recognition (NOR) test results exhibited alterations, possibly due to the inherent swimming difficulties of SAMP8 mice.

Molecular Mechanisms and Pathways

a. AMPK Activation and FNDC5 Expression

The study postulates that the improvement induced by 1,5-AF may be linked to AMPK activation, though the intricacies of in vivo AMPK regulation remain unclear. The potential involvement of FNDC5, a key player in the AMPK/PGC-1α/BDNF pathway, is evident in increased expression after 1,5-AF intake across the AIS model and SHRSPs. This consistency in FNDC5 expression aligns with the proposed activation of the AMPK/PGC-1α/BDNF pathway, reinforcing the potential molecular mechanisms at play.

b. Consideration of Other AMPK Activators

Comparisons with other AMPK activators, such as metformin and 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR), shed light on the benefits of 1,5-AF. While metformin and AICAR exhibit similar effects on BDNF expression, the clinical limitations and adverse effects associated with these compounds underscore the potential clinical utility of 1,5-AF in preventing aging-associated brain diseases.

Considerations and Limitations

The study acknowledges certain limitations, such as the small number of rats in the AIS model, necessitated by the model’s high mortality rate. The decision to limit the number of animals euthanized emphasizes ethical considerations. Additionally, the systemic alterations in SHRSPs and SAMP8 mice highlight the challenges in comparing their tissue with healthy aging human brain tissue. Despite these limitations, the study offers valuable insights into the preventive effects of 1,5-AF on aging-associated brain diseases.

Future Directions and Clinical Implications

The study calls for further research into cognitive impairment among the growing global population of older adults. The preventive effects of 1,5-AF on aging-associated brain diseases, as elucidated through the AMPK/PGC-1α/BDNF pathway, open avenues for future clinical trials. The consistent expression of FNDC5 and the potential central effects of 1,5-AF comparable to exercise highlight its promising role as a therapeutic option for a diverse range of individuals, irrespective of exercise ability.

In conclusion, this in-depth exploration of 1,5-Anhydro-D-Fructose unveils its potential as a novel and multifaceted intervention in aging-associated brain diseases. The intricate interplay of AMPK activation, downstream pathways, and molecular mechanisms across diverse animal models lays the foundation for future translational research, offering hope for innovative strategies in the prevention and treatment of age-related cognitive decline.

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