As an inevitable part of life, aging is a topic we can all relate to — whether we embrace or dread the process. Especially for those in the latter camp, finding ways to mitigate the natural aging process on a cellular level is extremely appealing.

On the cellular level, aging goes hand in hand with a loss of protein homeostasis (or “proteostasis”), in which protein synthesis and folding are in equilibrium with protein degradation.

As we grow older, protein misfolding and aggregation occur more regularly, potentially leading to heart disease, metabolic syndrome, and neurodegeneration. The onset of Alzheimer’s disease, for example, is characterized by the accumulation of beta-amyloid and tau proteins in the brain, killing neurons.

During youth, our cells can handle misfolded proteins through a protective mechanism initiated by the endoplasmic reticulum (ER) called the “unfolded protein response” (UPR), which restores proteostasis. But aging affects the ER’s ability to activate this response, reducing ER stress resistance.

Members of the Dillin Lab at University of California, Berkeley are keen to understand this loss of control over proteostasis and the UPR and have uncovered an alternative stress response mechanism that leads to enhanced longevity in C. elegans, a nematode that responds to ER stress similarly to humans at a cellular level.

The researchers had previously found that nonautonomous activation of the UPR in neurons by overexpressing a spliced and active form of the transcription factor XBP1 — XBP-1s — could also activate the UPR in distal intestinal cells through intertissue signaling. This allowed C. elegans to live about 25% longer than normal.

Their most recent findings show that alongside neurons, four specific glial cells — “support cells” that protect neurons and include astrocytes, oligodendrocytes, Schwann cells, and microglia — play a direct (and perhaps more important) role in communicating ER stress to intestinal cells, leading to a surprising 75% increase in the lifespan of C. elegans.

The mechanism by which glial cells initiate nonautonomous activation of the UPR in peripheral cells is entirely independent of the way in which neurons accomplish this. That is, glial cells use neuropeptide signaling to coordinate the stress response. In contrast, the neuronal XBP-1s pathway involves small, clear synaptic vesicles containing neurotransmitters.

Identifying exactly which neuropeptides glial cells secrete could lead to new therapies to conserve or restore these pathways during aging, potentially preventing age-related disease and muscle degeneration, and even extending the human lifespan.