Fight Aging!

Glia of various sorts are supporting cells in the brain, assisting the function of neurons. Dysfunction and stress in glial cells is nonetheless important. A growing body of evidence suggests that cellular senescence in astrocytes and microglia contribute to age-related neurodegenerative conditions, for example. Further, stress of various forms in these cells may be provoking both inflammation and altered signaling throughout the brain and body. Overly active, pro-inflammatory astrocytes and microglia are implicated in neurodegeneration, even when these cells are not senescent. It isn't clear as to how much of this is a reaction to damage in the environment, such as the presence of protein aggregates, versus harmful changes that are intrinsic to cells, such as altered epigenetics and mitochondrial dysfunction.

In today's open access paper, researchers report on a study of the way in which mitochondrial stress in glial cells can result in signaling to provoke compensatory responses throughout the organism. The study involved nematode worms, a much simpler organism than mammals, but one might expect much of this process to be similar in humans nonetheless. It suggests that novel ways to induce greater cell maintenance in the whole body might start by manipulating astrocytes and microglia. So far, little headway has been made in producing therapies to meaningfully slow aging by boosting cell stress responses. The research community has so far collectively failed to much improve on the effects of exercise in this regard. Is this a limitation of this class of therapy, or do greater gains lie in the future? Time will tell.

Glial-derived mitochondrial signals affect neuronal proteostasis and aging

Historically, much scientific work interrogating the homeostatic roles of the nervous system focused on neurons. While it is clear that glia, the other main cell type of the nervous system, can serve many roles in neuronal development and function, these roles are normally associated with support roles, including regulating cell number, neuronal migration, axon specification and growth, synapse formation and pruning, ion homeostasis, and synaptic plasticity and providing metabolic support for neurons. However, in recent years, it has become increasingly clear that glial health can affect aging and progression of neurodegenerative diseases, like Alzheimer's disease (AD).

For example, expression of apolipoprotein E4 (ApoE4), one of the strongest risk factors for AD, specifically in astrocytes resulted in increased neuronal tau aggregation. Moreover, hyperactivation of the unfolded protein response of the endoplasmic reticulum (UPRER), which drives ER stress resilience, solely in astrocyte-like glial cells resulted in a significant life-span extension in Caenorhabditis elegans. While these studies show the importance of glial function in organismal health, what they lacked is an active function of glia in promoting these beneficial effects.

To uncover an active role for glia in stress signaling and longevity, we aimed to determine whether glial cells can sense mitochondrial stress and initiate an organism-wide response to promote mitochondrial stress resilience and longevity. We used multiple genetic methods to activate the mitochondrial unfolded protein response (UPRMT) in nonneuronal cells, including cell-type-specific application of mitochondrial stress and direct activation of the UPRMT in the absence of stress.

We found that, regardless of method, activation of UPRMT in a small subset of glial cells, the cephalic sheath glia, provided robust organismal benefits, including prolonged life span and increased resistance to oxidative stress. Perhaps most unique in this model is that UPRMT activation in cephalic sheath glia promotes neuronal health by alleviating protein aggregation in neurons of a Huntington's disease (HD) model. Cephalic sheath glia directly communicate with neurons through the release of small clear vesicles (SCVs) and relay the coordination to the periphery via downstream neuronal mechanisms. This glia to neuron signal results in induction of the UPRMT in distal tissues, through a cell nonautonomous mechanism, which is dependent on the canonical UPRMT pathway, yet unexpectedly distinct from paradigms where UPRMT is directly activated in neurons.

Collectively, these results reveal a previously unknown function for cephalic sheath glia in sensing mitochondrial stress, which initiates a signal to promote protein homeostasis in neurons and ultimately prolongs longevity. Therefore, glial cells serve as one of the upstream mediators of mitochondrial stress and its coordination across the entire organism.