Ageing Cells Rewire their Protein Factories

Aging leads to remodeling of the endoplasmic reticulum, a complex cellular organelle. This protective process helps cells endure aging-associated stress to maintain homeostasis.

Within aging organisms, cells slowly lose their youthful precision: Membranes stiffen, repair systems malfunction, and proteins begin to misfold and pile up. One of the cell organelles that experiences age-associated changes is the endoplasmic reticulum (ER), which is home to fundamental processes such as protein and lipid synthesis, protein folding, and export.

Kristopher Burkewitz, a cell and developmental biologist at Vanderbilt University School of Medicine, sought to study more about how the ER responds to aging. However, digging into the literature revealed that most researchers focused on the unfolded protein stress response, wherein the ER senses wrongly folded proteins and triggers a cascade to restore balance or induce cell death. “But [people were] not actually thinking so much about the structure of the ER itself,” said Burkewitz.

One of the major barriers to exploring this aspect is the ER’s complexity, which makes it difficult to visualize, so Burkewitz decided to develop tools that would help him peek into the organelle.

Now, using these methods, Burkewitz and his team observed that cells in aging organisms actively remodel their ER as a protective response to age-associated cell damage.¹ The findings, published in Nature Cell Biology, offer potential therapeutic targets to delay the onset of age-related diseases.

“This study is very interesting, and it’s interesting because here the people show that aging cells actively change the structure of [the] endoplasmic reticulum,” said Ivan Đikić, a biochemist at Goethe University Frankfurt, who was not associated with the study. “[It] is exciting because it provides an adaptive mechanism [of] how ER remodeling is connected with aging.”

For their study, Burkewitz and his team generated Caenorhabditis elegans, a nematode model commonly used for aging studies, wherein they labeled different ER subdomains in different colors. Tracking the worms as they aged using super-resolution microscopy revealed that the amount of protein-synthesizing rough ER declined significantly.

Using transmission electron microscopy, the researchers further observed that as the worms aged, densely packed stacks of rough ER sheets gave way to scarce smooth ER tubules involved in lipid synthesis. Previously published data of the C. elegans proteome throughout the course of aging revealed reduced protein homeostasis-associated molecules and constant levels of those linked with lipid metabolism, validating that aging induces shifts the worm from proteostasis to lipid metabolism.²

To investigate whether age-linked ER remodeling was evolutionarily conserved, Burkewitz and his team examined this process in aging mice. Microscopy of cortical neurons of three- and 18-month-old mice revealed a decline in ER volume in the latter. The researchers also explored the ER of aging yeast and observed a similar reduction of ER volume in aged cells.

While they expected to see some ER remodeling, it was striking how dramatic the changes were, said Burkewitz. The timing also surprised him. “It was one of the earliest changes that we were seeing,” said Burkewitz. “So, we got really excited about that.”

Next, the researchers sought to understand the mechanisms promoting ER remodeling. Inhibiting an autophagy pathway in worms blocked these structural changes, suggesting that selective autophagy—ER-phagy, which helps preserve the organelle—drives age-linked ER remodeling.³ Similar autophagy-associated molecules were involved in ER remodeling in yeast, indicating that ER-phagy is evolutionarily conserved.

Lifespan extension interventions such as reduced insulin-signaling in the worm induced ER remodeling, further validating that the ER-phagy-mediated dynamic shifts were protective. “Naively, usually we assume that anything that we see that changes during aging is going to be bad,” said Burkewitz. But ER-phagy is a way for cells to respond to damaging changes during aging to maintain homeostasis. Given that this process drives ER remodeling early in the aging process, “it started to make a lot of sense to us that some of the earliest changes in aging might be potentially beneficial adaptations,” said Burkewitz.

Đikić noted that the comprehensive approach in the study was innovative and novel. He said that while the study offers important insights into aging and ER remodeling, “at this particular moment, [it is] constrained to yeast and C. elegans.”

He added that the study convincingly demonstrates that ER remodeling plays a role in longevity, but “the conclusions that go deeper molecularly and therapeutically and how to regulate that process [are] still open.” Despite this, he noted, “This is a really very important first piece of evidence that shows us that we need to work more.”

Burkewitz believes that these findings offer an important structural dimension to the ER-associated stress pathways that scientists in the field focus on. “Our research just goes back a step and asks, is there a structural basis for any of these changes in ER functions that we see occurring later in life in different contexts?” said Burkewitz. “I think that that opens the door to there being an earlier step at which we might intervene. We’ve created a new context to explore that idea, and that could be the underpinning of a lot of age-related pathology.”