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Smart Worms for the Discovery of Smart Bioactives

Why Cognitive Health Matters

In today's fast-paced world, cognitive health has emerged as a critical pillar of overall well-being. As we navigate the complexities of modern life, maintaining a sharp and agile mind is essential not only for personal success but also for a fulfilling and enriched life. Cognitive health impacts our ability to think, learn, remember, and manage stress, forming the foundation of our daily functioning. Prioritizing cognitive health can enhance productivity, emotional regulation, and overall quality of life.

 

The human brain, a marvel of intricate neural networks and complex processes, is the epicenter of our cognitive functions. It governs everything from our ability to solve problems and make decisions to our capacity for creativity and emotional depth. As we age, however, the brain's efficiency can decline, leading to issues such as memory loss, reduced mental agility, and a diminished ability to learn new skills. This cognitive decline is particularly prevalent in aging populations, posing significant challenges to individuals and societies alike. Understanding the mechanisms behind this decline and finding ways to mitigate its effects are essential for enhancing the quality of life for older adults and ensuring that they remain active, engaged, and independent for as long as possible.


Fig. 1: Different dimensions of human cognitive function.

Cognition encompasses a broad array of mental processes that enable us to carry out everyday tasks and engage with the world around us. These processes include memory, learning, alertness, reasoning, focus, and concentration (Fig. 1). Memory allows us to retain and recall information, while learning enables us to acquire new knowledge and skills. Alertness helps us stay aware and responsive to our environment, and reasoning involves critical thinking and problem-solving abilities. Focus and concentration enable us to direct our attention and sustain mental effort on specific tasks. Each of these cognitive functions is crucial for navigating daily life and achieving our personal and professional goals. By nurturing and supporting these mental processes, we can enhance our overall mental performance and resilience, fostering a more fulfilling and productive life.


Alertness is a vital component of cognitive health, serving as the foundation for our ability to respond to stimuli and engage with our environment. It encompasses our capacity to stay awake, maintain attention, and react swiftly to changes around us. High levels of alertness are crucial for tasks that require sustained concentration, such as driving, studying, or performing complex work duties. Conversely, reduced alertness can lead to lapses in attention, decreased productivity, and an increased risk of accidents. Factors such as sleep quality, nutrition, physical activity, and stress levels can significantly impact our alertness. 


Nutritional Bioactives Supporting Cognitive Health

Incorporating bioactives derived from food or plant sources into our diets is a powerful strategy to support and enhance cognitive health. These ingredients consist of nutrients and bioactive compounds that play crucial roles in brain function and protection. They help maintain the structure and function of brain cells, combat oxidative stress, support energy production, and regulate neurotransmitter activity. By integrating these nutrient-rich components into our daily diets, we can nourish our brains, improve mental clarity, and potentially slow the progression of age-related cognitive decline. Embracing functional foods is a proactive approach to maintaining cognitive vitality and overall mental well-being, offering a natural and effective way to support our mental health.


Fig. 2: Growing market for dietary supplements supporting brain health. Source: Grandview Research

As of 2022, the global brain health supplements market was valued at 8.63 billion and is expected to grow at a compound annual growth rate (CAGR) of 13.3% from 2023 to 2030. (Fig. 2) This growth is fueled by increasing awareness of mental health issues such as lack of attention and focus, declining memory, anxiety, and depression. Additionally, the rising adoption of natural and herbal health products is expected to drive the industry's expansion over the forecast period.

 

Functional ingredients can be categorized into various classes, each with unique benefits for cognitive health. Probiotics, beneficial bacteria that support gut health, have been linked to improved brain function through the gut-brain axis, influencing mood and cognitive processes. Botanicals, derived from plants, contain bioactive compounds that can enhance cognitive performance and reduce neuroinflammation. Vitamins, essential nutrients for overall health, play critical roles in brain function by supporting energy production, protecting neurons, and aiding neurotransmitter synthesis. A survey of literature indicates that published articles focusing on brain health are growing with more articles focused on vitamins and less so on probiotics and botanicals (Fig. 3). Thus, there is a need for generating science-based evidence including preclinical and clinical trials to support the next wave of best-in-class cognitive health products.


Fig. 3: Cumulative number of published articles by supplement type. Source: Pubmed

Preclinical models for cognitive health

Incorporating functional ingredients into our diets is a powerful strategy to support and enhance cognitive health. These ingredients consist of nutrients and bioactive compounds that play crucial roles in brain function and overall mental well-being. To understand and validate the efficacy of these bioactives, there is a need for preclinical models, which typically involve both in vivo and in vitro screening methods.

 

In vitro models include primary neurons, glial cells, or immortalized neuronal cell lines that can be used to study the effects of bioactives on neuronal health, survival, differentiation, and signaling pathways relevant to cognitive function. More advanced in vitro models include organ-on-chip, and brain organoids which provide a more realistic microenvironment. However, organismal phenotypes such as memory, learning, alertness are difficult to recapitulate in these in vitro models.

 

In vivo models can address the limitations of in vitro models by providing holistic view of an organism’s response, encompassing complex interactions between different systems and organs. For example, the effects of metabolism, immune response, and other systemic factors on cognitive health can be evaluated. However, traditional in vivo models such as rodents are limited in terms of throughput and are cost prohibitive for screening bioactives. Moreover, rise in conscious consumerism in the functional ingredient industry and concerns regarding animal welfare during testing, have led to a reduced reliance on traditional animal models.


Fig. 4: Caenorhabditis elegans is a celebrated preclinical model with multiple organs including the nervous, muscular, reproductive, and gastrointestinal systems. Adapted from: Ann K. Corsi, Bruce Wightman, and Martin Chalfie. WormBook, 2015.

C. elegans as an efficient and translatable model to discover and develop bioactives for cognitive health

 

The C. elegans model has the been the cornerstone for fundamental understanding of neurobiology (Fig. 4). It has 302 neurons and 56 glial cells (37% of the somatic cells)​. The neurons are organized in several ganglia in the head and tail and into a spinal cord-like ventral nerve cord​. The neurons of C. elegans generally fall under 3 broad categories, including 88 sensory neurons, 87 interneurons and 119 motor neurons. Specialized functions and behaviors are coordinated through highly conserved, specialized neurons including 98 cholinergic neurons, 26 GABAergic neurons, 78 glutamatergic neurons and 26 aminergic (i.e. serotonergic, dopaminergic, etc) neurons.


C. elegans and humans share several conserved neurobiology aspects despite their evolutionary distance, making C. elegans a useful model for discovery and development of bioactives for cognitive health. Some of the conserved neurobiology aspects include:


1.     Neurotransmission: Both C. elegans and humans use neurotransmitters such as acetylcholine, serotonin, dopamine, and GABA (gamma-aminobutyric acid) for neuronal communication.

2.     Neuronal Development: The basic processes of neuronal development, including neurite outgrowth, axon guidance, and synapse formation, are conserved. Genes and pathways involved in these processes often have homologs or functional equivalents in both species.

3.     Neuronal Signaling Pathways: Critical signaling pathways that regulate neuronal function, such as MAPK (mitogen-activated protein kinase), Notch, Wnt, and insulin/IGF-1 signaling pathways, are conserved and play similar roles in both organisms.

4.     Neurodegenerative Diseases: While C. elegans does not naturally develop diseases like Alzheimer's or Parkinson's, researchers have created genetic and toxin-induced models of neurodegeneration. Many genes and pathways implicated in human neurodegenerative diseases have conserved counterparts in C. elegans, facilitating mechanistic studies.

5.     Behavioral Responses: C. elegans exhibits behaviors relevant to neurobiology, such as chemotaxis, thermotaxis, and learning and memory responses, which involve conserved neuronal circuits and molecular mechanisms.

6.     Aging and Longevity: Molecular pathways regulating aging and longevity, including insulin/IGF-1 signaling and dietary restriction pathways, are conserved between C. elegans and higher organisms, offering insights into decline in neuronal function with age.


Overall, the conservation of these neurobiology aspects allows C. elegans as a human-relevant model for discovery and development of bioactives promoting cognitive health.  Functional assays in C. elegans pertaining to memory, alertness, learning can be used to screen bioactives present in foods, setting the stage for de-risking human clinical trials in a cost and time efficient manner.

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