How Immune Cells and Brain Cells Interact During Brain Aging

One of the most consistent features of neuronal aging is the gradual decline in synaptic integrity and plasticity. Structural and functional changes at synapses include reductions in dendritic spine density, alterations in synaptic protein expression, and impaired neurotransmission (Figure 1). These changes can disrupt synaptic connectivity and reduce the efficiency of information transfer across neural circuits (Abrous et al., 2026; Barrantes, 2024; Di Benedetto et al., 2017).

Experimental studies in rodents and human have demonstrated that aging is associated with reduced long-term potentiation (LTP) and altered synaptic plasticity, particularly in the hippocampus, a region critical for learning and memory (Barnes, 1994; Burke and Barnes, 2006; Villarreal et al., 2002). Age-dependent reductions in dendritic spine density and synaptic contacts have also been reported in cortical and hippocampal neurons, suggesting that synaptic remodeling contributes to functional decline in aging neural circuits (Morrison and Baxter, 2012; Bloss et al., 2011; Radulescu et al., 2025).

Human studies provide converging evidence for synaptic vulnerability during aging. Postmortem and neuroimaging studies further support the presence of age-associated synaptic alterations, including reductions in synaptic density markers, changes in dendritic spine morphology, and altered functional connectivity within hippocampal and cortical networks associated with cognitive decline (Morrison and Baxter, 2012). Postmortem analyses have revealed age-associated decreases in synaptic markers, including synaptophysin and PSD-95, in cortical regions involved in cognition (Henstridge et al., 2015; Head et al., 2009). Moreover, imaging and electrophysiological studies suggest that changes in synaptic connectivity and plasticity may contribute to age-related cognitive decline even in the absence of overt neurodegeneration (Morrison and Baxter, 2012; Radulescu et al., 2025).

Mitochondrial dysfunction represents another key feature of neuronal aging. Neurons rely heavily on oxidative phosphorylation to sustain synaptic transmission and ion homeostasis, making mitochondrial integrity essential for neuronal survival and function. With advancing age, mitochondria exhibit reduced respiratory capacity, increased production of reactive oxygen species (ROS), and impaired mitochondrial dynamics (Pass et al., 2021; Bondy, 2024; Srivastava, 2017).

Experimental evidence indicates that aging neurons accumulate mitochondrial DNA mutations and display deficits in mitochondrial biogenesis and quality control pathways. These alterations can compromise ATP production and increase oxidative stress, thereby affecting synaptic transmission and neuronal resilience. In mouse models, impaired mitochondrial transport along axons has also been shown to disrupt synaptic energy supply and contribute to synaptic dysfunction (Pass et al., 2021; Bondy, 2024; Zong et al., 2024).

Evidence from human studies similarly implicates mitochondrial decline in neuronal aging. Analyses of human cortical tissue have revealed age-related changes in mitochondrial gene expression and reductions in respiratory chain activity (Theurey and Pizzo, 2018; Ojaimi et al., 1999). In addition, neuroimaging studies indicate that metabolic activity declines in specific brain regions with age, including the prefrontal cortex and hippocampus, consistent with impaired neuronal energy metabolism (Zhang X. et al., 2025; Deery et al., 2023).

Age-related changes in neuronal physiology also include alterations in intrinsic excitability and calcium homeostasis. Electrophysiological recordings from aged hippocampal neurons have demonstrated increased calcium influx and prolonged afterhyperpolarization currents, which can modify firing patterns and impair synaptic plasticity (Kumar et al., 2009). These changes may arise from altered ion channel expression, disrupted calcium buffering, or mitochondrial dysfunction.

Such shifts in excitability can have important consequences for network dynamics, affecting synaptic integration, signal fidelity, and the balance between compensatory activity and circuit instability during aging. In some circuits, aging is associated with reduced signal-to-noise ratios and impaired synaptic integration, whereas in others, compensatory increases in neuronal activity may occur (Cabeza et al., 2002; Heuninckx et al., 2008; Müller et al., 2019). Functional MRI studies in aging humans have frequently reported increased bilateral recruitment of frontal and parietal cortical regions during memory and executive tasks, a phenomenon interpreted as compensatory network reorganization aimed at preserving cognitive performance despite declining neural efficiency. Mechanistically, such adaptations may involve altered excitatory–inhibitory balance, redistribution of network activity, and increased functional connectivity among higher-order association regions (Cabeza et al., 2002).

The combined effects of synaptic dysfunction, metabolic decline, and altered excitability ultimately influence the organization and performance of neural circuits. Aging-related disruptions in neuronal signaling can impair communication across distributed brain networks that support cognitive functions such as memory, attention, and executive control (Navakkode and Kennedy, 2024).

At the systems level, these alterations may contribute to reduced network flexibility and decreased efficiency of information processing. However, the aging brain also exhibits considerable plasticity, and compensatory mechanisms—including synaptic remodeling and recruitment of alternative circuits—may help sustain cognitive function in many individuals (Müller et al., 2025a,c; Abrous et al., 2026; Cabeza et al., 2002; Navakkode and Kennedy, 2024).

Together, these findings highlight that neuronal aging reflects a complex interplay between synaptic, metabolic, and electrophysiological changes rather than simple neuronal loss. In the context of the broader cellular networks of the brain, these neuronal alterations interact closely with age-related changes in glial and vascular populations, which modulate neuronal function and contribute to the evolving cellular landscape of the aging brain (Figure 1).

Microglia are the resident innate immune cells of the CNS and serve as the primary mediators of neuroimmune responses. Under physiological conditions, microglia continuously survey the brain parenchyma, clearing cellular debris, remodeling synapses, and supporting neuronal survival (Figure 1, right). Aging, however, profoundly alters microglial phenotype and function, leading to a state commonly referred to as microglial priming (Norden and Godbout, 2013).

Primed microglia display increased basal expression of pro-inflammatory cytokines and heightened responsiveness to secondary stimuli. Even in the absence of overt pathology, aged microglia show elevated levels of inflammatory mediators such as tumor necrosis factor (TNF), interleukin-1β (IL-1β), and interleukin-6 (IL-6), reflecting a chronic low-grade inflammatory state. This persistent inflammatory signaling contributes to the phenomenon of inflammaging, which is characterized by systemic and brain-specific increases in inflammatory mediators during aging (Soraci et al., 2024; Norden and Godbout, 2013; Woodburn et al., 2021; Masuda et al., 2019).

Mechanistically, several processes contribute to microglial priming. Aging microglia exhibit altered transcriptional programs involving immune signaling pathways such as NF-κB, reduced phagocytic efficiency, and accumulation of cellular waste due to impaired lysosomal degradation. These changes can lead to a progressive decline in the ability of microglia to maintain tissue homeostasis. In addition, aged microglia accumulate myelin debris resulting from ongoing myelin turnover, which can overload lysosomal pathways and promote cellular senescence (Müller and Di Benedetto, 2025a; Masuda et al., 2019; Kwon and Koh, 2020).

Recent single-cell transcriptomic studies have further revealed the emergence of distinct microglial states associated with aging. These include populations characterized by inflammatory signaling, altered lipid metabolism, and stress-response pathways. Some of these transcriptional profiles resemble microglial states observed in neurodegenerative diseases, suggesting that aging may predispose microglia toward disease-associated phenotypes (Wei and Li, 2022; Lauro and Limatola, 2020; Wendimu and Hooks, 2022; Valiukas et al., 2025; Colombo et al., 2022).

Importantly, microglial priming has significant consequences for neuronal circuits. Activated microglia release cytokines, chemokines, and ROS that can alter synaptic transmission, disrupt neuronal plasticity, and modulate astrocyte activation (Lana et al., 2016; Kabba et al., 2018). Microglia also interact with oligodendrocyte progenitor cells (OPCs), influencing myelin repair and regeneration. In aging, dysregulated microglial signaling may impair OPC differentiation and contribute to myelin degeneration, illustrating how microglial dysfunction can propagate pathology across multiple glial and neuronal compartments (Müller and Di Benedetto, 2025a; Benarroch, 2023; Fang and Bai, 2023).

Astrocytes represent the most abundant glial population in the CNS and perform a wide range of functions essential for neuronal survival and synaptic activity (Figure 1, left). These include regulation of neurotransmitter clearance, maintenance of extracellular ion balance, modulation of synaptic plasticity, and metabolic support of neurons through the astrocyte–neuron metabolic coupling system (Müller et al., 2025c; Singh, 2022; Lee et al., 2022).

During aging, astrocytes undergo significant phenotypic changes that give rise to a spectrum of reactive states. Reactive astrocytes display altered gene expression patterns, hypertrophic morphology, and changes in the secretion of cytokines and growth factors. Importantly, astrocyte can adopt diverse functional states ranging from protective to neurotoxic phenotypes depending on the surrounding microenvironment (Liddelow et al., 2017; Clarke et al., 2018; Patani et al., 2023).

A key mechanism driving astrocyte reactivity involves signaling from activated microglia. Pro-inflammatory molecules such as TNF-α, IL-1α, and complement component C1q released by microglia can induce astrocytes to adopt a neuroinflammatory phenotype often referred to as A1-like reactive astrocytes. These astrocytes downregulate genes involved in synaptic support and begin to release inflammatory mediators and complement proteins that may contribute to neuronal damage and synapse loss (Lawrence et al., 2025).

Beyond their immune-related functions, astrocytes play a central role in metabolic support of neurons, particularly through the astrocyte–neuron lactate shuttle. Astrocytes metabolize glucose and provide lactate as an energy substrate for neurons during periods of high activity. Aging may disrupt this metabolic coupling by altering astrocytic glycolysis, mitochondrial metabolism, and substrate transport. Such metabolic changes can exacerbate neuronal energy deficits and contribute to age-related declines in synaptic function (Müller et al., 2025a; Müller and Di Benedetto, 2025a; Beard et al., 2021).

Astrocytes also interact closely with the cerebral vasculature through perivascular endfeet that regulate BBB integrity and neurovascular coupling. Consequently, astrocytic dysfunction during aging can affect vascular signaling, highlighting interactions between glial reactivity and neurovascular changes that are addressed in later sections (Knox et al., 2022; Sanmarco et al., 2021).

Oligodendrocytes and their progenitor cells, OPCs, are responsible for the formation and maintenance of myelin sheaths that insulate axons and facilitate rapid action potential conduction. Myelin is increasingly recognized as a dynamic structure that undergoes continuous remodeling throughout life. However, aging is associated with progressive disruptions in myelin maintenance and regeneration (Williamson and Lyons, 2018; Osso and Hughes, 2024). Structural studies have shown that aging leads to myelin fragmentation, thinning of myelin sheaths, and accumulation of myelin debris, particularly in white matter tracts and association fibers. These changes can impair axonal conduction velocity and disrupt synchronization within neural circuits, potentially contributing to cognitive slowing observed in aging populations (Huang et al., 2025; Groh and Simons, 2025).

At the cellular level, oligodendrocyte lineage cells exhibit age-related alterations in differentiation and regenerative capacity (Figure 1). OPCs persist in the adult brain and normally respond to demyelination by generating new oligodendrocytes. During aging, however, OPC proliferation and differentiation become less efficient, reducing the capacity for myelin repair. This decline may result from intrinsic changes in OPC transcriptional programs as well as extrinsic factors within the aging brain microenvironment (Mironova et al., 2026).

Interactions with other glial cells play an important role in regulating oligodendrocyte aging. Microglia participate in the clearance of myelin debris and release signals that influence OPC differentiation. However, in the aged brain, microglial dysfunction can impair this process and inhibit efficient remyelination. Similarly, astrocytes contribute to oligodendrocyte metabolism by supplying lipids and metabolic substrates required for myelin synthesis. Dysregulation of astrocytic metabolic pathways may therefore indirectly affect myelin maintenance during aging (Lopez-Muguruza and Matute, 2023; Fang and Bai, 2023; Matejuk et al., 2021).

Together, these findings illustrate that glial aging represents an interconnected network process involving immune activation, metabolic remodeling, and structural alterations in myelin integrity. Microglial priming, astrocyte reactivity, and oligodendrocyte dysfunction do not occur independently but rather interact dynamically with neuronal and vascular components of the brain. These complex glial responses play a critical role in shaping the inflammatory and metabolic landscape of the aging brain and contribute to the cellular environment in which neuronal aging and neurodegenerative processes unfold.

One of the most prominent vascular changes associated with aging is the gradual decline in BBB integrity. The BBB is formed primarily by specialized endothelial cells connected by tight junctions and supported by perivascular cells and astrocytic endfeet (Figure 2). This structure tightly regulates the exchange of molecules between the circulation and the CNS, ensuring stable ionic conditions and protecting neural tissue from toxins and pathogens (Knox et al., 2022).

During aging, several structural and molecular changes compromise BBB function. These include reduced expression of tight junction proteins, increased endothelial permeability, and impaired transport mechanisms that regulate nutrient influx and waste clearance (Figure 2). Experimental studies in rodents have shown that aging is associated with increased leakage of plasma proteins into the brain parenchyma, indicating reduced barrier selectivity and compromised BBB integrity. Human neuroimaging and cerebrospinal fluid studies further suggest that BBB permeability increases with age, particularly within hippocampal regions associated with cognitive decline (Montagne et al., 2015). Age-related vascular dysfunction in humans has also been linked to impaired neurovascular coupling and reduced cerebral perfusion (Knox et al., 2022; Takata et al., 2021).

Recent work suggests that endothelial cell senescence may be a key driver of BBB deterioration. With age, these cells undergo molecular and functional changes characterized by oxidative stress, chronic low-grade inflammation, and reduced nitric oxide bioavailability. These alterations impair vasodilation and disrupt communication between vascular and neural cells (Graves and Baker, 2020; Csik et al., 2025). Senescent endothelial cells display altered metabolic and inflammatory profiles, reduced tight junction integrity, and diminished interactions with pericytes and astrocytes, collectively weakening the barrier function of cerebral microvessels (Graves and Baker, 2020).

Thus, endothelial dysfunction during aging may emerge not only as a vascular phenomenon but also as a network-level process involving bidirectional signaling between vascular and neural cell types (Neyra Chauca et al., 2026). Importantly, BBB disruption has consequences that extend beyond vascular pathology. Increased permeability can expose neural tissue to circulating inflammatory mediators, immune cells, and plasma proteins that promote glial activation and neuronal dysfunction, thereby linking vascular aging to neuroinflammatory processes.

Neurovascular coupling (NVC) refers to the dynamic process by which local neuronal activity triggers rapid increases in cerebral blood flow to meet metabolic demand. This process involves coordinated signaling between neurons, astrocytes, endothelial cells, and vascular smooth muscle cells. Aging can disrupt this finely tuned communication, leading to impaired matching between neuronal activity and vascular supply (Csipo et al., 2019).

Experimental studies in aged animal models demonstrate reduced NVC responses following sensory or neuronal stimulation, indicating diminished vascular responsiveness to neural signals. Mechanistically, these impairments may arise from astrocytic dysfunction, endothelial oxidative stress, or alterations in vasoactive signaling pathways such as nitric oxide and prostaglandin signaling (Csipo et al., 2019; Negri et al., 2026).

Human functional imaging studies also suggest that NVC becomes less efficient with age. Altered hemodynamic responses measured by functional MRI indicate that the vascular response to neuronal activation is delayed or attenuated in older adults, reflecting reduced vascular adaptability. Such changes can complicate the interpretation of neuroimaging signals and may contribute to decreased cognitive flexibility and processing efficiency in aging populations (Fesharaki et al., 2026; Zhao et al., 2021; Hu et al., 2025).

Taken together, these findings highlight that vascular aging is not limited to structural changes within blood vessels but represents a broader systems-level transformation of the neurovascular unit. Endothelial dysfunction, BBB disruption, and reduced perfusion interact closely with glial reactivity and neuronal metabolic stress, creating feedback loops that can amplify cellular vulnerability across the brain (Takata et al., 2021). Understanding these interactions is therefore essential for interpreting brain aging as a multi-cellular network phenomenon, in which vascular components play a critical role in shaping neuronal resilience and susceptibility to neurodegenerative disease (Müller et al., 2025a; Müller and Di Benedetto, 2025a). In the following sections, we further examine how molecular stress pathways and inflammatory signaling intersect with these cellular interactions to influence the trajectory of brain aging.

Mitochondria are central regulators of cellular energy metabolism, calcium homeostasis, and apoptotic signaling (Pandey, 2025). In the aging brain, mitochondrial function declines across multiple cell types, leading to reduced ATP production, increased generation of ROS, and impaired metabolic flexibility (Bondy, 2024; Srivastava, 2017; Jimenez-Loygorri et al., 2024).

Age-related changes in mitochondrial dynamics—including dysregulation of fusion, fission, and mitophagy—further contribute to the accumulation of damaged mitochondria within cells. Impaired mitochondrial quality control can exacerbate oxidative stress and disrupt cellular metabolism, creating a feedback loop that accelerates cellular aging. In glial cells, mitochondrial dysfunction may also influence inflammatory signaling pathways, thereby linking metabolic decline to neuroinflammation. Collectively, these processes highlight mitochondria as key regulators of cellular resilience and vulnerability during brain aging (Bondy, 2024; Chen and Chan, 2009).

Maintenance of protein homeostasis, or proteostasis, is essential for cellular function and survival. Proteostasis networks encompass protein synthesis, folding, trafficking, and degradation pathways, including the ubiquitin-proteasome system and autophagy-lysosomal pathways. During aging, these systems gradually lose efficiency, leading to the accumulation of misfolded or damaged proteins (Pandey, 2025; Shukla and Narayan, 2025).

In neurons, impaired proteostasis can disrupt synaptic function by altering the turnover of synaptic proteins and signaling molecules. Similarly, glial cells rely on efficient protein quality control mechanisms to maintain their diverse physiological roles, including immune surveillance and metabolic support. Dysfunction of autophagic and lysosomal pathways has been observed in aged microglia and astrocytes, potentially contributing to the accumulation of cellular debris and exacerbation of inflammatory signaling (Tseng et al., 2023; Hakim et al., 2016; Quick et al., 2023).

The decline of proteostasis is particularly relevant to neurodegenerative diseases, where pathological protein aggregates represent a defining feature. However, even in normal aging, subtle impairments in proteostasis can alter cellular signaling and stress responses, suggesting that protein quality control pathways represent a critical determinant of brain aging trajectories (Tseng et al., 2023).

Cellular senescence is characterized by a stable state of cell cycle arrest accompanied by profound changes in gene expression, metabolic activity, and secretory behavior. While this state plays important physiological roles in processes such as tissue repair and tumor suppression, the accumulation of senescent cells with age can contribute to tissue dysfunction (Pandey, 2025; Melo Dos Santos et al., 2024).

In the brain, senescence has been described in multiple cell types, including astrocytes, microglia, oligodendrocyte progenitor cells, and endothelial cells. Senescent cells typically adopt a senescence-associated secretory phenotype (SASP) characterized by the release of inflammatory cytokines, chemokines, proteases, and growth factors. This secretory profile can influence neighboring cells and alter the surrounding microenvironment, thereby amplifying inflammatory signaling and promoting cellular dysfunction across the NVU (Melo Dos Santos et al., 2024; Shafqat et al., 2023).

Recent evidence suggests that senescent glial cells may contribute to chronic neuroinflammation and impair regenerative processes such as remyelination and synaptic remodeling. Similarly, endothelial senescence has been implicated in BBB disruption and vascular dysfunction, linking cellular senescence to broader neurovascular alterations observed in aging (Shafqat et al., 2023; Hruby and Higuchi-Sanabria, 2025).

The accumulation of genomic damage represents another central driver of cellular aging. DNA lesions arise from multiple sources, including oxidative stress, replication errors, and environmental insults. Although cells possess sophisticated DNA repair mechanisms, the efficiency of these systems declines with age, leading to the gradual accumulation of genomic instability (Pandey, 2025; Delint-Ramirez and Madabhushi, 2025; Caldecott et al., 2022).

Neurons are particularly vulnerable to DNA damage due to their high metabolic activity and long lifespan. Persistent DNA lesions can disrupt transcriptional programs and impair neuronal function (Delint-Ramirez and Madabhushi, 2025). In glial and vascular cells, DNA damage can activate stress signaling pathways and inflammatory responses, further contributing to cellular dysfunction (Dash et al., 2025).

Activation of DNA damage response pathways can also promote cellular senescence and apoptosis, linking genomic instability to other hallmarks of aging. These processes may therefore act as upstream triggers that initiate broader molecular cascades affecting cellular homeostasis across the aging brain.

Epigenetic mechanisms—including DNA methylation, histone modifications, and chromatin remodeling—play crucial roles in regulating gene expression and maintaining cellular identity. During aging, epigenetic landscapes undergo progressive alterations that can lead to transcriptional drift, characterized by increased variability and dysregulation of gene expression patterns (Pandey, 2025; la Torre et al., 2023).

Age-associated changes in DNA methylation patterns have been widely documented and form the basis of epigenetic clocks that estimate biological age across tissues. In the brain, epigenetic remodeling affects genes involved in synaptic function, immune signaling, and metabolic regulation. Such changes may influence the responsiveness of neurons and glial cells to environmental stimuli and stress signals (Lossi et al., 2024).

Importantly, epigenetic alterations can also interact with other molecular aging processes. For example, mitochondrial dysfunction and metabolic changes can influence chromatin-modifying enzymes through alterations in cellular metabolite levels, while DNA damage responses can trigger chromatin remodeling events. These interactions highlight the integrated nature of molecular aging pathways (Lossi et al., 2024; van der Rijt et al., 2020).

Together, mitochondrial dysfunction, proteostasis decline, cellular senescence, genomic instability, and epigenetic remodeling form a network of interconnected processes that collectively drive cellular aging in the brain (Lopez-Otin et al., 2023). While each mechanism can affect specific cellular functions, their interactions may create systemic changes that influence neuronal signaling, glial activation, and vascular integrity. Importantly, these molecular programs can operate across multiple cell types, suggesting that brain aging arises from the integration of shared cellular stress pathways within complex cellular networks (Lopez-Otin et al., 2023; Glavan et al., 2026).

Communication between brain cell types relies on complicated signaling networks involving neurotransmitters, cytokines, growth factors, metabolic intermediates, and extracellular vesicles. These signals enable neurons, glia, and vascular cells to coordinate metabolic supply, immune responses, and synaptic plasticity. During aging, however, the architecture of these signaling networks can undergo significant remodeling (Seguin et al., 2023; Di Benedetto et al., 2019; Chalmers et al., 2022).

Single-cell and spatial transcriptomic studies have revealed age-related changes in ligand–receptor signaling pathways across multiple cell types, indicating shifts in intercellular communication within the brain microenvironment (Li et al., 2023; Tsai et al., 2025). For example, alterations in cytokine signaling, complement pathways, and metabolic communication networks have been identified across neuronal and glial populations in aging tissues. These changes can influence synaptic regulation, immune activation, and tissue repair processes, highlighting how molecular signaling networks integrate cellular responses across the aging brain (Zheng et al., 2025).

Importantly, these signaling pathways often involve bidirectional and multidirectional interactions. Neurons influence microglial activation through neurotransmitter signaling and neuronal activity patterns, while glial cells regulate neuronal excitability and synaptic remodeling through cytokine and metabolic signaling. Astrocytes additionally coordinate metabolic exchange between neurons and blood vessels, linking neuronal activity to vascular responses. Such interconnected communication networks enable the brain to dynamically regulate its functional state but may also propagate dysfunction when regulatory mechanisms become impaired with age (Müller et al., 2025c; Zheng et al., 2025).

A central feature of systems-level brain aging is the close integration of immune, neural, and vascular signaling systems. The NVU provides a structural and functional framework for these interactions, integrating neurons, astrocytes, microglia, endothelial cells, pericytes, and vascular smooth muscle cells into a coordinated regulatory system. This unit controls cerebral blood flow, maintains BBB integrity, and modulates immune surveillance within the central nervous system (Iadecola, 2017; Neyra Chauca et al., 2026).

During aging, dysfunction in one component of this system can influence the entire network. For instance, endothelial dysfunction and impaired BBB integrity can permit the infiltration of peripheral immune factors into the brain, altering microglial activation and astrocytic signaling (Figure 2). Conversely, inflammatory mediators produced by activated microglia and astrocytes can influence vascular function, altering endothelial signaling pathways and vascular tone (Knox et al., 2022; Takata et al., 2021).

Recent work on neurovascular aging highlights how vascular cells themselves undergo transcriptional and functional remodeling that affects neuronal metabolism, immune trafficking, and the clearance of metabolic waste products from the brain. These vascular changes can compromise oxygen and glucose delivery, impair transport mechanisms across the BBB, and disrupt the clearance of potentially toxic proteins (Iadecola, 2017; Graves and Baker, 2020; Csik et al., 2025).

Through these mechanisms, age-related alterations in immune, neural, and vascular signaling pathways may converge to influence brain function at multiple levels, from cellular metabolism to large-scale neural network activity.

A key feature of systems-level brain aging is the emergence of self-reinforcing feedback loops that amplify inflammatory signaling across cellular networks. Chronic low-grade inflammation arises from the interaction of multiple molecular and cellular processes, including mitochondrial dysfunction, cellular senescence, DNA damage responses, and impaired immune regulation (Müller et al., 2025b; Voicu et al., 2025).

These processes create interconnected feedback loops. For example, mitochondrial dysfunction increases ROS production, which can activate inflammatory signaling pathways such as NF-κB. In turn, inflammatory mediators can further impair mitochondrial function and promote cellular senescence, reinforcing the inflammatory state. Similarly, senescent cells produce a pro-inflammatory secretome that affects neighboring cells and can modify the surrounding microenvironment (Müller et al., 2025a,c; Müller and Di Benedetto, 2026; Voicu et al., 2025).

Such interactions can propagate inflammation across cellular networks, influencing neurons, glia, and vascular cells simultaneously. As a result, inflammaging emerges not from a single molecular pathway but from network-level interactions between multiple cellular stress responses. Recent systems-level analyses of aging biology emphasize how mitochondrial dysfunction, DNA damage, and impaired mitophagy converge as central hubs connecting cellular aging mechanisms with inflammatory signaling pathways (Voicu et al., 2025).

The complexity of these interconnected processes has motivated the development of integrative approaches that combine diverse biological datasets to construct comprehensive models of brain aging. Advances in high-throughput technologies now allow simultaneous profiling of genomic, epigenomic, transcriptomic, proteomic, metabolomic, and lipidomic data from the same biological samples. Integrating these datasets through systems biology frameworks can reveal relationships between molecular pathways that may not be detectable using single-omics approaches (Cohen et al., 2022; Adewale et al., 2021; Vitorino, 2024).

Large-scale human multiomic and neuroimaging datasets increasingly support the concept that brain aging reflects coordinated alterations across interacting neuronal, glial, immune, and vascular systems rather than isolated cellular dysfunction. Integrative analyses combining transcriptomic, imaging, and biomarker data have begun to identify systems-level signatures associated with cognitive resilience and vulnerability during aging (Dong and Zhong, 2025; Ren et al., 2025; De Jager et al., 2018).

Systems biology tools—including network modeling, machine learning, and genome-scale metabolic reconstructions—are increasingly used to interpret these datasets. By constructing molecular interaction networks and identifying key regulatory nodes, these approaches allow researchers to map the hierarchical organization of biological processes that drive brain aging (Ren et al., 2025). Such models can also predict how perturbations in specific pathways may propagate through cellular networks to influence overall brain function.

Taken together, these findings suggest that brain aging should be conceptualized not as a collection of independent cellular processes but as an emergent property of multi-layered biological networks. Intercellular signaling pathways, immune–vascular interactions, metabolic regulation, and gene expression programs form interconnected systems that operate across multiple spatial and temporal scales (Müller et al., 2025a; Müller and Di Benedetto, 2026).

Within this framework, resilience or vulnerability to aging-related decline may depend on the stability and adaptability of these networks (Müller et al., 2025a). Disruptions in key regulatory nodes—such as mitochondrial metabolism, immune signaling pathways, or vascular function—can propagate through cellular interactions and alter the functional organization of neural circuits.

By integrating molecular, cellular, and systems-level perspectives, network-based approaches provide a powerful framework for understanding the complexity of brain aging. Such approaches may ultimately enable the identification of critical network hubs and early biomarkers that can guide strategies to preserve brain function and promote healthy aging.

Longitudinal studies provide a critical framework for understanding how brain structure and function change over time. Repeated measurements within individuals allow researchers to distinguish true aging trajectories from stable interindividual differences (Jockwitz et al., 2021; Vinci-Booher et al., 2025). Advances in multimodal neuroimaging and computational modeling now enable the simultaneous assessment of structural, functional, and metabolic changes across aging populations, revealing that different brain features may follow partially independent temporal trajectories that influence cognitive outcomes (Vinci-Booher et al., 2025; Chen et al., 2026).

Large population cohorts such as the UK Biobank further support the development of normative models of brain aging. Machine-learning approaches applied to neuroimaging data have generated “brain age” metrics that estimate biological brain age from structural and functional features. Deviations between predicted and chronological age may indicate accelerated aging and increased disease risk (Zhang R. et al., 2025; Li et al., 2026).

Human induced pluripotent stem cells (iPSCs) and brain organoids provide powerful experimental platforms for studying cellular mechanisms of brain aging. iPSC-derived neurons, astrocytes, and microglia allow investigation of cell-type–specific processes such as mitochondrial dysfunction, proteostasis impairment, and inflammatory signaling (Mrza et al., 2024).

Organoid systems extend these approaches by reconstructing three-dimensional neural tissue environments that support neuronal–glial interactions and early circuit formation (Guo et al., 2025). Recent developments incorporate microglia and vascular-like components to model aspects of the neurovascular unit and intercellular communication networks. Although current organoid systems primarily resemble early developmental stages, strategies including prolonged culture and metabolic stress are being explored to induce aging-like phenotypes in vitro (Guo et al., 2025; O'Halloran et al., 2025).

Identifying early biomarkers capable of predicting vulnerability to cognitive decline remains a major goal in aging research. Neuroimaging-derived measures—including brain age estimates, cortical thickness, and connectivity patterns—have emerged as promising indicators of biological brain aging (Yusri et al., 2024; Kocar et al., 2026). Complementary efforts are identifying circulating metabolic and inflammatory markers associated with brain aging phenotypes. Integrating imaging, molecular, and clinical data through multiomic frameworks may ultimately enable predictive signatures of brain aging and early identification of individuals at risk for neurodegenerative disease (Zwilling et al., 2024). Several longitudinal human cohort studies further suggest that combined imaging and circulating biomarker signatures may predict accelerated brain aging before overt clinical symptoms emerge (Cole and Franke, 2017; Franke and Gaser, 2019).

Understanding cellular aging trajectories also creates opportunities for intervention. Lifestyle factors such as physical activity, diet, sleep regulation, and cardiovascular health are consistently associated with improved cognitive outcomes and reduced signatures of brain aging (Di Benedetto et al., 2017; Behrenbruch et al., 2026; Di Benedetto and Müller, 2019; Müller and Di Benedetto, 2025b).

At the molecular level, therapeutic strategies targeting mitochondrial dysfunction, chronic inflammation, and impaired proteostasis are under investigation in preclinical models (Delrue et al., 2025). In parallel, regenerative approaches—including stem cell therapies, gene editing technologies, and strategies aimed at rejuvenating neural stem cell populations—represent emerging avenues for restoring cellular function in the aging brain (Saliev and Singh, 2024; Joshi et al., 2025).

Taken together, future advances in brain aging research will likely arise from integrating longitudinal human studies, experimental cellular systems, and systems-level computational analyses. By combining multiomic data with predictive modeling frameworks, researchers may begin to trace cellular aging trajectories across biological scales—from molecular networks to neural circuits and whole-brain systems—ultimately enabling earlier detection and more effective prevention of age-related neurological disease.