Unraveling Aging: How Protein Misfolding Relates to Aging and Disease

Many major age-related neurodegenerative diseases share a common trait: proteins lose shape and clump into harmful, insoluble aggregates. For example, in Alzheimer’s disease a protein called amyloid-beta aggregates into plaques in the brain and contributes to neurodegeneration. While many treatments aim to remove these aggregates, a deeper question remains: could this conserved feature of protein aggregation in neurodegenerative disease reveal insights about how proteins behave as we age?

Protein aggregation is thought to result from disruptions in protein homeostasis—or proteostasis—the balance that ensures proteins are properly folded, functional, and degraded when no longer needed. Buck Institute Professor Gordon Lithgow, PhD, and the Lithgow lab investigate how the deterioration of proteostasis drives neurodegenerative diseases and potentially aging, aiming to uncover mechanisms to counteract both.

Edward Anderton, PhD, a postdoctoral researcher in the Lithgow lab, seeks to understand the mechanism behind proteostasis loss in Alzheimer’s disease, and questions if this loss of proteostasis in age-related disease is an exacerbation of what occurs during the normal aging process. This ties closely to the geroscience hypothesis, which posits that aging itself is the root cause of many chronic diseases—and that targeting the aging process itself could delay or prevent these conditions. By examining the role of proteostasis in healthy aging and age-related disease, Dr. Anderton hopes to reveal how the two intersect and, in doing so, find targets for therapeutics to slow neurodegenerative disease progression and aging.

The Lithgow lab studies lifespan in C. elegans, microscopic worms ideal for aging research due to their two-week lifespan and well-characterized biology. C. elegans features many of the same tissues as humans and show age-related changes akin to those seen in mammals such as loss of muscle, skin changes, and cognitive decline. In 2012, the Lithgow lab published a seminal study in Aging Cell showing that aging worms lose the ability to maintain proteostasis, leading to the aggregation of hundreds of proteins--many of which regulate lifespan. This discovery highlighted a link between protein aggregation and aging in worms, driving the lab’s continued efforts to identify aggregation-prone proteins and understand their role in aging and disease.

In a recent Geroscience study, Dr. Edward Anderton and Dr. Manish Chamoli explored whether aggregation of the harmful form of the protein amyloid beta, implicated in Alzheimer’s disease, influences the aggregation of other proteins and how this compares to protein aggregation during normal worm aging.

Their research revealed that amyloid beta accelerates protein misfolding in worms, with 66% of the proteins aggregated by amyloid beta overlapping with those aggregated during normal aging. This discovery highlights a conserved vulnerability among a specific set of proteins, which they termed the “core insoluble proteome.” These proteins, particularly prone to aggregation, provide valuable insights into pathways and mechanisms susceptible to dysfunction in aging and disease. Notably, many are mitochondrial proteins essential for cellular energy production, supporting longstanding evidence that mitochondrial health is central to aging and age-related conditions.

Further, this shared set of aggregation-prone proteins is rich in proteins linked not only to neurodegenerative diseases like Parkinson’s and Huntington’s Disease, but also to age-related conditions such as heart disease and nonalcoholic fatty liver disease. This finding piqued Dr. Anderton’s interest, as it suggests that proteostasis loss might extend beyond neurodegenerative diseases, potentially connecting diverse age-related conditions like diabetes and heart disease.

The core insoluble proteome offers a framework to understand how dysfunction of proteins involved in common cellular pathways could impact disease development and aging. While this research is still in its early stages, Anderton reflects, “It’s just a case of showing some overlaps and saying, isn’t that interesting? But I hope people who read this will start to look at their own research through this lens and explore common pathways between different age-related conditions.”

Anderton hopes that future studies at the Buck will expand on these findings and investigate widespread protein misfolding in conditions like Parkinson’s disease, ALS, and other neurodegenerative disorders. By shifting the focus from individual diseases to the shared molecular roots of protein misfolding, this research could transform how we approach aging, paving the way for therapies that restore proteostasis and simultaneously combat multiple age-related conditions.