Long-term calorie restriction preserves myelin and glial homeostasis in aging rhesus monkey brain
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Abstract
In the aging mammalian brain, neuroglia accumulate oxidative damage and demonstrate metabolic dysfunction, impairing myelin maintenance and contributing to age-related white matter degeneration which is associated with cognitive decline. Calorie restriction (CR) is a well-established intervention known to slow biological aging and extend lifespan in a range of species, yet its effects on brain aging outcomes in long-lived primates remain unclear. The overall goal of this dissertation project was to test the hypothesis that decades-long CR in rhesus monkeys can mitigate age-related cellular and molecular glial alterations, thereby preserving glial and myelin homeostasis and brain function. Here, we evaluated post mortem brain tissue from rhesus monkeys in the National Institute on Aging Health and Longevity study, where rhesus monkeys followed a control or 30% calorie restricted diet for over 20 years. We investigated the cellular and molecular profiles of oligodendrocytes and microglia within frontal white matter regions, implicated in cognition, with previously demonstrated myelin pathology. Using single nucleus transcriptomics, we found that oligodendrocytes from CR subjects exhibited increased expression of myelin-related genes and showed enrichment in glycolytic and biosynthetic fatty acid pathways. A specialized subpopulation of oligodendrocytes designated “synaptic” OLs and implicated in myelination, demonstrated enrichment in glutamatergic signaling and synaptic cell adhesion pathways. Moreover, these synaptic OLs were observed in closer proximity to axons. Notably, the synaptic adhesion genes, which facilitate oligo-axon crosstalk, were upregulated in the CR group. Microglia from CR subjects showed transcriptional upregulation of amino acid and peptide metabolic pathways, alongside a reduced abundance of cells with an inflammatory, myelin-debris-associated signature. Histological analysis showed that CR subjects had significantly fewer cells with oxidative DNA damage, with oligodendrocytes showing the greatest reduction, specifically within mitochondrial DNA. Microglia did not exhibit the same reduction of DNA damage but displayed a morphological shift towards ramified, homeostatic morphologies with fewer hypertrophic microglia compared to controls. Birefringence microscopy was used to assess the structural integrity of myelin within these white matter regions to determine if the cellular and molecular benefit extended to the structural architecture of myelin. This assessment showed no significant effects of CR on myelin integrity or density. Finally, we developed an ex vivo brain slice culture model to use as a platform to test pharmacological manipulation of remyelination, oligodendrocyte maturation, and microglia activation in response to induced demyelination. Treatment with the CR mimetic, metformin, or the potent antioxidant curcumin, improved aspects of the glial-myelin environment following demyelination. Our findings point to oligodendrocytes as primary drivers of age-related myelin damage through dysregulated energy metabolism and increased oxidative damage. The accumulation of damaged oligodendrocytes, together with lipid oxidation of the myelin sheath, overwhelms the phagocytic clearance capacity of microglia, leading to myelin debris accumulation and microglia-driven secondary inflammation. We have provided evidence that long term calorie restriction reduces the primary damage burden in oligodendrocytes and thereby attenuates downstream inflammatory responses and morphological alterations in microglia. However, we also identified potential limitations of CR, as it does not appear to mitigate structural deterioration of myelin. Furthermore, our ex vivo studies confer comparable, cell-type-specific neuroprotection to both oligodendrocytes and microglia, suggesting potential strategies to preserve glial and myelin homeostasis in aging.
Description
2026
License
Attribution 4.0 International