Worms and Aging: How Non-Neural Cells in the Central Nervous System Could Spur Longevity
Summary
- The Miller School of Medicine’s Dr. Laura Bianchi led a study analyzing how glial cells impact lifespan and health.
- The study zeroed in on the chloride channel CLH-1, found in a pair of glial cells (AMsh glia) in C. elegans.
- By shifting the pH in just two glial cells, the researchers triggered a cascade of protective gene programs, suggesting that glial alkalinization could be harnessed to promote healthy aging and protect against neurodegenerative diseases.
What if tweaking the chemistry of just two glial cells could help organisms live longer, healthier lives?
That’s the provocative question at the heart of new research from a team of researchers at the University of Miami Miller School of Medicine, led by Laura Bianchi, Ph.D., professor of physiology and biophysics, and Lei Wang, Ph.D., a scientist in the Dr. Bianchi’s laboratory.
Their study, published in Science Advances, explores how the loss of a specific chloride channel in glial cells can extend lifespan, boost stress resistance and even protect against neurodegenerative disease, all in the nematode C. elegans.
Glial pH and Aging
Aging is a complex process, influenced by genetics, environment and the interplay of different cell types. While neurons often get the spotlight, glial cells, which comprise about half the nervous system, are increasingly recognized as key players in brain health and aging. Glia regulates ionic balance, supports neurons and helps defend against stress. But as we age, glial cells can shift from protectors to promoters of inflammation and degeneration.
The study by Dr. Bianchi, Dr. Wang and colleagues, zeroes in on the chloride channel CLH-1, found in a pair of glial cells (AMsh glia) in C. elegans. The Bianchi lab discovered a few years back that CLH-1 is an important pH regulator in the nervous system.
“This approach has been instrumental in uncovering how these interactions can become dysregulated in neurological and psychiatric disorders,” Dr. Bianchi said. “The use of C. elegans accelerates the discovery of underlying genes, allowing us to understand the mechanisms in a significantly shorter time frame. Given that nematodes and mammals share fundamental biological processes, it is highly likely that these mechanisms are conserved in mammals.”
The researchers asked a simple question. What happens if you knock out this channel?
From Genes to Lifespan
Using genetic engineering, the team created C. elegans mutants lacking the CLH-1 channel. They tracked lifespan, health span (including locomotion) and resistance to oxidative stress.
They also used RNA sequencing to map changes in gene expression and fluorescent markers to visualize cell recycling mechanisms and protein aggregation. To probe the underlying mechanisms, they manipulated glial pH by targeting carbonic anhydrase (CAH-4) and bicarbonate transporter (ABTS-3) genes.
What did the research reveal?
Using worms to test their hypotheses, the researcher team revealed a number of impactful conclusions:
• Lifespan and health span extension: Worms lacking CLH-1 lived longer and maintained youthful movement as they aged. This wasn’t due to reduced food intake or sensory deficits, but rather to changes in glial cell chemistry.
• Stress resistance: Mutant worms showed lower levels of reactive oxygen species and survived better under oxidative stress.
• Autophagy and neuroprotection: Loss of CLH-1 ramped up autophagy (cellular recycling) both locally in glia and globally throughout the worm. These mutants also had fewer toxic protein aggregates in a model of Huntington’s disease, suggesting protection against neurodegeneration.
• The role of glial alkalinity: Health benefits were traced to increased alkalinity (higher pH) inside the AMsh glia. When researchers neutralized this alkalinity by knocking down CAH-4 or ABTS-3, the benefits disappeared. Conversely, overexpressing CAH-4 to artificially raise glial pH in normal worms mimicked the protective effects.
“Our research indicates that increased alkalinity, particularly in glial cells, could be beneficial,” Dr. Bianchi said. “This finding suggests that developing drugs to activate carbonic anhydrase, rather than inhibiting it, might be worth considering.”
The work of Dr. Bianchi and team highlights glial pH as a master regulator of aging and stress resistance. By shifting the pH in just two glial cells, the researchers triggered a cascade of protective gene programs, boosting antioxidant defenses, autophagy and resilience to cellular stress.
As Dr. Bianchi reiterated, the team’s findings suggest that glial alkalinization could be harnessed to promote healthy aging and protect against neurodegenerative diseases.
Tags: aging, Aging Research, C. elegans, Department of Physiology & Biophysics, Dr. Laura Bianchi, Huntington's disease, neurodegenerative diseases