Various forms of glial cell exist in the brain, supporting and protecting neurons. Over the years, researchers have discovered that glial cells are deeply involved in many of the important functions of neurons, such as the establishment and maintenance of synaptic connections. Some forms of glial cell, such as microglia, are a part of the innate immune system. They differ in many aspects from similar types of immune cell elsewhere in the body, macrophages, but have much the same set of responsibilities: clean up debris; consume pathogens; destroy errant cells; assist in regeneration from injury. In the aging brain, immune dysfunction sets in similarly to the rest of the body. Immune cells become overly activated, inflammatory signaling grows, but at the same time the immune system becomes less capable of carrying out its core tasks.
Of late, the research community has devoted increasing attention to the balance of states in microglia and macrophage populations. These cells have a number of overlapping states, or polarizations, a way of characterizing their behavior. The M1 state is less helpful in regeneration, and more inflammatory and aggressive in pursuit of pathogens. The M2 state, on the other hand, suppresses inflammation and helps to generate a supportive environment for regeneration. A wide range of age-related conditions are characterized by the presence of too many M2 and too few M1 microglia or macrophages, likely one of the many complex detrimental reactions to accumulations of underlying cell and tissue damage. Adjusting this balance many prove to be helpful, even in the absence of efforts to address low-level damage, but reliable methods of achieving that goal have yet to emerge.
In this open access paper, the authors review the present state of research into glial cells and aging in flies, and the relevance of these studies to the understanding of mammalian aging. They focus on parts of the bigger picture in which enough is known to pick out relationships, but not yet enough to understand how the same mechanism can apparently contribute to both neurodegeneration and defense against neurodegeneration. Cell metabolism is complex, the immune system is complex, and the brain is particularly complex. These are good reasons not to try too hard to intervene downstream from the comparatively simple root causes of aging; if less complicated opportunities arise, then by all means, but in most cases trying to manipulate the damaged state of metabolism is an expensive path to poor results.
The chronic inflammatory status that accompanies human aging, also known as inflammaging, is considered a significant risk factor for many chronic pathologies including cancer, cardiovascular and neurodegenerative disorders. In the context of aging, increased levels of pro-inflammatory cytokines such as TNF-alpha and Interleukine (IL)-6 are found upregulated in brain tissue. With age, mammalian microglia, which are the brain immune cells exhibit primed profile characterized by increased activation and enhanced secretion of pro-inflammatory cytokines. Decline in microglial function, migration, and chemotaxis are also observed with age. For instance, microglia's engulfment capacity of amyloid-beta (Aβ) or alpha-synuclein (α-Syn) oligomers, whose accumulation is characteristic for Alzheimer's and Parkinson's disease, respectively, are compromised in aged animals. Moreover, activated microglia and neuroinflammatory profiles are observed in most neurodegenerative disorders.
Drosophila, the common fruit fly, is an excellent versatile model organism to investigate the interplay between innate immune function and brain physiology among the effects of this interaction to host lifespan. There is a high degree of evolutionary conservation of the molecular mechanisms of innate immunity between flies and mammals. Similar to mammalian models, both chronic innate immune activation as well as decline in phagocytic activity of glia are observed in the aging Drosophila brain. It is thus apparent that glial immunity is linked to both, healthy aging and age-dependent neurodegeneration.
In the mammalian brain, under normal physiological conditions, microglia provide the first line of defense against brain injury and infection. These cells are able to sense pathogens via pathogen recognition receptors, activate innate immune signaling pathways, phagocytose microorganisms, and clear cellular debris. Microglia also have the capacity to secrete neurotrophic factors and anti-inflammatory molecules, therefore, playing a protective role in these contexts. On the other hand, the neurodegenerative process itself can trigger inflammation, leading to detrimental effects on the brain. It is, therefore, important to understand the mechanisms by which, changes in the same signaling pathway (e.g., NF-kB) lead to two distinct phenotypes, namely healthy aging associated with neuroprotection and neurodegeneration.
It is becoming increasingly evident that glial cells play an important role in neuroprotection and in organismal physiology throughout lifespan. In the recent years, studies in the model organism Drosophila have revealed numerous aspects of glial contribution toward both, healthy aging, and the development and progression of age-related pathologies of the nervous system. Dysregulation of glial innate immune reactions such as improper NF-κB signaling or impaired Draper-based phagocytosis results in early onset neurodegeneration and lifespan shortening. Thus, both branches of the innate immune response seem to contribute in host neuroprotection and longevity. Additional work is needed to investigate whether these two pieces of the innate immune response possess synergistic properties and identify possible cellular factors that regulate both the inflammatory and phagocytic pathways in glial cells.