Decline and fall of aging astrocytes: the human perspective

"Last scene of all that ends this strange, eventful history, is second childishness and mere oblivion. I am sans teeth, sans eyes, sans taste, sans everything." William Shakespeare 'As You Like It' Act 2, Sc. 7, l. 139 Aging of the human brain is characterized by a progressive decline of its functional capacity; this decline however varies widely, and cognitive longevity differs substantially between individuals. Aging is associated with an increased prevalence of neurodegenerative diseases ultimately causing dementia; again the cognitive outcome of age-dependent neurodegenerative diseases is widely different and is not directly correlated with the pathological damage to the nervous tissue. This disparity between age-dependent deterioration of the brain and cognitive presentation is defined by the individual properties of every given individual generally referred to as cognitive reserve (Stern and Barulli, 2019). The cognitive reserve is the function of the life-long interaction of the organism and its brain with the exposome, the latter being a cumulative effect of all environmental challenges and intrinsic responses (adaptations and learning) that occur during the life span. The brain, because of its remarkable plasticity, is significantly modified during life; learning affects active milieu of the brain (Semyanov and Verkhratsky, 2021) thus defining its resilience (or vulnerability) to aging and age-associated brain disorders. Neuroglia, which represent the homeostatic arm of the nervous tissue and active milieu of the brain (Verkhratsky and Nedergaard, 2016; Semyanov and Verkhratsky, 2021) is fundamental for the cognitive reserve. This latter comprises several components, which include (i) the brain reserve, (ii) the brain maintenance, (iii) the brain resilience, and (iv) the brain compensation. Neuroglia contribute, and to a large degree define, each and every of these components (Verkhratsky and Butt, 2023). Indeed, the brain reserve, which reflects the neuroanatomical state of neuronal networks achieved through life experience and learning, is centered about synaptic plasticity and synaptogenesis, both being influenced by neuroglia with astrocytes secreting synaptogenic and synapse maturation factors, whereas microglia pruning synapses thus tailoring neuronal ensembles. Neurons also trigger the morphological and physiological plasticity of neuroglia secreting neurotransmitters and neuromodulators. The brain maintenance essentially reflects the capacity of the central nervous system – a wide homeostatic system to sustain brain function, to remove waste, to supply energy substrates, and to maintain catabolism of neuroactive molecules – these all being essentially the fundamental functions of astroglia. The brain resilience that signifies the ability of the nervous tissue to withstand environmental challenges and pathological damages without developing overt pathology reflects the state of intrinsic brain defense, which in turn is largely defined by neuroglial cells, as neuronal defensive capabilities are severely limited. Finally, the brain compensation, which is the ability of the nervous tissue to recover after pathological lesions is almost completely controlled by neuroglia through perilesional barriers created by reactive gliocytes, which isolate damaged tissue and orchestrate postlesional regeneration as well as though neuronogensis supported by stem astrocytes residing in neurogenic niches. Thus, aging of neuroglia which limits its homeostatic and defensive capabilities is of paramount importance for cognitive reserve and cognitive longevity. Astroglia, which include various types of parenchymal astrocytes (protoplasmic, fibrous, velate, etc.), radial astrocytes (Bergmann glia, Muller glia, interlaminar astrocytes, etc.), and cells lining ventricular walls (ependymoglia, tanycytes, etc.) are the main homeostatic cells of the central nervous system (Verkhratsky and Butt, 2023). These cells regulate the ionic composition of the interstitium (ionostasis), metabolism of neurotransmitters, they supply neurons with essential neurotransmitter precursors, provide scavengers of reactive oxygen species, and act as neural stem cells (stem radial astrocytes) and orchestrate defense of the nervous tissue through evolutionary conserved reactive astrogliosis. Pathophysiology of astroglia is complex and mutable: it includes astrogliosis, astrocytopathies, characterized by the emergence of aberrant astrocytes driving the pathogenesis of certain diseases, astroglial atrophy and loss of function (which limits astrocytic homeostatic support and defense, being often the main cause of neuronal damage and death), and astroglial death through clasmatodendrosis (Verkhratsky et al., 2023). Different pathological forms of astroglial cells may coexist or emerge according to various disease stages; these pathological forms are highly heterogeneous and are disease-, age-, and context-specific. Mechanisms underlying brain aging remain mainly enigmatic, and most likely include multiple changes, which affect various elements of active milieu of the brain; in addition, the systemic influences are fundamental, as the state of, for example, cardiovascular, endocrine, or digestive systems directly and profoundly affect the nervous tissue and brain functions. It is generally believed (although not experimentally proven) that brain aging is associated with an increased glial reactivity; the prevalence of reactive astrocytes and microglia exert neurotoxicity that actively destroys the nervous tissue (Palmer and Ousman, 2018). These ideas of progressive age-dependent reactivity are in close agreement with the concept of inflammaging (Franceschi et al., 2017), in the framework of which aged brains are considered to be chronically inflamed. Our knowledge of neuroglial aging is however very much limited. As far as astrocytes are concerned morphological and immunocytochemical evidence are quite controversial, and mostly are limited to analyses of astrocytic profiles immunostained staining with antibodies against glial fibrillary acidic protein (GFAP). Morphometry of GFAP-positive astrocytic profiles in the aging brain is inconclusive; some studies show an increase in these profiles, some – their decrease, and some found no changes at all (Verkhratsky et al., 2021). Moreover, GFAP antibodies do not stain all astrocytes in the healthy nervous tissue, while GFAP expression is highly labile, and an increase in GFAP expression is often induced by perfectly physiological stimulations and activities, such as physical exercise, environmental stimulation, or dieting (Verkhratsky and Butt, 2023). More accurate investigation of aged astrocytes using 3D confocal microscopy of astrocytes loaded with fluorescent dye demonstrated substantial morphological atrophy of protoplasmic astrocytes in the cortex of 20–24 months old mice (Figure 1A; Popov et al., 2021).Figure 1: Age-dependent morphological atrophy of astrocytes from mice to human.(A) Left panel: Three-dimensional reconstructions of hippocampal astrocytes loaded with a fluorescent dye (Alexa Fluor 594) from young, adult, and old mice. Right panel: An example of single astrocyte 3D Sholl-analysis which reveals cell complexity by quantifying the number of intersections of astrocytic branches with concentric spheres centered in the middle of cell soma. Reprinted with permission from Popov et al. (2021). (B) Left panel: Representative three-dimensional reconstructions of cortical astrocytes loaded with a fluorescent dye (Alexa Fluor 594) through patch pipette in younger and older human patients. Right panel: 3D Sholl analysis of these astrocytes. Reprinted with permission from Popov et al. (2023).The question however remains, whether these changes are similar to those occurring in the human brain; the problem of translation from rodents to humans is notorious. Morphological properties of human astrocytes differ from rodents substantially: protoplasmic and fibrous human astrocytes are substantially larger and immensely more complex (Popov et al., 2023). In addition, the brains of humans and higher primates contain several unique types of astrocytes (interlaminar astrocytes and astrocytes with varicose projections) which are absent in all other species (Oberheim et al., 2009). In-depth analysis of metabolism and morphology of protoplasmic cortical astrocytes obtained from the brains of younger (< 50 years old) and older (51–72 years old) patients, who underwent subcortical brain tumors removal surgery revealed an age-dependent decline in both morphology and mitochondrial metabolism. In particular, single-cell Raman microspectrometry demonstrated a significant decrease in the amount of reduced cytochromes in old human astrocytes, indicative of mitochondrial failure; no such changes were observed in neurons from the same brain slices (Popov et al., 2023). In addition, aged astrocytes have a decreased protein-to-lipid ratio, which possibly arises from the accumulation of lipid droplets in astrocytes linked to diminished mitochondrial fatty acid oxidation. Morphological analysis of 3D reconstructed (from a series of confocal Z-stacks of astrocytes filled with fluorescent dye Alexa Fluour 594) human astrocytes revealed prominent age-dependent atrophy manifested by decreased complexity and reduced size of astrocytic territorial domains (Figure 1B; Popov et al., 2023). Thus, age-dependent astrocyte remodeling is similar between rodents and humans, likely reflecting fundamental mechanisms contributing to the aging of the brain. A decrease in morphological presence and metabolism of astrocytes can contribute to age-dependent cognitive decline. Astrocytic atrophy impairs synaptic transmission through reduced glutamate clearance, decreased glutamine supply, impaired K+ buffering, and limited energy support. In addition, astrocytic decline limits astrocytic defensive and regenerative capabilities, such as scavenging of reactive oxygen species, reactivity in response to various lesions, and neurogenesis (Verkhratsky et al., 2021). Astrocytic atrophy is also prevalent in many psychiatric conditions and is particularly obvious in depression and stress-induced depressive-like behaviors (Lin et al., 2023). It is probably more the coincidence that old people are more vulnerable to mood disorders and depression (Alexopoulos, 2019). Brain aging is also accompanied by an accumulation of senescent non-functional microglia and a decrease in the remyelinating capacity of oligodendroglial precursor cells (Streit et al., 2004; Yi et al., 2023). In conclusion, age-dependent neuroglial decline reduces cognitive reserve, decreases homeostatic support, and impairs brain defense. Asthenia and paralysis of old neuroglia opens gates to neurodegenerative diseases and promotes cognitive decline. Targeting neuroglia through life style modifications, pharmacological treatments, or specific gene therapy may represent a novel strategy for maintaining cognitive longevity. Open peer reviewer:Xianshu Bai, Saarland University, Germany. Additional file:Open peer review report 1.P-Reviewer: Bai X; C-Editors: Zhao M, Liu WJ, Qiu Y; T-Editor: Jia Y