Review Reports - Interleukin-6 in Natural and Pathophysiological Kidney Aging

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The article is well structured, contains a lot of scientific data, but also presents the following aspects, which, in my opinion, need to be improved:

various scientific aspects are gathered, without the authors offering a connection between them, even as a hypothesis. So the personal imprint is much reduced;
the mechanisms by which aging generates chronic inflammation are not described, but only experimental data confirming inflammation;
cellular senescence could be presented in more detail. The changes in cellular organelles are not specifically described. However, it is only a suggestion;
the authors should insist on presenting the vicious circle mechanisms that link inflammation and cellular senescence. The direction cellular senescence -> inflammation was mainly presented, not the other way around;
it is useful to slightly systematize the new research directions suggested by the data presented.

Author Response

We thank the reviewer for the constructive criticism and provide our point-to-point response below.

various scientific aspects are gathered, without the authors offering a connection between them, even as a hypothesis. So the personal imprint is much reduced;

Our idea is that interleukin-6 is placed at the intersection of the natural and pathophysiological kidney aging. The imbalance in the production and release of this cytokine may accelerate kidney aging or provoke/aggravate kidney disease. We have now partially rewritten the manuscript to clarify this idea.

the mechanisms by which aging generates chronic inflammation are not described, but only experimental data confirming inflammation;

We have extended the manuscript to provide more mechanistic details.

cellular senescence could be presented in more detail. The changes in cellular organelles are not specifically described. However, it is only a suggestion;

We have added cell-morphological details related to senescence.

the authors should insist on presenting the vicious circle mechanisms that link inflammation and cellular senescence. The direction cellular senescence -> inflammation was mainly presented, not the other way around;

We have added the new Figure 1 to demonstrate mutual links between sterile inflammation, senescence, and renal aging.

it is useful to slightly systematize the new research directions suggested by the data presented.

We have followed this recommendation.

Reviewer 2 Report

Comments and Suggestions for Authors

The dual role of Interleukin-6 (IL-6) in pathological conditions like Chronic Kidney Disease (CKD) and natural kidney aging is thoroughly reviewed by the authors. The idea that IL-6 serves as a crucial link between "inflammaging" and clinically significant renal disease is effectively established in the manuscript.

One of the manuscript's strong points is the differentiation between accelerated aging and benign nephrosclerosis, which offers a clear conceptual framework. Furthermore, since these subtleties are frequently missed in more general reviews, the thorough analysis of IL-6 signaling modes (classic, trans-signaling, and trans-presentation) adds substantial value.

However, I suggest addressing a few areas where the manuscript's clarity, strength of evidence, and visual presentation could be strengthened in order to raise it to the highest level. In particular, the review would benefit from elaborating on the clinical implications of IL-6 inhibition and substituting evidence-based discussion for speculative language.

1-Although the abstract flows well, it could have greater impact if the clinical implications of the review's conclusions were made clear. The abstract should refer to the "potential renal consequences" of IL-6 inhibitors (e.g., are they protective or detrimental in the aged kidney?) that are mentioned in the last sentence.

2-Please correct the header "Cells 2026"; this appears to be a typo.

3-The distinction between "natural kidney aging" and "CKD" is well drawn. However, ensure that the definition of "benign nephrosclerosis" is consistent throughout.

4-The discussion on RFR is excellent. To make this section more accessible, consider a small table or diagram summarizing how RFR changes in healthy aging vs. diabetes/CKD.

5-It's interesting to compare compensatory hyperfiltration—or lack thereof—in aging. The statement that "nephron loss exceeds 50◦ before compensation occurs in natural aging" requires strong evidence, so please double-check the citation support.

6-The discussion on the KL gene is highly relevant. You mention Klotho downregulation by inflammation. It would be beneficial to explicitly discuss if IL-6 specifically has been shown to downregulate Klotho in human renal cells, or if this is largely extrapolated from murine models.

7-The discussion on IL-6 stimulating FGF23 via STAT3 is a key insight. Please expand on the pathological consequence of this: does this create a feedback loop that further suppresses Klotho?

8-Line 528: "AKI has been sown to provoke..." should likely be "shown".

Author Response

We thank th reviewer for the constructive criticism and provide our point-to-point response below.

We thank the reviewer for the encouraging comments. An additional section on the clinical use of IL-6 inhibitors has now been added to the manuscript.

We have adjusted the abstract accordingly.

2-Please correct the header "Cells 2026"; this appears to be a typo.

This header was introduced by the journal.

3-The distinction between "natural kidney aging" and "CKD" is well drawn. However, ensure that the definition of "benign nephrosclerosis" is consistent throughout.

We have changed the wording to consistently use the term “benign nephrosclerosis”.

4-The discussion on RFR is excellent. To make this section more accessible, consider a small table or diagram summarizing how RFR changes in healthy aging vs. diabetes/CKD.

We have added a new Table 1 as suggested.

We have rephrased the statement for “unless the nephron loss exceeds that expected for age” to avoid any unintentional confusions, thank you.

Unfortunately, the data linking interleukin-6 and Klotho directly are strictly limited. However, inflammation and other pro-inflammatory cytokines such as TNF have been shown to suppress Klotho. Klotho, in turn, has been shown to reduce inflammation. Therefore, we have speculated that interleukin 6 participates in the suppression of Klotho during inflammaging. We have explicitly stated that this extrapolation requires experimental validation.

7-The discussion on IL-6 stimulating FGF23 via STAT3 is a key insight. Please expand on the pathological consequence of this: does this create a feedback loop that further suppresses Klotho?

Indeed, there is evidence for such negative feedback although the data is scarce. We have added a speculative statement on the existence of this mechanism.

8-Line 528: "AKI has been sown to provoke..." should likely be "shown".

We have corrected this typo, thank you.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

I am pleased to note that you have addressed all my concerns properly