Systemic modulation of brain aging and plasticity: from gut microbiome to circulating factors

Systemic factors, including gut-derived metabolites, immune mediators, and blood‑borne factors, play essential roles in regulating key aspects of neural plasticity by modulating synaptic remodeling, neurogenesis, vascular dynamics, and glial function. Across lifespan, these peripheral systems (and their inputs) undergo substantial shift. Age-associated changes in the gut microbiome, immune network, and circulating environment significantly alter the brain’s adaptive capacity, contributing to decline in cognitive performance and circuit flexibility.

Rodent studies provide compelling evidence that multiple strategies such as heterochronic parabiosis, young-plasma administration, exercise and caloric restriction can restore specific features of youthful plasticity, supporting the concept of systemically driven brain rejuvenation. support the concept of systemic-driven brain plasticity restoration. Recent work also shows that systemic interventions such as gut microbiome depletion or enrichment, and administration of specific circulating proteins (e.g., GDF11, Klotho, PF4), can partially reverse aging-associated deficits. These effects appear to operate through glial modulation, neurogenesis, synaptic remodeling, and improved neurovascular function.

Growing attention highlights the role of extracellular vesicles as potent carriers of systemic signals able to influence brain function, alongside exercise-induced circulating factors and immune-modulatory cytokines, able to reactivate latent regenerative programs in the aging brain.

This Research Topic aims to advance mechanistic understanding of how systemic cues shape neural circuit dynamics in aging, identifying pathways that drive vulnerability or resilience, and determine how systemic manipulation can reopen windows of plasticity or enhance cognitive function later in life.

Contributions will explore how systemic interventions affect the aging brain’s capacity for repair. Functional outputs such as hippocampal neurogenesis, synaptic plasticity, and behavioral performance in learning and memory tasks will serve as key readouts. The integration of multi-omics approaches will be critical to map the molecular pathways through which systemic states alter neural circuit function and integrity. We welcome contributions that span from molecular mechanisms to system-level interpretations.

Topics of interest:

• Gut microbiome remodeling in aging and rejuvenation: Age-related microbial shifts and interventions (e.g., depletion, enrichment, fecal transfer) that modulate cognition and neuroplasticity.

• Immune cytokines and neural plasticity in aging: Role of systemic immune signals (e.g., IL-6, TNF-α) in modulating hippocampal neurogenesis and synaptic remodeling in aged brains.

• Circulating rejuvenating factors and their impact on brain function: effects of GDF11, Klotho, PF4 and other systemic proteins on excitability, neurogenesis, myelination, and cognitive performance in aged rodents.

• Mechanisms of brain accessibility and cellular targeting: understanding how systemic factors act on the brain, whether they cross the BBB, act through endothelial or perivascular pathways, signal via receptors on specific brain cell types (e.g., astrocytes, microglia, oligodendrocytes, neurons), or exert indirect effects via vascular, immune, or metabolic interfaces.

• Neurovascular integrity and inflammation-driven circuit breakdown: interactions between systemic inflammation, endothelial aging, BBB alterations, and circuit integrity. Extracellular vesicle-mediated communication across BBB: how exosomes and microvesicles transmit peripheral molecular signals across the BBB, impacting brain structure and function.

• Exercise-induced peripheral factors and brain plasticity: Identification and impact of systemic factors (e.g., irisin, BDNF precursors) released during exercise on neurogenesis and connectivity.

• Systemic drivers of glial cell aging and reactivity: how systemic factors drive aging-related changes in astrocytes and microglia, influencing brain repair and plasticity.

• Multi-omics dissection of brain–body crosstalk in aging: integrative metabolomics, transcriptomics, proteomics and epigenomic approaches to decode systemic regulators of neural aging.

Article types and fees

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• ... View all formats

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Article types

This Research Topic accepts the following article types, unless otherwise specified in the Research Topic description:

• Brief Research Report
• Data Report
• Editorial
• FAIR² Data
• FAIR² DATA Direct Submission
• General Commentary
• Hypothesis and Theory
• Methods
• Mini Review
• Opinion
• Original Research
• Perspective
• Review
• Study Protocol
• Systematic Review
• Technology and Code

Keywords: microbiome, gut, neural circuit, plasticity, aging, neuroinflammation, modulation, peripheral systems, neurogenesis

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.