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Effect of Caloric Restriction on the in vivo Functional Properties of Aging Microglia.

ABSTRACT: Throughout the lifespan, microglia, the primary innate immune cells of the brain, fulfill a plethora of homeostatic as well as active immune defense functions, and their aging-induced dysfunctionality is now considered as a key trigger of aging-related brain disorders. Recent evidence suggests that both organism's sex and age critically impact the functional state of microglia but in vivo determinants of such state(s) remain unclear. Therefore, we analyzed in vivo the sex-specific functional states of microglia in young adult, middle aged and old wild type mice by means of multicolor two-photon imaging, using the microglial Ca2 + signaling and directed process motility as main readouts. Our data revealed the sex-specific differences in microglial Ca2 + signaling at all ages tested, beginning with young adults. Furthermore, for both sexes it showed that during the lifespan the functional state of microglia changes at least twice. Already at middle age the cells are found in the reactive or immune alerted state, characterized by heightened Ca2 + signaling but normal process motility whereas old mice harbor senescent microglia with decreased Ca2 + signaling, and faster but disorganized directed movement of microglial processes. The 6-12 months long caloric restriction (70% of ad libitum food intake) counteracted these aging-induced changes shifting many but not all functional properties of microglia toward a younger phenotype. The improvement of Ca2 + signaling was more pronounced in males. Importantly, even short-term (6-week-long) caloric restriction beginning at old age strongly improved microglial process motility and induced a significant albeit weaker improvement of microglial Ca2 + signaling. Together, these data provide first sex-specific in vivo characterization of functional properties of microglia along the lifespan and identify caloric restriction as a potent, cost-effective, and clinically relevant tool for rejuvenation of microglia.

SUBMITTER: Olmedillas Del Moral M

PROVIDER: S-EPMC7198715 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Effect of Caloric Restriction on the in vivo Functional Properties of Aging Microglia.

Olmedillas Del Moral Maria M Fröhlich Nicole N Figarella Katherine K Mojtahedi Nima N Garaschuk Olga O

Frontiers in immunology 20200428

Throughout the lifespan, microglia, the primary innate immune cells of the brain, fulfill a plethora of homeostatic as well as active immune defense functions, and their aging-induced dysfunctionality is now considered as a key trigger of aging-related brain disorders. Recent evidence suggests that both organism's sex and age critically impact the functional state of microglia but in vivo determinants of such state(s) remain unclear. Therefore, we analyzed in vivo the sex-specific ...[more]

PMID: 32411143

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Project description:BackgroundChronic kidney disease and end-stage renal disease are major causes of morbidity and mortality that are seen far more commonly in the aged population. Interestingly, kidney function declines during aging even in the absence of underlying renal disease. Declining renal function has been associated with age-related cellular damage and dysfunction with reports of increased levels of apoptosis, necrosis, and inflammation in the aged kidney. Bioactive sphingolipids have been shown to regulate these same cellular processes, and have also been suggested to play a role in aging and cellular senescence.Methodology/principal findingsWe hypothesized that alterations in kidney sphingolipids play a role in the declining kidney function that occurs during aging. To begin to address this, the sphingolipid profile was measured in young (3 mo), middle aged (9 mo) and old (17 mo) C57BL/6 male mice. Interestingly, while modest changes in ceramides and sphingoid bases were evident in kidneys from older mice, the most dramatic elevations were seen in long-chain hexosylceramides (HexCer) and lactosylceramides (LacCer), with C14- and C16-lactosylceramides elevated as much as 8 and 12-fold, respectively. Increases in long-chain LacCers during aging are not exclusive to the kidney, as they also occur in the liver and brain. Importantly, caloric restriction, previously shown to prevent the declining kidney function seen in aging, inhibits accumulation of long-chain HexCer/LacCers and prevents the age-associated elevation of enzymes involved in their synthesis. Additionally, long-chain LacCers are also significantly elevated in human fibroblasts isolated from elderly individuals.Conclusion/significanceThis study demonstrates accumulation of the glycosphingolipids HexCer and LacCer in several different organs in rodents and humans during aging. In addition, data demonstrate that HexCer and LacCer metabolism is regulated by caloric restriction. Taken together, data suggest that HexCer/LacCers are important mediators of cellular processes fundamental to mammalian aging.

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Effect of Caloric Restriction on the in vivo Functional Properties of Aging Microglia.

Publications

Effect of Caloric Restriction on the <i>in vivo</i> Functional Properties of Aging Microglia.

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