Summary: New evidence indicates that increased inflammation accelerates the biological aging process. These findings point to a delicate balance between keeping the immune system active and preserving longevity.
Source: Max Planck Institute
As organisms age, the immune system gradually loses efficiency. One prominent feature of this decline is a state of chronic, low-grade inflammation commonly observed in older individuals. This persistent immune activation—often called “inflammaging”—is linked to a range of age-related conditions, from arthritis to neurodegenerative disorders such as Alzheimer’s disease, and it also undermines the ability to respond effectively to new infections. A key question in aging research is whether chronic inflammation drives aging, or whether it is primarily a downstream consequence of other aging processes. Researchers led by Director Adam Antebi at the Max Planck Institute for Biology of Ageing in Cologne have produced experimental evidence suggesting that heightened inflammation can actively accelerate aging, revealing a trade-off between immune responsiveness and lifespan.
Using the model organism Caenorhabditis elegans, the team studied an evolutionarily conserved gene known as PUF60. A specific alteration in this gene produced worms that lived significantly longer—about 20% beyond the normal lifespan—while simultaneously suppressing their immune responses. Those genetically altered worms showed reduced resistance to certain bacterial infections and died more rapidly when challenged by pathogens. The results highlight a biological trade-off: a more active immune system may protect against infection but can shorten lifespan, whereas reduced immune activation can extend lifespan provided the organism does not succumb to infection.
PUF60 encodes a splicing factor, a protein involved in the essential cellular process of RNA splicing. Splicing removes non-coding segments and joins coding sequences in RNA to produce mature messenger RNA (mRNA), which is then translated into functional proteins. The study found that the PUF60 variant perturbs normal splicing patterns, which in turn alters the expression and regulation of genes involved in innate immunity. By modifying how certain transcripts are processed, changes in PUF60 shift immune-related gene activity and influence the balance between immune defense and longevity.
The research team showed that altering PUF60 activity influences downstream immune signaling pathways. In C. elegans, PUF60 acts through the TIR-1/PMK-1/MAPK signaling cascade to modulate immune responses. The investigators also examined another splicing factor, SFA-1, which similarly promotes longevity while dampening immunity, and appears to work downstream of or in parallel with PUF60. Together, these observations implicate specific components of the splicing machinery as conserved regulators of innate immune activity and aging across species.
Importantly, the mammalian homolog PUF60 also displayed anti-inflammatory behavior in cell-based experiments. The researchers observed that levels of PUF60 decline rapidly in mammalian cells following bacterial exposure, suggesting that dynamic regulation of this splicing factor is part of the host response to infection. This cross-species conservation strengthens the idea that regulated RNA splicing contributes to a fundamental trade-off: sustaining immune vigilance versus promoting longevity.
These findings raise several key questions for future investigation. Pinpointing the exact splicing events and target transcripts through which PUF60 influences immunity will be essential to understand how RNA processing links immune regulation and aging. Additionally, understanding when and how to modulate splicing factor activity could offer strategies to reduce harmful chronic inflammation without compromising the ability to fight infections. Any therapeutic approach will need to preserve this delicate balance to avoid unintended consequences such as increased susceptibility to pathogens.
About this aging research article
Source:
Max Planck Institute
Media Contacts:
Adam Antebi – Max Planck Institute
Image Source:
The image is credited to Raymond Laboy.
Original Research: Open access
“Evolutionarily conserved regulation of immunity by the splicing factor RNP-6/PUF60” by Chun Kew, Wenming Huang, Julia Fischer, Raja Ganesan, Nirmal Robinson, Adam Antebi. eLife. DOI: 10.7554/eLife.57591
Abstract
Evolutionarily conserved regulation of immunity by the splicing factor RNP-6/PUF60
Splicing is a fundamental cellular process that shapes gene expression and modulates physiological functions, yet its roles in innate immune regulation remain underexplored. Through genetic screens in C. elegans, the study identified the splicing factor RNP-6/PUF60 as a modulator that suppresses immune activity while promoting longevity, revealing a trade-off between these processes. Exposure to bacterial pathogens alters gene expression and splicing in an rnp-6-dependent manner. Both gain- and loss-of-function manipulations of rnp-6 demonstrate an active role for this factor in immune regulation. Another longevity-associated splicing factor, SFA-1, exerts a similar immunosuppressive effect and appears to act downstream of or in parallel with RNP-6. RNP-6 modulates immunity via the TIR-1/PMK-1/MAPK signaling pathway. The mammalian homolog PUF60 shows anti-inflammatory properties and is rapidly downregulated after bacterial infection in mammalian cells, suggesting a conserved role in host responses. Overall, these results reveal an evolutionarily conserved mechanism by which specific components of the splicing machinery balance immunity and lifespan.