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.
Highlights
Aging is the main risk factor for neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s or Huntington’s disease), many of which have a clear gender-specific prevalence
Alzheimer’s disease (AD), for example, has a higher (1.6–3:1) prevalence in women compared to men, whereas Parkinson’s disease (PD) has a higher (3.5:1) prevalence in men compared to women [1]
Aging is often accompanied by high blood pressure, obesity, physical inactivity, and unhealthy diet, Effect of Caloric Restriction on Microglia all leading to accumulation of modified or displaced self molecules and activation of the immune system
Summary
Aging is the main risk factor for neurodegenerative diseases (e.g., Alzheimer’s, Parkinson’s or Huntington’s disease), many of which have a clear gender-specific prevalence. The transcriptome analyses of brains of cognitively normal subjects revealed a profound change (mostly upregulation) in the expression of immune/inflammation-related genes with aging [5]. Much fewer genes (6% of immune-related probe sets) differed between AD patients and age-matched controls [5]. Of these differentially expressed immune- and microglia-specific genes, many underwent just incremental changes [5], pointing to exaggerated response of immune system to aging as one of the key contributors to AD pathology [6, 7]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
