Bacterial RNA promotes proteostasis through inter-tissue communication in C. elegans
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Abstract
Life expectancy has been increasing over the last decades, which is not matched by an increase in healthspan. Besides genetic composition, environmental and nutritional factors influence both health- and lifespan. Diet is thought to be a major factor for healthy ageing. Here, we show that dietary RNA species extend healthspan in C. elegans . Inherent bacterial-derived double stranded RNA reduces protein aggregation in a C. elegans muscle proteostasis model. This beneficial effect depends on low levels of systemic selective autophagy, the RNAi machinery in the germline, even when the RNA is delivered through ingestion in the intestine and the integrity of muscle cells. Our data suggest a requirement of inter-organ communication between the intestine, the germline and muscles. Our results demonstrate that bacterial-derived RNAs elicit a systemic response in C. elegans , which protects the animal from protein aggregation during ageing. We provide evidence that low stress levels are beneficial for healthspan.
One-Sentence Summary
Bacteria-derived dietary cues and inter-tissue communication promote proteostasis and fitness in C. elegans
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/12660067.
The manuscript demonstrates that dietary RNAs from bacteria can have a systemic, beneficial impact on the healthspan of C. elegans by reducing protein aggregation through a mechanism involving systemic autophagy, ribonuclease-dependent bacterial-RNA species, RNAi machinery and the germline, and improved muscle function. This work highlights the potential of dietary components in promoting healthy aging. Overall, the textual content is well written, the figures are clear, and the results support the conclusion. However, there are several concerns that require further attention.
Major points:
1. Since the authors claim that worms fed on OP50 produce a significantly higher number of progenies …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/12660067.
The manuscript demonstrates that dietary RNAs from bacteria can have a systemic, beneficial impact on the healthspan of C. elegans by reducing protein aggregation through a mechanism involving systemic autophagy, ribonuclease-dependent bacterial-RNA species, RNAi machinery and the germline, and improved muscle function. This work highlights the potential of dietary components in promoting healthy aging. Overall, the textual content is well written, the figures are clear, and the results support the conclusion. However, there are several concerns that require further attention.
Major points:
1. Since the authors claim that worms fed on OP50 produce a significantly higher number of progenies with faster development, it's better to show the daily brood size and the developmental time difference in the progenies between OP50 and HT115 conditions.
2. It is known that different diets affect worm's mitochondrial morphology in germline. Even though the authors claimed muscle proteotoxicity is not due to VB12. However, a functional germline is indispensable to prevent muscle proteotoxicity. Could the authors comment on the mitochondrial morphology in muscle cells when comparing different diets?
3. The authors should measure the pharyngeal pumping rate to evaluate if worms consume the same amount of food.
4. HSF-1 is essential for maintaining proteostasis and can suppress protein aggregation. Does activate HSF-1 reduce polyQ40 aggregation?
5. Since dsRNA/ssRNA in HT115 is important for healthspan, what levels of endogenous dsRNA/ssRNA do E. coli OP50 and HT115 generate? Is there any difference regarding aggregate formation in muscle cells between using OP50-derived RNA and HT115-derived RNA?
6. It is not clear which type(s) of RNA, other than bacteria-derived RNA, play an important role in reducing aggregate formation. It would be important to narrow down the identity of RNA types. Thus, the authors should examine whether the absence of different types of ribonucleases could reduce aggregate formation in muscle cells.
7. Clarification and discussion are needed for the mutants that have significant changes among groups in Fig 4C-H.
8. It is not clear when the bacterial RNA is important to promote proteostasis in worms. Does feeding HT115 E. coli at later ages after feeding OP50 E. coli reduce aggregate formation compared to feeding OP50 alone?
9. Please provide correction method used for proteomics data analysis for multiple testing and adjust the y axis of the volcano plots accordingly.
Minor:
1) Please define "fitness" used in this paper, and it's not clear about the difference of fitness and healthspan.
2) Determining whether worms move or not by touching them is subjective, so it's better to define the area of body wall muscle considered as paralyzed for evaluation in this paper.
3) There are some statements that do not clearly or fully conveyed the information from the figures. For example, line 78-80 for Figure 1A and 1B.
4) Line 54-56 may lack references.
5) Line 234: OP50(xu363), the name form is not consistent.
6) Figure 5: "Scale bars in all panels are 100 µm" should be deleted.
7) More details are needed for the conclusion of vitamin B12 is not involved.
8) How about fat metabolism difference contributing to proteostasis between OP50 and HT115? Please discuss.
9) Do the 194 significantly changed proteins from proteomic analysis include the key muscle genes that are studied in this paper?
10) There is no access to all the supplementary information, so it is not possible to evaluate the related observations or conclusions.
Competing interests
The authors declare that they have no competing interests.
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This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/12640500.
This study investigates the role of bacterial RNA in promoting proteostasis in C. elegans, demonstrating that dietary RNA species derived from bacteria can reduce protein aggregation in muscle cells. It was shown that this effect depends on RNAi machinery and inter-organ communication between the intestine, germline, and muscle. The findings suggest that bacterial-derived RNA elicits a systemic response in C. elegans, protecting against protein aggregation through mechanisms involving autophagy, RNAi, and inter-tissue communication. While the manuscript is generally well-written, some concerns still require further attention.
Major points:
1. Although the OP50 diet results in more protein …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/12640500.
This study investigates the role of bacterial RNA in promoting proteostasis in C. elegans, demonstrating that dietary RNA species derived from bacteria can reduce protein aggregation in muscle cells. It was shown that this effect depends on RNAi machinery and inter-organ communication between the intestine, germline, and muscle. The findings suggest that bacterial-derived RNA elicits a systemic response in C. elegans, protecting against protein aggregation through mechanisms involving autophagy, RNAi, and inter-tissue communication. While the manuscript is generally well-written, some concerns still require further attention.
Major points:
1. Although the OP50 diet results in more protein aggregates in the worms than the HT115 diet, it also led to a higher brood size and better fitness. The authors should elaborate on the correlation between the protein aggregate phenotype and the brood size/development phenotypes. Additionally, how do bacterial RNAs and the host RNAi machinery differentially regulate these two phenotypes?
2. The authors observed that autophagy induction protects animals from protein aggregation in body wall muscles when fed on HT115 diet compared to OP50 diet. However, autophagy was examined in hypodermal seam cells. The authors should include images of autophagosomes in body wall muscles. Also, are there more protein aggregates observed in other tissues (e.g. intestine, germline and hypodermis)? Did the authors conduct tissue-specific knockdown experiments of autophagy genes to determine if the regulation of protein aggregation by autophagy is cell-autonomous or non-autonomous?
3. The authors showed that while germline RNAi machinery is required for the protective effect against protein aggregation in the body wall muscle of HT115-fed worms, it is not sufficient on its own. Similarly, the intestine alone does not provide this protection. The authors should discuss the possible underlying regulatory mechanism. How do RNAi machinery in other tissues contribute to this process? Additionally, is the germline RNAi machinery involved in any transgenerational effects?
4. In the mixed dietary experiments, the OP50/HT115 ratios of 1:1, 1:10, and 10:1 all conferred significant protection against protein aggregates. Are there any significant differences in protein aggregation between these ratios? The authors should discuss how this is regulated by RNAi machinery activities. Is it due to the dose-dependent regulation of bacterial RNA concentration? or just a certain type of RNA could be enough to elicit protection?
Minor points:
1. Figure 3G, besides HT115-derived RNA, did the authors also test the injection of RNA derived from OP50 and OP50(xu363) to see if protein aggregation in OP50-fed worms can be rescued? Is there any difference between using OP50-derived RNA and HT115-derived RNA regarding aggregate formation in muscle cells?
2. Does the length of RNA matter in this regulation of protein aggregation?
3. Line 234: The name OP50(xu363) is not consistent in its format.
4. No comment on the supplementary figures is provided due to their absence in the biorxiv version.
Competing interests
The authors declare that they have no competing interests.
-
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/12640520.
This study investigates the role of bacterial RNA in promoting proteostasis in C. elegans, demonstrating that dietary RNA species derived from bacteria can reduce protein aggregation in muscle cells. It was shown that this effect is dependent on RNAi machinery and inter-organ communication between the intestine, germline, and muscle. The findings suggest that bacterial-derived RNA elicits a systemic response in C. elegans, protecting against protein aggregation through mechanisms involving autophagy, RNAi, and inter-tissue communication. While the manuscript is generally well-written, some concerns still require further attention.
Major points:
1. Although the OP50 diet results in more …
This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/12640520.
This study investigates the role of bacterial RNA in promoting proteostasis in C. elegans, demonstrating that dietary RNA species derived from bacteria can reduce protein aggregation in muscle cells. It was shown that this effect is dependent on RNAi machinery and inter-organ communication between the intestine, germline, and muscle. The findings suggest that bacterial-derived RNA elicits a systemic response in C. elegans, protecting against protein aggregation through mechanisms involving autophagy, RNAi, and inter-tissue communication. While the manuscript is generally well-written, some concerns still require further attention.
Major points:
1. Although the OP50 diet results in more protein aggregates in the worms compared to the HT115 diet, it also led to a higher brood size and better fitness. The authors should elaborate on the correlation between the protein aggregate phenotype and the brood size/development phenotypes. Additionally, how do bacterial RNAs and the host RNAi machinery differentially regulate these two phenotypes?
2. The authors observed that autophagy induction protects animals from protein aggregation in body wall muscles when fed on HT115 diet compared to OP50 diet. However, autophagy was examined in hypodermal seam cells. The authors should include images of autophagosomes in body wall muscles. Also, are there more protein aggregates observed in other tissues (e.g. intestine, germline and hypodermis)? Did the authors conduct tissue-specific knockdown experiments of autophagy genes to determine if the regulation of protein aggregation by autophagy is cell-autonomous or non-autonomous?
3. The authors showed that while germline RNAi machinery is required for the protective effect against protein aggregation in the body wall muscle of HT115-fed worms, it is not sufficient on its own. Similarly, the intestine alone does not provide this protection. The authors should discuss the possible underlying regulatory mechanism. How do RNAi machineries in other tissues contribute to this process? Additionally, is the germline RNAi machinery involved in any transgenerational effects?
4. In the mixed dietary experiments, the OP50/HT115 ratios of 1:1, 1:10, and 10:1 all conferred significant protection against protein aggregates. Are there any significant differences in protein aggregation between these ratios? The authors should discuss how this is regulated by RNAi machinery activities. Is it due to the dose-dependent regulation of bacterial RNA concentration? or just a certain type of RNA could be enough to elicit protection?
Minor points:
1. Figure 3G, besides HT115-derived RNA, did the authors also test the injection of RNA derived from OP50 and OP50(xu363) to see if protein aggregation in OP50-fed worms can be rescued? Is there any difference between using OP50-derived RNA and HT115-derived RNA regarding aggregate formation in muscle cells?
2. Does the length of RNA matter in this regulation of protein aggregation?
3. Line 234: The name OP50(xu363) is not consistent in its format.
4. No comment on the supplementary figures is provided due to their absence in the biorxiv version.
Competing interests
The authors declare that they have no competing interests.
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