Microglia are immune cells of the brain, analogous to macrophages in the rest of the body. They take on a broad range of tasks: chasing down pathogens; clearing up cell debris and molecular waste; assisting in regeneration and tissue maintenance; assisting neurons in remodeling of synapses. Microglia, like macrophages, can shift between behavior patterns in response to environmental circumstances, such as M1 (inflammatory and aggressive) and M2 (anti-inflammatory and regenerative).
With advancing age, microglia become increasingly inflammatory: this may be the result of too much molecular waste, such as the amyloid-β associated with Alzheimer’s disease, it may be the consequence of persistent infections such as herpeviruses, or there may be other reasons connected to the underlying damage of aging, such as the signaling of chronic inflammation started elsewhere. Evidence from animal studies suggests that inflammatory microglia, and particularly senescent microglia, are quite important in the progression of brain aging. Removing the worst offenders via senolytic drugs, or forcing microglia into the anti-inflammatory M2 state via any one of a number of strategies, appears to be beneficial, a potential basis for therapy.
Calorie restriction, eating up to 40% fewer calories while still obtaining optimal nutrient intake, is the most studied of all interventions known to slow aging in laboratory species. Given that it does slow aging overall, it isn’t surprising to find it slowing or improving any particular manifestation of aging. This is the case for the prevalence of inflammatory microglia in the brain, as researchers discuss in today’s open access paper. Calorie restriction isn’t a way to achieve meaningful rejuvenation in humans – it produces a much greater impact on life span in short-lived mammals than in long-lived mammals – but it is nonetheless one of the most reliable and cost-effective interventions when it comes to improving long-term health. That is more a statement on the presently poor state of medicine to treat the causes of aging than it is on the merits of calorie restriction, however. Senolytics to clear senescent cells are the only form of treatment on the very near horizon likely to do better than calorie restriction.
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 states 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.