Age-Related Cognitive Decline and Dementia: Interface of Microbiome–Immune–Neuronal Interactions

Abstract

The microbiome plays a critical role in both promoting human health and contributing to diseases. Multiple emerging evidence shows that it contributes to aging and cognitive decline; however, the mechanisms are not fully understood. Changes in the microbiome and immune system occur with age, and immune functions are one of the key mechanisms linking the microbiome to the brain. Disrupted immunological balance may lead to neuroinflammation and blood–brain barrier dysfunction, contributing to cognitive decline. However, comprehensive knowledge regarding the types of microbiome and immune interactions influencing neuronal and cognitive health in aging remains largely unknown. This review presents evidence about the types of microbiome alterations associated with healthy versus unhealthy aging and how they interact with immune cells linked to neuronal and cognitive functions. It also explores whether and how microbiome modulators like probiotics, prebiotics, and postbiotics can be potential interventions to help preserve cognitive function in older adults.

Cognitive decline is a prevalent issue among older adults, impacting a substantial portion of the aging population. Emerging research indicates that nearly one-third of individuals over the age of 65 experience some form of cognitive impairment, and many develop dementia, while others remain stable in a mild cognitive impairment (MCI) state (1). Alzheimer’s disease (AD) is the most common form of dementia in older adults. The precise reason for this cognitive decline or AD remains elusive, and several factors, including lifestyle choices, underlying medical conditions, and genetic predispositions, have been linked (2,3). Therefore, understanding the etiology and pathophysiology of cognitive decline and AD is crucial for developing effective interventions to mitigate the adversities in older adults and the healthcare system caused by these debilitating public health problems in the elderly (2,3). The recently FDA-approved AD medicine Aducanumab (Aduhelm) decreases brain amyloids, unlike previous treatments (donepezil and memantine) that focused on symptom management (4,5). Additionally, lifestyle modifications like regular exercise, healthy dietary patterns, and cognitive stimulation have shown promise in delaying age-related cognitive decline and AD-related dementia (6). However, we still lack understanding of how such nonpharmacological interventions can contribute to slowing brain aging.

Of growing importance in this field is the role of the microbiome in dementia and aging, shedding light on how gut flora composition influences these processes. The symbiotic relationship between a healthy gut and a healthy brain is well recognized, with trillions of bacteria, viruses, fungi, and archaea comprising the gut microbiome playing crucial roles in various physiological processes, including immune response, metabolism, and neurobehavioral regulation (7). Abnormalities in gut microbiome diversity, composition, and function are associated with aging and age-related physiological changes such as inflammation, immunological dysfunction, and metabolic abnormalities (8,9). Evidence suggests that dysbiosis contributes to the onset and progression of age-related illnesses, including dementia (9–11). Thus, the microbiome-derived metabolites influence host health by either enhancing or impairing cellular functions of intestinal cells, immune cells, and neuronal cells. These effect are particularly relevant to the cognitive decline, including AD.

This review aims to elucidate the patterns of microbiome alteration and their connection with immune regulation in both healthy and age-related cognitively impaired older adults. Moreover, it explores how dysbiosis in the gut microbiota is linked to clinical features of AD and dementia, such as neuroinflammation and cognitive impairment. Interestingly, both beneficial and pathogenic bacteria in the gut microbiome have been implicated in aging and dementia, with the former exhibiting neuroprotective effects and the latter contributing to neurodegeneration and cognitive decline. Furthermore, metabolites from microbiomes, such as short-chain fatty acids (SCFAs), exert profound effects on immune system modulation and neuroprotection, while toxic metabolites like trimethylamine N-oxide (TMAO) and lipopolysaccharide (LPS) are associated with neuroinflammation and cognitive impairment. Despite these findings, the precise connection between the microbiome–immune–neuronal axis remains largely unexplored. Thus, this review seeks to consolidate existing knowledge on how microbiome–immune cell interactions influence neuronal function in the regulation of age-related cognitive decline and the onset of AD or dementia.

Microbiome Changes With Aging-Related Cognitive Decline

Aging is characterized by a gradual loss of microbial diversity, immune system function, and cellular homeostasis, accompanied by deteriorating cognitive and physical function, and an increased risk of several life-threatening diseases (12). However, the mechanisms through which aging accelerates the risk of these conditions remain elusive. Multiple emerging pieces of evidence show that the microbiome changes with aging, and these changes also become significant between cognitively healthy and unhealthy aging (13). Therefore, the changes in the microbiome with aging can be broadly categorized into 2 ways: the changes associated with unhealthy aging, and the changes in individuals experiencing healthy or normal aging where the microbiome remains relatively balanced supporting immune function and metabolic health with minimal variations due to chronological age (13) (see Tables 1 and 2).

Table 1.

Changes in Microbiomes With Healthy Aging

Microbiome	Changes With Age	Mechanism of Action	References
Faecalibacterium	Reduced with aging	They metabolize carbohydrates via the butyryl-CoA:acetate CoA-transferase pathway and butyrate kinase terminal enzymes to produce most of the butyrate.	(14–16)
Eubacterium rectale
Copococus
Roseburia
Anaerotruncus
Akkermansia	Increased with aging	They produce SCFAs which regulate gut–brain axis to maintain homeostasis between the gut and brain.	(14,15,17)
Odoribacter
Butyricimonas
Bacteroides
Barnesiella
Osillospira

Note: SCFA = short-chain fatty acid.

Table 2.

Changes in Microbiome With Unhealthy or Cognitively Decline Aging

Microbiome	Changes With Age	Mechanism of Action	References
Fusobacterium	Increased with aging	Gut dysbiosis by producing LPS and increased leakage of intestinal tight junction proteins.	(14,15,17)
Prevotella
Desulfovibrio
Eggerthella
Bilophila
Enterobacteriaceae
Enterococcus
Clostridium difficile
Streptococuccs
Ruminococcus gnavus

Note: LPS = lipopolysaccharide.

Furthermore, commensal taxa/genera likelihood refer to the populations of microorganisms, primarily bacteria, that naturally reside in and on the human body without causing harm; however, their diversity decreases during the transition from healthy to unhealthy aging (18,19). The abundance of beneficial commensal taxa, including Akkermansia, Odoribacter, Butyricimonas, Barnesiella, and Oscillospira, has been found to increase in older adults and is linked to reduced age-related conditions and overall healthy aging (14,15). These taxa play roles in the production of SCFAs, including butyrate, and are linked to a low prevalence of age-related neurodegeneration (17). Specifically, Odoribacter, Butyricimonas, and Bacteroides are positively associated with increased levels of SCFA acetate, which is linked with an increased hippocampus volume, suggesting a favorable impact on preventing cognitive decline (17).

Gut dysbiosis, characterized by a reduction in microbial diversity, is associated with age-related diseases such as diabetes, cardiovascular disease, and neurological disorders (14,15). Reports highlight an increased diversity of pathobionts like Eggerthella, Bilophila, Fusobacteria, Streptococcus, and Enterobacteriaceae in unhealthy aging, contributing to age-related disorders (14,15). Additionally, various studies demonstrate alterations in microbial diversity, abundance, and functionality in AD patients, suggesting that dysbiosis in the gut microbiome is crucial for the pathogenesis of cognitive deficits leading to AD (14,15). Numerous studies suggest a decrease in dominant commensal taxa such as Eubacterium rectale, Faecalibacterium, Coprococcus, Roseburia, Anaerotruncus, and Bifidobacterium with unhealthy aging (14–16). These communities produce butyrate in the gut, which is a key metabolite that provides energy to intestinal epithelial cells and contributes to maintaining gut health and controlling mucin, immunoglobulin A (IgA), and other beneficial secretions (20,21).

However, with age, specifically in unhealthy aging, the production of butyrate significantly declines, which is associated with a decline in butyrate-producing microbes as mentioned above, thus causing many gut-related issues, including increased gut permeability (“leaky gut”), which allows the proinflammatory compounds such as bacterial LPS, microbial cells, and others endotoxins to enter the bloodstream, thus promoting an inflammatory response (20,21). These abnormalities lead to macrophage hyperresponsiveness and dysregulated antibacterial nitric oxide production (20,21), driving systemic inflammation and increasing the risk of cognitive decline and age-related illnesses. Butyrate is produced by the fermentation of dietary fiber and is a key energy source for colonocytes (22). By regulating gut microbiota composition and promoting the growth of beneficial bacteria, butyrate helps sustain a balanced and healthy gut ecosystem, which is essential for overall gut health and barrier function (22). Mechanistically, butyrate strengthens tight junctions between epithelial cells by stimulating mucus production by goblet cells, preventing the translocation of harmful substances like pathogens and toxins into the bloodstream (23). Butyrate inhibits histone deacetylases (HDACs), enhancing gene expression for epithelial integrity and anti-inflammatory cytokines and ultimately contributing to healthy intestinal lining (22,24).

Altogether, abnormalities in the microbiome can promote anomalies in intestinal epithelial cells, increasing leaky gut, which in turn can accelerate systemic inflammation that can reach different organs, including the brain, and can promote accelerated aging, including cognitive decline and dementia. Furthermore, maintaining populations of beneficial microbes in the gut is linked to reduction in these abnormalities, including dementia prevalence, thus highlighting the importance of maintaining gut microbiome health to promote healthy aging. However, we still do not understand how the gut microbiome communicates with brain health in aging.

Immune Cell Contribution in Aging and Cognitive Health

Aging is associated with alterations in both humoral and innate immunity, yet the underlying reasons remain elusive. Humoral immunity is a component of adaptive immunity mediated by antibodies produced by B cells, targeting extracellular pathogens and toxins for neutralization or destruction (25). However, innate immunity is the first line of defense against infections, involving nonspecific responses by physical barriers, immune cells (eg, macrophages, neutrophils), and proteins to recognize and eliminate pathogens quickly (25). While a wide range of changes occurs in the humoral immune system as we grow older, similar to the microbiome, unhealthy older adults develop distinct immune patterns compared to healthy older adults (8). Furthermore, it is unclear whether these changes contribute to age-related cognitive decline or are a consequence of such changes (8). Nevertheless, these alterations present opportunities to be used as biomarkers for age-related changes in cognitive function.

Certain immune cell populations become more dominant than others depending on health conditions or age-related comorbidities. For instance, the three subtypes of monocytes—classical, nonclassical, and intermediate monocytes—significantly change with aging (26). Classical monocytes (CD14⁺ + CD16⁻) are the most abundant subsets (~80%−90%), primarily involved in phagocytosis and inflammation. They migrate to tissues in response to infection or injury, where they differentiate into macrophages or dendritic cells (DCs) (27). Nonclassical monocytes (CD14⁺ + CD16⁺) are smaller subsets (~5%–10%) that monitor blood vessel walls and play a role in tissue repair and resolving inflammation (27). They exhibit high mobility and are involved in vascular homeostasis. Moreover, intermediate monocytes (CD14⁺ + CD16⁺) is a transitional subset (~2%–8%) with characteristics of both classical and nonclassical monocytes. They are associated with antigen presentation, inflammatory cytokine production, and a heightened response to infections and chronic inflammation (27). A study demonstrated that nonclassical monocytes compared to classical monocytes increase in unhealthy older adults, and these represent proinflammatory and senescent phenotype with shorter telomeres (28). Similarly, a change in macrophage phenotypes such as proinflammatory M1 macrophages and anti-inflammatory or immunomodulatory M2 macrophages appears with aging. M1 macrophages are activated by infectious microorganism-related molecules (eg, the gram-negative product LPS) and promotes the release of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6; conversely, the M2 macrophages releases anti-inflammatory molecules such as IL-10, transforming growth factor-beta (TGF-β), and glucocorticoids (29). A shift toward the M1 (proinflammatory) phenotype during aging may exacerbate the M1/M2 imbalance, which leads to greater baseline cytokine production; these processes may cause inflammation, and activation of immunosenescence markers such as sCD163, sCD28, sCD80, and sCTLA-4 that are linked to accelerated age-related disorders including cognitive decline (30,31). Functionally, these senescence mechanisms result in aberrant chemotaxis, reduced phagocytosis, impaired activation, and reduced pathogen detection (32).

Particulate blood lymphocytes comprise around 15% of innate lymphoid cells known as natural killer (NK) cells and characterized by CD56 and CD16 markers. The NK cells exhibit distractive alteration between MCI and AD. Le Page et al. demonstrated that the blood peripheral NK cells show higher activation (with CD16 + CD56^dim markers) with increased expression of CCR7 in amnestic MCI (aMCI) compared to mild AD. Furthermore, an increase in cytokine production (TNF-α and IFN-γ) in aMCI but not in mild AD has been detected (33). These findings imply NK cells may be involved in AD pathogenesis and emphasize the relevance of immunological activation early in decline of cognition in aMCI. Increased NK cell activation has been observed in individuals with MCI compared to healthy controls. Elevated activation markers like CD69 and granzyme B are associated with a heightened inflammatory response, possibly driven by early neurodegenerative processes (34). CCR7 expression is upregulated in the blood–brain barrier (BBB) during age-related disorders, facilitating immune cell migration to inflamed tissues, including the central nervous system (CNS) in contrast to healthy controls (35). Healthy aging shows moderate increases in proinflammatory cytokines (“inflammaging”), such as IL-1β, IL-6, and TNF-α, but the levels are significantly higher in MCI (36).

Similarly, other immune cells like lymphocytes also go through significant changes with aging. For example, although the overall number of T cells remains constant, the percentages of T-cell subpopulations (CD4⁺ vs. CD8⁺ T cells) vary significantly during aging (26) (see Table 3). CD4⁺ T cells are major histocompatibility complex class II (MHC-II)-restricted and preprogrammed for helper (Th) functions, whereas CD8⁺ T cells are MHC-I-restricted and preprogrammed for cytotoxic (Tc) functions (38). Interestingly, low levels of CD4⁺ T cells with substantial higher CD8⁺ T cells, causing skewed reduction in the CD4⁺:CD8⁺ T-cell ratio, are often detected in older adults with cognitive impairment (26). This decrease in CD4⁺:CD8⁺ T-cell ratio is associated with an increase in senescence T-cell clearance (CD28–CD57⁺ T cells) and a decrease in naive T cells (expressing surface receptors including CD45RA and CD28). An appropriate immune response against freshly encountered infections is ensured by naive CD4⁺ T cells, which are a bunch of lymphocytes without antigen exposures. The decrease in naive T cells leads to a reduction in the T-cell receptor (TCR) repertoire. These events are more pronounced in CD8⁺ T cells, which results in improper antigen-induced proliferation (39) as well as reduced proliferation because of their shorter telomeres (40). These cells produce proinflammatory cytokines, thus aggravating “inflammation.” However, the specific immune cells involved as well as whether and how they enters in the brain remain less known. Similarly, older persons often have higher levels of antigen-specific B cells and fewer new B cells (41). As people age, their bone marrow produces less naive B cells (CD19⁺ and CD27⁻). This could be due to age-related suppression of genes like λ5 and VpreB, which are necessary for the maturation of B-cell precursors (42–44). This leads to a decrease in clonal proliferation, reduction in cytokine production (including TNF-α and IL-6), and the inability to produce antibodies in response to novel stressors, making older hosts more susceptible to chronic inflammatory illnesses (42). Levels of activated B-cell markers such as CD40L (43,44) are compromised in the circulation (43), and enhanced infiltration of B cells into the CNS results in microglial activation and Ig deposits around Aβ plaques. However, interactions of B cells, microbiome, and neurons remain elusive.

Table 3.

Changes in Systemic Immune Cells With Aging-Related Cognitive Decline

Immune Cells	Changes With Unhealthy Aging	Outcome	References
Innate immunity		Decreased phagocytosis and abnormal chemotaxis	(26,37)
NK cells: CD56bright	Decreased
CD56dim	Increased
Monocytes	Increased
Shifting from M1 to M2	Abnormal macrophage activity
Adaptive immunity			(26,28)
CD/C8 ratio	Increased	Decreased proliferation
		Lose effector function
Memory or effector T cells	Increased	Increased inflammation
		Increased inflammaging
Senescent/exhausted T cells	Increased
IL-6, TNF-α, and CRP	Increased
IL-4, IL-7, IL-8, and IL-15	Decreased

Note: CRP = C-reactive protein; IL = interleukin; NK = natural killer cells; TNF = tumor necrosis factor.

The number of resident immune cells including neutrophils, DCs, T cells, and B cells increase in the brains of older adults (45). In normal physiological conditions, the migration of peripheral immune cell and their cytokine to the brain is strictly controlled by the BBB (46). However, the cerebrospinal fluid and blood of AD patients often show higher levels of clonal and antigen-experienced T cells with profile, suggesting a significantly altered adaptive immune response during AD (47) (see Figure 1). Although the exact cause of the increasing numbers of immune cells in the CNS of older adults with AD is unknown, it is most likely due to aging-related alterations in the vasculature of the brain that allow for their entry. In addition, the microbiome–immune–BBB interactions that play a role in the entry of such immune cells from circulation to brain also remain largely unknown.

Figure 1.

The illustration of variations in microbiome, immune cells, and AD pathology markers during healthy (left; light green) and unhealthy (right; light red) aging. (A) During healthy aging, the abundance of beneficial microbiomes, such as Akkermansia, Odoribacter, Faecalibacterium, Eubacterium, and Roseburia, remains high, and (B) immune cells, such as monocytes, the CD4/CD8 ratio, and T-cell senescence, remain balanced, along with (C) low levels of AD markers such as Aβ, Tau, neurofibrillary tangle, and neuroinflammation or microglia activation. In contrast, during unhealthy aging, there is (D) a higher abundance of harmful microbiomes, such as Prevotella, Desulfovibrio, Eggerthella, Enterobacteriaceae, and Enterococcus, in the gut; (E) an imbalance in immune cells, such as monocyte activation, CD4/CD8 ratio, and T-cell senescence in circulation; and (F) an increase in Aβ, Tau, neurofibrillary tangles, and neuroinflammation or microglia activation in brain.

Microbiome–Immune–Neuronal Axis in Age-Related Cognitive Decline

Multiple emerging evidence show that the interactions of the microbiome with immune and neuronal cells play a key role in cognitive health during aging (48). The mucosal immune system is the largest reservoir of immune cells in human body, that closely interact with microbiome living around them (49). The microbiome and their metabolites influence both mucosal and systemic immune cells (49). Interestingly, these immune cells, once influenced by the surrounding microbiome and its metabolites, they can not only regulate the local gut environment but also migrate to distant organs, such as the brain, or transmit signals through cytokines and chemokines, thereby impacting neuronal and cognitive functions (50). With age, significant changes occur in microbiomes and so the immune functions, that are closely linked with brain health, depending on the type of changes. It has now been established that many abnormalities in the microbiome can accelerate abnormalities in brain including progression of cognitive decline, dementia, and neurodegeneration (51). The gut microbiota produces a diverse range of proinflammatory neurotoxins that can harm brain (52). Additionally, certain microbes produce amyloids that interact with intestinal neurons and immune cells, facilitating their migration to the brain and contributing to neurodegeneration (52). For example, pathogenic bacteria, such as Proteobacteria, can compromise gut barrier integrity, leading to the release of toxic compounds like LPS into circulation (53). These toxins trigger immune activation and the production of proinflammatory cytokines, including IL-6, IL-1β, and TNF-α, a process referred to as “leaky gut.” This condition is increasingly recognized as a contributor to systemic inflammation in aging and is linked to age-related cognitive decline (53). The circulating inflammatory mediators and toxins can cross the BBB, disrupting its integrity and activating brain macrophages, such as microglia and astrocytes (5). This neuroinflammatory cascade contributes to neurodegeneration, as observed in diseases like AD (5) (Figure 3). On the other hand, increased numbers of beneficial gut bacteria linked with better maintenance of the integrity of the BBB while decreasing their permeability (54,55). Such beneficial bacteria also produce neurotransmitters crucial for mood control and cognition, such as dopamine and serotonin (55). Additionally, SCFAs, especially butyrate, regulate the production, trafficking, and activity of innate and adaptive immune cells, thereby reducing inflammation (56).

Figure 3.

Mechanistic understanding about the aging and poor dietary habits on microbiome, leaky gut, inflammation, and brain abnormalities. (A) The panel depicts how aging and poor dietary habits reduce gut microbial diversity. (B) Reduced microbial diversity favors the proliferation of pathogenic bacteria (pathobionts), leading to increased production and release of lipopolysaccharide (LPS). (C) LPS binds to Toll-like receptor-4 (TLR-4) on intestinal epithelial cells, disrupting tight junction proteins such as zonulin-1 and occludin, which are critical for maintaining gut barrier integrity, causing leaky gut. (D) LPS enters systemic circulation, triggering immune activation and the release of proinflammatory cytokines (eg, interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α]). This inflammatory cascade disrupts the blood–brain barrier (BBB), contributing to neuroinflammation and neurodegeneration. (E) Interventions like prebiotics (eg, fructans, inulins, oligosaccharides), probiotics (eg, Lactobacillus rhamnosus, Lactobacillus reuteri, Bifidobacteria), postbiotics (eg, heat-inactivated Lactobacillus paracasei [D3-5]) and dietary approaches such as the Mediterranean diet rich in omega-3 fatty acids and vitamin B increase short-chain fatty acid (SCFA) production. SCFAs enhance mucin secretion, reinforce tight junction proteins, and reduce leaky gut and BBB disruption. (F) Drugs like metformin, rapamycin, senolytics, and GLP-1 receptor agonists (GLP-1RAs) act via the AMPK/mTOR/SCAP pathway, improving mitochondrial function in the gut and brain, thereby mitigating neurodegeneration. This explanation highlights the interplay between aging, diet, microbiota, and interventions, emphasizing their role in preserving gut and brain health.

Many metabolites produced by microbiomes positively or negatively impact the brain health by impacting distinct components of the brain including BBB, microglia, and neurons via gut and systemic circulation. Butyrate is one of the most commonly studied microbial metabolites that impacts tight junction proteins in the BBB and reduces its leakiness. However, these phenomena are still understudied and require more comprehensive research to develop better understanding toward interaction of the microbiome–immune–brain axis to ameliorate brain-related anomalies in older adults.

Potential of Microbiome–Gut–Immune–Neuronal Axis in Clinical Studies and Trials

Clinical studies and trials are needed to further explore the gut–immune–neuronal axis and its potential in understanding cognitive decline. The use of microbiome and immune structure/function as biomarkers for cognitive decline offers a novel and complementary approach to existing biomarkers, such as genetic markers, blood tests, and brain imaging (57). Current biomarkers—including genetic markers (eg, APOE-ε4), blood biomarkers (amyloid-β, tau) and neuroimaging techniques such as magnetic resonance imaging (MRI) and positron emission tomography (PET) are key tools for detecting and monitoring cognitive decline. Studies demonstrate that microbiome-derived metabolites, such as SCFAs, influence microglial maturation and function, which are critical for maintaining cognitive health (58). Moreover, significant differences in gut microbiota composition have been observed between individuals with AD and cognitively healthy controls. For example, reduced levels of beneficial bacteria like Faecalibacterium and Bifidobacterium and increased proinflammatory taxa have been linked to cognitive decline (59). Additionally, immune markers such as elevated cytokines (eg, IL-6, TNF-α) in peripheral blood have been associated with neuroinflammatory processes contributing to cognitive impairments (59). These findings highlight the sensitivity of microbiome alterations to neurophysiological changes, making them promising biomarkers. Compared to genetic markers (APOE-ε4), microbiome and immune markers may be more dynamic, reflecting real-time changes in response to interventions or early disease progression (60). Unlike neuroimaging, which requires expensive and specialized equipment, microbiome analysis via stool samples and immune profiling from blood tests could offer more practical, noninvasive, and cost-effective options. However, challenges remain, such as standardizing microbiome analysis techniques and accounting for interindividual variability due to diet, lifestyle, and environmental factors.

Emerging clinical trials testing microbiome-modulating therapies, such as prebiotics, probiotics, dietary interventions, and other gut modulators or drugs, show promise in improving cognitive outcomes, further supporting their role as functional indicators of brain health. Therefore, this review elaborates on possible interventions that impact the microbiome–immune–brain axis and highlights how future clinical studies and trials should incorporate microbiome and immune biomarkers as clinical outcomes to assess their effectiveness in early diagnosis, monitor disease progression, and evaluate therapeutic responses.

Interventions Impacting Microbiome–Immune–Brain Axis

Modulating the microbiome has become one of the most significant targets for improving human health. Further, aging and poor dietary habits significantly reduce gut microbial diversity, leading to an imbalance favoring pathogenic bacteria (pathobionts). This dysbiosis increases the production and systemic release of LPS, which bind to Toll-like receptor-4 (TLR-4) in the gut, disrupting tight junction proteins such as zonulin-1 and occludin. The resulting “leaky gut” facilitates the entry of LPS into systemic circulation, triggering immune activation, proinflammatory cytokine release, and ultimately BBB disruption. These processes drive neuroinflammation and neurodegeneration, common in aging-related cognitive decline (Figure 3).

Interventions, including prebiotics, probiotics, and dietary changes like the Mediterranean diet, enhance SCFA production, which strengthens the gut barrier, reduces inflammation, and protects the BBB. Pharmacological agents like metformin, rapamycin, senolytics, and GLP-1 receptor agonists (GLP-1RAs) further restore mitochondrial and cellular homeostasis via the AMPK/mTOR pathway, modulating the microbiome–immune–brain axis, and are summarized below and illustrated in Figures 2 and 3.

Figure 2.

Impact of prebiotics, probiotics, postbiotics, diets and interventions on the gut–immune–brain axis in age-related cognitive decline. (A) Prebiotics such as fructans, inulins, and oligosaccharides promote the colonization of healthy bacteria in the gut, which either directly activates T regulatory cells to balance Th1/Th2 or promotes short-chain fatty acid (SCFA) production to enhance phagocytic activity and natural killer (NK) cell activation in systemic circulation and improve neuronal function in the brain. (B) Probiotics such as Lactobacillus rhamnosus, Lactobacillus reuteri, and Bifidobacteria either increase the production of SCFA or increase mitochondrial ATP production in the gut, ultimately activating phagocytic activity and NK cells in the systemic circulation and improving cognitive performance. (C) Postbiotics such as SCFAs, butyrates, and heat-inactivated Lactobacillus paracasei (D3-5) either impact immune cell activation and/or increase energy production to boost immune functions and improve brain performance. Similarly, (D) diets, including the mediterranean diet rich with omega-3 fatty acids and vitamins B, also act as immune boosters and increase brain performance during aging. Moreover, (E) drugs like metformin, rapamycin, senolytics, and GLP-1 receptor agonists (GLP-1RAs) act through the AMPK/mTOR/SCAP pathway to maintain mitochondrial function and ultimately promote the maturation of dendritic cells to increase synaptic communication and brain function.

Probiotics

Probiotics are live microorganisms that exert beneficial health effects when consumed in sufficient amounts. They enter the gut in an active condition and beneficially modulate the gut microbiome to exhibit their benefits on health. Commonly used probiotics include Lactobacillus and Bifidobacteria, while other microorganisms such as Streptococcus thermophilus and Saccharomyces cerevisiae have also been utilized as probiotics. Probiotics are an integral part of our microbiome and can partner with many commensal microbes living in our gut to exert beneficial effects by producing beneficial metabolites like SCFAs and others. Probiotics are known to boost the immune system, enhancing NK cell and phagocytic activity in both healthy and older adults (61,62). Additionally, probiotics improve nutritional and immunological health in older individuals by increasing serum albumin and intestinal IgA production (63,64). Furthermore, probiotic supplementation studies in older adults have shown reductions in the production of inflammatory markers, such as TNF-α, IL-1β, and IL-6, while increasing the production of the anti-inflammatory cytokine IL-10. Probiotics have garnered attention for their potential to modulate immune cell types in older adults, thereby influencing brain health outcomes. Studies have demonstrated that, probiotic supplementation can alter the composition and activity of immune cells, such as T cells, B cells, and DCs, in the gut-associated lymphoid tissue (GALT) and systemic circulation (65). This immune modulation may have implications for neuroinflammation and cognitive function, suggesting a potential avenue for promoting brain health in aging populations. Many probiotics produce active neurotransmitters like GABA and glutamine, directly influencing intestinal neurons that manipulate CNS-mediated behaviors, and/or reach the brain through circulation to impact brain functions.

GABA binds to GABA-A, GABA-B, and GABA-C receptors located on the intestinal neurons (66). These receptors regulate neuronal excitability and gut motility. This modulation can influence peristalsis (coordinated contraction of intestinal muscles) and secretion of intestinal fluids, indirectly affecting gut–brain axis. Moreover, glutamine serves as a substrate for the synthesis of glutamate, an excitatory neurotransmitter, and subsequently GABA, in the enteric nervous system (ENS) (66). Glutamate acts on ionotropic (eg, AMPA, NMDA) and metabotropic glutamate receptors in intestinal neurons, driving excitatory signaling that regulates gut motility and secretion (67). Research has shown that probiotics producing GABA, such as Lactobacillus species, improve anxiety and cognitive symptoms in animal models of aging and neurodegeneration (66). Furthermore, studies in elderly populations have observed reduced gut-derived GABA and glutamine metabolites, correlating with cognitive decline and higher systemic inflammation (67). Such probiotics are also referred to as “psychobiotic.”

Several clinical studies have investigated the effects of probiotics on immune and brain health outcomes in older adults, highlighting their potential benefits. A randomized controlled trial (RCT) by Akbari et al. investigated a multistrain probiotic containing Lactobacillus acidophilus, Lactobacillus casei, Bifidobacterium bifidum, and Lactobacillus fermentum. This 12-week trial in elderly participants showed improved cognitive function (measured by Mini-Mental State Examination [MMSE]) and reduced markers of systemic inflammation, such as C-reactive protein (CRP) and malondialdehyde (MDA), indicating the anti-inflammatory potential of probiotics in cognitive health (68). Similarly, a study by Kobayashi et al. demonstrated beneficial effect of Bifidobacterium breve A1 in older adults with memory impairments. This RCT found significant improvements in memory function and reductions in inflammatory markers, suggesting that B. breve A1 may reduce neuroinflammation and enhance cognitive performance (69). Further, Bashir et al. revealed that aging and gut dysbiosis disrupt the tolerogenic function of DCs, leading to immune dysregulation characterized by decreased regulatory T cells (Tregs), overactive proinflammatory pathways, and reduced anti-inflammatory mediators (70). Importantly, supplementation with Lactobacillus plantarum restored DC tolerance by rebalancing inflammatory and metabolic pathways, highlighting its therapeutic potential for age-related disorders (70). Collectively, these trials provide compelling evidence for the potential of probiotics to positively impact immune and brain health outcomes in aging populations. Therefore, probiotic research offers significant strengths, including mechanistic insights linking gut microbiota to brain health via SCFAs, immune regulation, and neurotransmitter production. Clinical trials, such as those by Akbari et al. and Kobayashi et al., show improved cognition and reduced inflammation, supporting probiotics’ therapeutic potential in aging populations (68,69). Additionally, probiotics are noninvasive and accessible. However, variability in outcomes due to differences in strains, dosages, and individual microbiome composition limits generalizability. The lack of standardization and short-term focus of studies further complicate their application. Long-term effects and consistent protocols are needed to fully harness probiotics’ potential for immune and brain health. These findings highlight the promising role of probiotics as a therapeutic intervention for promoting brain health in older adults.

Prebiotics

Prebiotics are soluble oligosaccharides/fibers that are indigestible by human digestive enzymes but fermentable by the microbiome, producing beneficial metabolites such as SCFAs (acetate, propionate, butyrate, and others) (71). They are commonly found in high-fiber diet ingredients as well as human milk. Additionally, prebiotics have been isolated from various sources and optimized for large-scale production. Among them, inulin and fructooligosaccharides are the most common and widely studied prebiotics, known for increasing the growth of beneficial bacteria in the gut and promoting the production of SCFAs (72). The SCFAs strengthen intestinal barrier functions, thereby reducing leaky gut and diminishing the exposure of immune cells to proinflammatory signals (73). Furthermore, prebiotics elevate SCFA levels in the blood, which can directly modulate neuronal functions in the brain. They are capable of passing the BBB and have specific transporters (monocarboxyl transport 1/2 [MCT1/2] and free fatty acid receptor 2 and 3 [FFAR2/3]) in brain cells, through which they impact neuronal and brain functions (73). Both fructo- and galacto-oligosaccharides are known to enhance brain-derived neurotrophic factor (BDNF) expression and reduce lipid peroxidation by scavenging reactive oxygen species (ROS) in the hippocampus (memory center) (74,75), indicating their significant impact on brain health. Fructans, which consist of branching β linkages termed agavins, including inulin-type fructans (ITFs), have been found to increase SCFA synthesis by up to 30%, particularly propionate and butyrate (75). Studies have demonstrated that ITFs maintain the balance of T-helper cell type-1 (Th1)/Th2 profile by regulating the immunophenotype of T cells (76). Additionally, ITFs increase DCs and the secretion of anti-inflammatory cytokines such as IL-2 and IL-10, thereby improving innate immunity barriers to maintain epithelial tight junction integrity (76). Moreover, our research has shown that prebiotics isolated from acorn and sago prevent high-fat diet-induced insulin resistance via modulation of the microbiome–gut–brain axis (72).

Clinical studies investigating the effects of novel prebiotics on immune and cognitive functions in aging populations have garnered increasing interest due to the potential therapeutic implications for age-related cognitive decline. One such study by Vulevic et al. examined the impact of a prebiotic, that is trans-galacto-oligosaccharide mixture (B-GOS), on older adults. When compared to the baseline and placebo, the addition of B-GOS dramatically raised the numbers of good bacteria, particularly Bifidobacteria, at the expense of less beneficial group (77). Proinflammatory cytokine production (IL-6, IL-1β, and TNF-α) was significantly reduced, whereas phagocytosis, NK cell activity, and the generation of the anti-inflammatory cytokine like IL-10 were all significantly increased (77). These studies collectively suggest that prebiotic supplementation may hold promise as a nutritional intervention to support immune and cognitive health in aging individuals, offering potential avenues for mitigating age-related cognitive decline (77–79). In conclusion, prebiotics play a crucial role in promoting gut health, immune function, and brain health through their modulation of the microbiome and production of SCFAs. Their diverse benefits underscore their potential as a therapeutic intervention for various health conditions of older adults. Overall, prebiotics are a natural, cost-effective intervention that promotes gut health, strengthens immune function, and supports brain health through the production of SCFAs. They modulate the gut–microbiome–brain axis, enhance beneficial gut bacteria, and improve intestinal barrier integrity. Prebiotics like inulin and galacto-oligosaccharides reduce inflammation, boost BDNF expression, and mitigate oxidative stress, showing promise in combating age-related cognitive decline. However, their efficacy may vary between individuals due to differences in microbiome composition and dietary habits. Potential side effects like bloating and gas may limit adherence, and the long-term effects of prebiotic supplementation remain underexplored.

Synbiotics

Synbiotics are the combination of probiotics and prebiotics, and consumption of synbiotics exerts health beneficial effects by providing synergistic benefits of probiotics and prebiotics. Synbiotics have been known to impact various gut–immune and brain functions including lowering the risk of dementia and AD. A study conducted by Gopal et al. revealed that the abundance of bifidobacteria and lactobacilli in the human gastrointestinal tract increased when milk containing oligosaccharides (prebiotic) and Bifidobacterium lactis HN019 (probiotic) was consumed (80). In a randomized, double-blind, crossover research with 30 healthy kids (16 boys and 14 girls), Piirainen et al. examined the effects of probiotic and synbiotics alone on the gut flora. After 3 weeks of research, the number of bifidobacteria was significantly higher in those who consumed synbiotic milk-based fruit juice daily that contained Lactobacillus rhamnosus GG and galacto-oligosaccharides than in those who consumed the probiotic L. rhamnosus GG alone (81). Probiotics and prebiotics alone were not as efficient as synbiotic treatment in treating inflammatory illnesses and enhancing quality of life (82). Study in our lab demonstrated that the synbiotic yogurt reduces the abundance of detrimental bacteria such as Proteobacteria and Enterobacteriaceae compared to control yogurt and thereby it reduced the development of hyperglycemia (diabetes) in rodent model (83). A clinical study by Hibberd et al. demonstrated that a 6-month administration of LU + B420 (synbiotics) increased the abundance of beneficial bacteria such as Akkermansia, Christensenellaceae, and Methanobrevibacter, while reducing Paraprevotella in overweight adults. Furthermore, the plasma bile acids glycocholic acid, glycoursodeoxycholic acid, taurohyodeoxycholic acid, and tauroursodeoxycholic acid were reduced compared to placebo (84). Another clinical study, conducted in 2016, discovered that the use of synbiotics, which include the prebiotics β-glucan, inulin, pectin, and resistant starch, along with the probiotics Pediococcus pentosaceus, Leuconostoc mesenteroides, Lactobacillus paracasei ssp. paracasei 19, and L. plantarum, could lower the risk of postoperative complications such as irritable bowel syndrome (IBS) in cancer patients (85). The likely cause of this could be an enhanced immunological response that modifies the actions of immune cells such as T and B cells, DCs, and macrophages (86). These findings suggest that using synbiotics in addition to probiotics or prebiotics may be more beneficial. However, their effectiveness can vary across populations due to microbiome diversity and individual responses. Limited long-term studies, inconsistent formulations, and high production costs pose challenges. Further in vitro and in vivo research is essential to standardize synbiotic products and confirm their safety and efficacy.

Postbiotics

Postbiotics are metabolic or microbial cell byproducts that exhibit beneficial biological activity for the host (87). Postbiotic metabolites, such as amino acids, bacteriocins, SCFAs, peptidoglycan-derived muropeptide, lipoteichoic acid, neurotransmitters, vitamins, and others, influence either mucosal and intestinal neurons or enter the bloodstream, thereby affecting the systemic immune system (87). Many of these compounds can also cross the BBB and influence brain function. By triggering pathways linked to specific immune responses, clinical trials examining the anti-inflammatory potential of postbiotics generated from the Bifidobacterium longum strain have demonstrated efficacy in regulating acute inflammatory responses and gastrointestinal disturbance (88). Furthermore, studies on mice fed fermented infant formula containing postbiotics made from St. thermophilus 065 and B. breve C50 have shown that these microbes can extend the life of DCs and induce high levels of IL-10 production through TLR-2, which may indicate immune regulatory functions (89,90). Further, evidence of the role of postbiotic components in host immune function comes from studies demonstrating that postbiotics from these strains enhance epithelial barrier function and trigger Th1 response in mice models (89,90). A study conducted on mice models shown that L. paracasei CBA L74’s reduced inflammatory responses in immune cells, shielding the host from enteric and pathogenic microorganisms and perhaps providing protection against colitis (91). We recently have shown that in Caenorhabditis elegans and mice, heat-inactivated L. paracasei (D3-5) dramatically reduced aging-related leaky gut and inflammation and recovered physical and cognitive impairments (92). Furthermore, these postbiotics have geroprotective properties that postpone immune system senescence and prevent or lessen mitochondrial dysfunction (93). Moreover, an ongoing clinical trial (SmartAge trial) is a pioneering study assessing the effects of 12-month spermidine supplementation on memory performance in older adults with subjective cognitive decline, a group at higher risk of dementia, including AD (94). The trial employs a randomized, double-blind, placebo-controlled design with primary and secondary outcomes, such as memory improvement, neurocognitive measures, and physiological biomarkers like autophagy markers and neuroimaging. This study aims to identify neurophysiological mechanisms underlying cognitive benefits and contribute to the development of nutritional interventions for dementia prevention (94). In addition to their strengths, postbiotics have certain limitations. Their effects can be highly strain-specific, necessitating precise identification and standardization. Moreover, the limited number of human clinical trials and variability in production processes underscore the need for further research to establish their safety and efficacy.

Ketogenic Diet

The importance of diet and other lifestyle variables in healthy brain aging has sparked growing research and public interest. Recent research suggests that modifying older people’s diets may assist in delaying or preventing the progression of age-related cognitive impairment by regulating the gut microbiome (95). The ketogenic diet, characterized by high fat, adequate protein, and low carbohydrate intake, promotes the production of ketone bodies through fatty acid metabolism. This dietary shift alters the gut microbiota composition, favoring the growth of certain taxa capable of metabolizing fats and producing SCFAs (96). SCFAs, particularly butyrate, can modulate immune cell function by promoting Treg differentiation and reducing proinflammatory cytokine such as IL-1β, IL-6, and TNF-α production, thereby attenuating neuroinflammation (97). These immunomodulatory effects of the ketogenic diet may play a role in its potential therapeutic benefits for neurological conditions such as neurodegenerative diseases. Therefore, the ketogenic diet uniquely alters gut microbiota composition, encouraging the growth of taxa that metabolizes fats and produce beneficial SCFAs like butyrate. However, the diet’s restrictive nature may limit adherence and long-term sustainability for many individuals. Additionally, its high-fat content could pose cardiovascular risks for certain populations.

High-Fiber Diet

High-fiber diets promote the growth of fiber-degrading bacteria like Bacteroidetes and Firmicutes, leading to increased production of SCFAs such as butyrate, acetate, and propionate. SCFAs support the development and function of Tregs and reduce inflammation by inhibiting the activation of proinflammatory immune cells (98–101). A high-fiber diet and the associated SCFAs have been linked to improved immune function, reduced inflammation, and healthy aging (102). Therefore, a high-fiber diet promotes the growth of beneficial bacteria like Bacteroidetes and Firmicutes, leading to increased production of SCFAs, which support Treg development, reduce inflammation, and enhance immune function. These effects contribute to healthy aging and disease prevention. However, the effectiveness of the diet may vary depending on individual microbiome composition, and some individuals may experience gastrointestinal discomfort, such as bloating or gas, when increasing fiber intake, which could hinder long-term adherence.

Mediterranean Diet

The Mediterranean diet is rich in plant-based foods, polyphenols, and omega-3 fatty acids, and linked with increased microbial diversity in the gut, characterized by a greater abundance of beneficial bacteria such as Bifidobacterium and Lactobacillus (103). Mediterranean diet containing polyphenols and omega-3 fatty acids modulates immune cell function such as macrophages, DCs, and T cells and reduces inflammation and oxidative stress. The Mediterranean diet is associated with reduced risk of age-related diseases and improved cognitive function (104). Nagpal et al. demonstrated that a 6-week administration of the mediterranean–ketogenic diet (MMKD) increased the abundance of Enterobacteriaceae, Akkermansia, Slackia, Christensenellaceae, and Erysipelotriaceae, while reducing Idobacterium and Lachnobacterium in MCI participants. Furthermore, there was an increase in propionate and butyrate levels (105). However, the effectiveness of the mediterranean diet may be influenced by individual dietary habits and could be difficult for individuals who do not follow mediterranean-style food patterns.

Metformin and Other Drugs

According to Guo et al., people with type 2 diabetes who use metformin had a decreased risk of cognitive impairment. Study found that middle-aged patients with type 2 diabetes who took metformin regularly experienced enhanced cognitive performance and antidepressant effects (106). According to a recent study, elderly diabetics using metformin showed a slower rate of cognitive deterioration progression and a decreased risk of dementia (107). Eight weeks of metformin medication improved executive function but not the other cognitive tests in nondiabetic individuals with moderate cognitive impairment or mild dementia associated to AD (108). Furthermore, a study by Ahmadi et al. demonstrated that metformin improves the gut microbiome/goblet cell/mucin axis, which in turn lowers aging-related leaky gut and enhances cognitive performance (56). Therefore, the majority of research showed that metformin helped diabetic patients’ cognitive ability. Although enhanced insulin signaling and mitochondrial metabolism are typically proposed as the mechanisms behind these advantageous effects (109), additional factors may also be involved, including adenosine monophosphate-activated protein kinase (AMPK) activation, altered microglial phenotype, mammalian target of rapamycin (mTOR) inhibition, and elevated brain autophagy. Moreover, a study by Soldevila-Domenech et al. examined the effects of metformin use and Mediterranean diet on cognitive performance in older adults with type 2 diabetes (110). Although, metformin users initially showed better executive functions, memory, and global cognition, these differences were not sustained after 3 years. Individuals not using metformin experienced greater cognitive improvements, particularly in memory and executive functions, and had higher compliance to the Mediterranean diet (110). The findings suggest that while both metformin and Mediterranean diet are promising for preventing cognitive decline, higher compliance to the Mediterranean diet may offer greater neuroprotective benefits than metformin alone in individuals with diabetes (110). However, the effects of metformin on nondiabetic individuals with cognitive impairment remain inconsistent, and further studies are needed to confirm its efficacy for age-related cognitive decline and the specific molecular mechanisms involved.

Rapamycin

Rapamycin, originally developed as an immunosuppressant, is a powerful inhibitor of the mTOR pathway, which regulates cell growth, metabolism, and autophagy (111). An increasing body of research indicates that mTOR signaling affects aging and longevity (112). Studies have demonstrated that rapamycin increased lifespan of males and females with greater effects in females, likely due to differences in drug blood levels (113). Unlike dietary restriction, rapamycin induces distinct endocrine, metabolic, and hepatic gene expression changes, indicating that these two lifespan-extending interventions work through different mechanisms (113). Numerous chronic disease processes, including deteriorating immunological function (114), cardiovascular disease (115), and neurodegeneration (116), have been connected to the mTOR pathway. The administration of rapamycin derivatives has been shown in RCTs to improve physiological parameters associated with aging in the immune, cardiovascular, and integumentary systems of healthy individuals or individuals with age-related diseases in humans (117). Moreover, in Kraig et al.’s study, short-term rapamycin treatment appears to be safe and well-tolerated in older adults aged 70–93 years, with no significant adverse clinical effects on cognitive, physical, or immune functions (118). Although some rapamycin-associated changes, such as mild reductions in erythrocyte parameters, were observed, they were not clinically significant (118). Therefore, low-dose rapamycin appears to be a feasible and safe intervention for improving immunological and physical parameters in older adults, with modest cognitive benefits (118). Further trials are needed to confirm these findings, optimize dosing, and evaluate long-term effects.

Senolytics

Cellular senescence is a basic aging mechanism that is receiving more and more attention. Senescent cells proliferate as people age and at the pathogenic locations of numerous illnesses (119). In aging and chronic disease models, targeting cellular senescence mitigates key aging mechanisms, reducing fibrosis, inflammation, progenitor exhaustion, mitochondrial dysfunction, and partially restoring the microbiome (119–121). There are several senolytics, such as dasatinib, quercetin, fisetin, navitoclax, and quercetin, under clinical trial for the treatment of age-related disorders (120). The mechanism involved in reduction in cell death and improvement in mitochondrial function and immune homeostasis by regulating senescent cell antiapoptotic pathways (SCAPs) (120). Senescent cells reduce a-Klotho levels, partly through the production of activin-A and IL-1a. Targeting and eliminating senescent cells have been shown to increase a-Klotho levels in both mice and humans (121). Considering this, Zhu et al. developed orally active small-molecule therapies or senolytics which enhanced a-Klotho in animals and humans and promoting healthy aging (121). Furthermore, an ongoing clinical trial by the Mayo Clinic is investigating the safety and efficacy of fisetin in reducing the senescence burden in elderly patients. Preliminary results suggest reduced inflammatory markers and improved physical performance. Thus, preclinical studies show benefits like improved immune homeostasis, progenitor cell function, and microbiome restoration. Early clinical trials with compounds like dasatinib, quercetin, and fisetin suggest potential for treating age-related diseases (120). However, the effects of senolytics are not yet fully understood in humans, and their efficacy may vary across individuals and conditions. Current clinical studies are limited in scale and duration, and long-term safety, dosing, and potential off-target effects remain to be fully elucidated.

GLP-1 Receptor Agonists

GLP-1 RAs are crucial for aging with the benefits such as reduced DNA damage, H₂O₂-induced senescence, and oxidative stress-induced cellular senescence (122). The activation of GLP-1 hormone is directly regulated by gut microbiome, and earlier we have shown that the beneficial effect of probiotics by regulating butyrate induced GLP-1 secretion in diabetic model (123). In neurological disorders, GLP-1 promotes DNA repair (122). Moreover, liraglutide can improve mitochondrial dysfunction via the cAMP/PKA pathway. Exenatide restores mitochondrial energy, morphology, and dynamics. Liraglutide offers cardiomyocyte protection against IL-1β-induced mitochondrial dysfunction. Through Sirt1, GLP-1 receptor activation prevents apoptosis, ROS generation, and inflammation (124). Through the PI3K/Akt/mTOR pathway, GLP-1 prevents cell apoptosis (125). Apoptosis in β cells is prevented by liraglutide via the AMPK/mTOR pathway. Inflammation is reduced by liraglutide via mTORC1 (126). The AMPK/Sirtuin 1 (SIRT1)/forkhead box O3a (FOXO3a) pathway controls cellular senescence via the dipeptidyl peptidase-4 (DPP4)-GLP-1 axis (127).

The AMPK is a key energy sensor that negatively regulates mTOR, a pathway central to cellular metabolism and aging. This activation suppresses mTOR signaling, promoting autophagy and reducing neuroinflammation, which is critical for protecting neuronal integrity. A study by Mannick et al. found that mTOR inhibitors like everolimus enhanced immune response and reduced infection rates in older adults by improving autophagic function in immune cells. This highlights the role of the AMPK/mTOR axis in immune aging (128). Metformin, an AMPK activator, has been shown in human trials to reduce systemic inflammation and lower the risk of neurodegenerative diseases like AD by modulating mTOR signaling and improving mitochondrial function (129). Studies have shown that diets high in fiber, which enhance SCFA production, improve systemic inflammation and neurodegeneration markers by modulating AMPK/mTOR signaling (130). Further, FOXO3 is a transcription factor regulated by AMPK and negatively influenced by mTOR signaling. FOXO3 promotes genes involved in oxidative stress resistance, DNA repair, and autophagy. During aging, decreased FOXO3 activity is associated with higher oxidative damage and reduced cellular stress resistance, leading to age-related diseases (131). A longitudinal cohort study identified FOXO3 genetic variants associated with increased lifespan in humans, highlighting its significance in aging-related resilience (131). Another study linked higher FOXO3 expression in peripheral blood mononuclear cells to better cognitive performance and lower inflammation in elderly participants with mild MCI, suggesting its neuroprotective role (132). Therefore, the microbiome context, SCFAs like butyrate, produced by gut bacteria, can be promising agents to regulate AMPK/FOXO3 to prevent unhealthy aging or age-related disorder. While GLP-1 RAs offer several therapeutic benefits, they also have certain limitations. Common adverse effects include gastrointestinal symptoms such as nausea, vomiting, and diarrhea. Additionally, the necessity for subcutaneous injections with most GLP-1 RAs may pose a barrier for some patients (133).

Overall, these results show that various microbiome modulators including probiotics, prebiotics, synbiotics, postbiotics, diet, and drugs can impact brain health via modulating immune functions; however, comprehensive clinical trials with strong biomarkers of aging and aging-related cognitive decline are necessary to well establish their preventive and therapeutic potential to fight with cognitive decline and dementia—debilitating public health problems in older adults.

Conclusion

The microbiome closely interacts with immune cells and influences neuronal or brain functions, either directly or indirectly. These interactions play a critical role in maintaining brain health during aging, age-related cognitive decline, and AD. Although the precise mechanisms remain unknown, multiple lines of evidence indicate that the microbiome influences gut barriers, which regulate permeability. Abnormalities in these barriers can induce leaky gut, disrupting systemic immune functions. This disruption can also impact BBB permeability, potentially allowing the infusion of systemic immune cells and their cytokines into the brain, thus influencing inflammation and neuronal functions. This cascade of events can lead to cognitive decline and the development of dementia. Interestingly, changes in the microbiome and immune cells are more pronounced in individuals at high risk of cognitive decline and dementia. Furthermore, compared to expensive neuroimaging techniques and genetic markers like APOE-ε4, stool-based microbiome analysis and blood immune profiling offer minimally invasive, accessible, and cost-effective alternatives. These approaches capture real-time changes influenced by environmental, lifestyle, and therapeutic factors, making them particularly valuable for monitoring disease progression and treatment responses. Sensitive to early-stage alterations, such as a decline in SCFA-producing bacteria and increased levels of cytokines like IL-6 and TNF-α, they often detect changes prior to those visible through neuroimaging. Furthermore, they provide unique insights into the gut–immune–brain axis, enabling personalized monitoring and complementing traditional biomarkers for a more comprehensive disease assessment. Microbiome modulators such as prebiotics, probiotics, synbiotics, postbiotics, diet, and drugs may represent potential approaches to prevent the progression of AD by improving immunological function. However, further studies are needed to elucidate the microbiome–immune–neuronal axis as a putative mechanism in AD pathogenesis. Additionally, more clinical evidence is required to validate their effect on the progression of aging and age-related disorders.

Future Perspectives

To investigate microbiome–immune–brain interactions, future studies should adopt longitudinal designs to track microbiome, immune, and cognitive changes over time across diverse age groups, establishing causal relationships. Integrative multimodal analyses, including metagenomics, metabolomics, transcriptomics, and proteomics, can uncover interactions between microbiome composition, immune responses, and brain activity. Germ-free and specific pathogen-free animal models are essential to dissect mechanisms and test microbiome-modulating interventions, while RCTs targeting probiotics, prebiotics, or fecal microbiota transplantation can evaluate their effects on immune and cognitive outcomes. Advanced neuroimaging techniques like MRI and PET scans can link microbiome and immune changes to brain structure and function, complemented by biomarker development to monitor intervention efficacy. Including diverse populations and fostering interdisciplinary collaboration among experts in microbiology, immunology, neurology, and bioinformatics will ensure a comprehensive understanding of the microbiome–immune–brain axis and its therapeutic potential for cognitive health in aging.

Funding

There was no specific grant provided for this review article from public, private, or nonprofit funding organizations. H.Y.’s lab would like to acknowledge and thank for funding support from National Institutes of Health, National of Institute of Aging (R56AG069676, R56AG064075, RF1AG071762, R21AG072379, U01AG076928), the Department of Defense (W81XWH-18-PRARP AZ180098), and the Ed and Ethel Moore Alzheimer’s Disease Research Program of the Florida Department of Health (22A17). Additional resources were provided by the University of South Florida (USF) Center for Microbiome Research, Microbiomes Institute, Center for Excellence in Aging and Brain Repair, Department of Neurosurgery and Brain Repair, USF Morsani College of Medicine.

Conflict of Interest

H.Y. is the cofounder and Chief Scientific Officer of Postbiotics Inc.; he is also a cofounder of BiomAge Inc., MusB LLC, and MusB Research LLC with S.J. However, they have no conflict of interest in studies and results described in this article. S.K.P. declares no conflict.

Author Contributions

S.K.P. and H.Y. conducted the literature search, and wrote and formatted the manuscript. S.J. reviewed the manuscript and provided corrections.