Bat-Inspired Longevity: Immune Damage Management and Nutritional Modulation for Healthy Aging

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

This review proposes that bat immunophysiology offers a mechanistic model of human healthy aging, arguing that exceptional longevity arises not from immune potency but from coordinated damage containment and resolution. The authors introduce the Core Longevity State Vector (CLSV-6) as a genuinely novel multidimensional immunotype model integrating six conserved mechanisms including damage tolerance, autophagy–mitophagy, proteostasis, basal immune readiness, inflammasome restraint, and inflammatory resolution capacity. The framework's key novelty lies in explaining why single inflammatory biomarkers (IL-6, CRP, interferons) inconsistently predict longevity: they capture isolated dimensions of a fundamentally coordinated system. By demonstrating that human centenarians converge toward a bat-like immunophysiological configuration decoupling immune sensing from inflammatory amplification  the review reframes inflammaging as a consequence of impaired damage handling rather than an autonomous driver of aging. Building on this, the authors systematically map functional foods (polyphenols, fermented foods, omega-3 fatty acids, caloric restriction mimetics) onto CLSV-6 dimensions, proposing a nutritional geroscience strategy oriented toward damage management rather than immune stimulation.

This comprehensive review is timely and relevant. It can be published. There are only several minor points.   

Abstract: a) Please, explain explicitly the paper's theoretical position suggesting that inflammaging is primarily a downstream consequence of impaired damage handling rather than an autonomous aging driver. This distinction is central to the entire review's argument and should appear in the abstract's opening framing to immediately signal the conceptual novelty to readers. b) It also would be good to explain what "immunotype" CLSV-6 means. c) Please, indicate which specific molecular or cellular features are shared between bats and centenarians.

Introduction The introduction conflates inflammaging as both cause and consequence of aging without sufficiently resolving this tension early on. The authors should explicitly state their conceptual position explaining that chronic inflammation is primarily a downstream marker of impaired damage clearance.

Section 4. Convergent Biological Principles. The argument for convergence between the immune architectures of bats and long-lived intelligent animals is compelling, but the method is insufficiently specific. The authors should propose specific criteria. Ideally, these comparisons should be grounded in shared molecular features. Without this foundation, claims of convergence risk devolving into post hoc interpretations drawn from models operating in entirely distinct biological contexts.

It also would be good to provide figure of better quality and to  add a couple of new figures: Please, illustrate section 4 "Convergent Biological Principles Across Species" .  The figure may present conceptual heart of the Article explaining that bats and centenarians converge on similar immunophysiological architectures despite phylogenetic distance A Venn diagram or convergence matrix comparing molecular and cellular features across four groups (young humans, typically aged humans, centenarians, and long-lived bats) across each CLSV-6 dimension would make the convergence argument concrete and falsifiable rather than descriptive. Color-coding by mechanistic similarity would reveal which dimensions show the strongest cross-species conservation and which remain divergent, guiding future research priorities.

One more addition could be a time-course figure showing the kinetics of inflammatory initiation, peak, and resolution in  bats, young humans, aged humans, and centenarians. This figure would distinguish the concept of "resolution capacity" from simple immune suppression, which is a critical conceptual distinction the review emphasizes.

Author Response

We appreciate the editor and reviewers for careful review of our paper. We sincerely revised the manuscripts according to each comment, and we changed the manuscript in red text to be easily distinguished.

Reviewer 1.

This review proposes that bat immunophysiology offers a mechanistic model of human healthy aging, arguing that exceptional longevity arises not from immune potency but from coordinated damage containment and resolution. The authors introduce the Core Longevity State Vector (CLSV-6) as a genuinely novel multidimensional immunotype model integrating six conserved mechanisms including damage tolerance, autophagy–mitophagy, proteostasis, basal immune readiness, inflammasome restraint, and inflammatory resolution capacity. The framework's key novelty lies in explaining why single inflammatory biomarkers (IL-6, CRP, interferons) inconsistently predict longevity: they capture isolated dimensions of a fundamentally coordinated system. By demonstrating that human centenarians converge toward a bat-like immunophysiological configuration decoupling immune sensing from inflammatory amplification  the review reframes inflammaging as a consequence of impaired damage handling rather than an autonomous driver of aging. Building on this, the authors systematically map functional foods (polyphenols, fermented foods, omega-3 fatty acids, caloric restriction mimetics) onto CLSV-6 dimensions, proposing a nutritional geroscience strategy oriented toward damage management rather than immune stimulation.

This comprehensive review is timely and relevant. It can be published. There are only several minor points.   

 

Abstract: a) Please, explain explicitly the paper's theoretical position suggesting that inflammaging is primarily a downstream consequence of impaired damage handling rather than an autonomous aging driver. This distinction is central to the entire review's argument and should appear in the abstract's opening framing to immediately signal the conceptual novelty to readers. b) It also would be good to explain what "immunotype" CLSV-6 means. c) Please, indicate which specific molecular or cellular features are shared between bats and centenarians.

Response: The abstract has been revised to better explain the important points of the paper has requested. Probably the most important shared molecular feature between bats and centenarians is the suppressed NLRP3 inflammasome activity which has been mentioned in the abstract.

 

Introduction The introduction conflates inflammaging as both cause and consequence of aging without sufficiently resolving this tension early on. The authors should explicitly state their conceptual position explaining that chronic inflammation is primarily a downstream marker of impaired damage clearance.

Response: These concerns have been addressed in the Introduction at the last paragraph of the introduction part.

 

Section 4. Convergent Biological Principles. The argument for convergence between the immune architectures of bats and long-lived intelligent animals is compelling, but the method is insufficiently specific. The authors should propose specific criteria. Ideally, these comparisons should be grounded in shared molecular features. Without this foundation, claims of convergence risk devolving into post hoc interpretations drawn from models operating in entirely distinct biological contexts.

Response: We acknowledge this risk and have tried to improve the manuscript accordingly. There are some shared mechanisms between bats and human centenarians, but often different mechanisms are utilized to obtain similar outcomes; this is a problem we have tried to address.

 

It also would be good to provide figure of better quality and to  add a couple of new figures: Please, illustrate section 4 "Convergent Biological Principles Across Species" .  The figure may present conceptual heart of the Article explaining that bats and centenarians converge on similar immunophysiological architectures despite phylogenetic distance A Venn diagram or convergence matrix comparing molecular and cellular features across four groups (young humans, typically aged humans, centenarians, and long-lived bats) across each CLSV-6 dimension would make the convergence argument concrete and falsifiable rather than descriptive. Color-coding by mechanistic similarity would reveal which dimensions show the strongest cross-species conservation and which remain divergent, guiding future research priorities. One more addition could be a time-course figure showing the kinetics of inflammatory initiation, peak, and resolution in  bats, young humans, aged humans, and centenarians. This figure would distinguish the concept of "resolution capacity" from simple immune suppression, which is a critical conceptual distinction the review emphasizes.

Response: We added Figure 2 (A and B) about Convergent immunophysiology architectures across species. It summarizes the convergent biological principles that decouple immune sensing from inflammatory amplification in long-lived models. A. Convergence matrix and B. Conceptual vie diagram.

 

We also added Table 2 about Mechanistic Convergence Matrix: Shared Molecular Features of Longevity-Associated Immunotypes.

 

Reviewer 2 Report

Comments and Suggestions for Authors

• In abstract:

The Core Longevity State Vector (CLSV-6) is interesting but not sufficiently defined. It reads as a conceptual aggregation rather than a clearly operationalized framework. Consider briefly stating whether CLSV-6 is descriptive, predictive, or experimentally testable.

Statements such as “centenarians converge toward this bat-like configuration” are strong but lack qualification. Indicate whether this is based on direct comparative data or inferred parallels.

The dismissal of markers like CRP and IL-6 as inconsistent predictors is valid but oversimplified. Acknowledge context dependency rather than implying limited utility.

• In introduction:

The text is conceptually strong but undermined by frequent typographical issues (e.g., “telomere a rition,” “be er,” “a ributable,” broken words like “in f lammaging”). These disrupt flow and must be corrected for professionalism and readability.

The first sentence is overloaded with all hallmarks of aging. While comprehensive, it reduces readability. Consider grouping or summarizing instead of listing all 12 hallmarks explicitly.

The discussion of IL-6 and CRP is valid but slightly reductive. These biomarkers do have predictive value in specific contexts. Acknowledge their conditional utility rather than implying broad failure.

The statement about Proteobacteria dominance in bats is interesting but oversimplified and not universally consistent across species or diets. Needs qualification.

The introduction of CLSV-6 is appropriate, but it appears suddenly. Add a clearer lead-in explaining the gap it addresses.

Phrases like “intrinsically linked,” “is achieved by,” or “confirming its causal role” are too definitive.

 Much of the evidence (especially in humans) is associative, not causal.

 Recommend softening to “associated with,” “supports,” “suggest

You repeatedly refer to CLSV-6 as if it is an established biological framework rather than a proposed model.

 Clarify earlier and consistently that this is a conceptual framework introduced in this review, not an empirically validated system

Statements about interferon signaling, microbiome composition, and inflammasome suppression are presented as universal across bats.

The transition from bat biology to human dietary strategies remains conceptually appealing but mechanistically under-supported.

Ensure consistent use of:

• IFN-α vs IFNα
• mtDNA vs mt DNA
• IL-1β formatting

Mechanisms like S358 STING mutation, PYHIN loss, and constitutive IFN-α are presented as broadly representative of bats.

Claims implying causation (e.g., RNASEH2C, senescent cell clearance) are not fully supported in humans.

• Improved compared to earlier sections, but still:
  • The leap from evolutionary adaptations → dietary modulation remains somewhat optimistic.
  • Needs clearer acknowledgment of magnitude differences (genetic vs. nutritional effects).

 

Claims like “suppress cytosolic DNA sensing and STING signaling” or “consistently integrate with all six CLSV-6 mechanisms” are too strong.

 Human evidence is often indirect or context-dependent.

Phrases like “centenarians converge toward this configuration” and “CLSV-6 provides an operational blueprint” remain too strong.

Damage vs. inflammation,” “immune quality vs. intensity,” and “six mechanisms” are repeated multiple times.

 

Dose–Response and Adherence

• Well addressed.
• Could be strengthened by:
  • Mentioning long-term compliance issues in dietary trials
  • Acknowledging confounding lifestyle factors

 

 

 

 

Author Response

We appreciate the editor and reviewers for the careful review of our paper. We sincerely revised the manuscripts according to each comment, and we changed the manuscript in red text to be easily distinguished.

Reviewer 2

• In abstract:

The Core Longevity State Vector (CLSV-6) is interesting but not sufficiently defined. It reads as a conceptual aggregation rather than a clearly operationalized framework. Consider briefly stating whether CLSV-6 is descriptive, predictive, or experimentally testable.

Response: We have improved the description and explanation of the CLSV-6 in the abstract and removed some points less central to main points of the paper.

 

Statements such as “centenarians converge toward this bat-like configuration” are strong but lack qualification. Indicate whether this is based on direct comparative data or inferred parallels.

Response: These comparisons of bats are more nuanced than can be fully explained in the abstract, but we have tried to make it more clearly expressed. Some shared features of human and bat immunity like suppressed NLRP3 inflammasome activity is shared by both, however some features such as microbiome features involve very different gut bacteria but confer similar advantages. However, this is better discussed in the main text than in the abstract.

 

The dismissal of markers like CRP and IL-6 as inconsistent predictors is valid but oversimplified. Acknowledge context dependency rather than implying limited utility.

Response: This is no longer in the abstract. However, we will try to improve it in the text.

 

• In introduction:

The text is conceptually strong but undermined by frequent typographical issues (e.g., “telomere a rition,” “be er,” “a ributable,” broken words like “in f lammaging”). These disrupt flow and must be corrected for professionalism and readability.

Response: We will locate and correct such errors that reviewer’s indicated.

 

The first sentence is overloaded with all hallmarks of aging. While comprehensive, it reduces readability. Consider grouping or summarizing instead of listing all 12 hallmarks explicitly.

Response: We understand your concern, however we believe this to be important information and helps the reader to have an integrated view of the characteristics of aging in the introduction. We can remove some of this if the reviewer considers it to be important, but would ask for deference on this point if appropriate.

 

The discussion of IL-6 and CRP is valid but slightly reductive. These biomarkers do have predictive value in specific contexts. Acknowledge their conditional utility rather than implying broad failure.

Response: We agree and have changed the wording accordingly.

 

The statement about Proteobacteria dominance in bats is interesting but oversimplified and not universally consistent across species or diets. Needs qualification.

Response: We agree and more qualified language is now used.

 

The introduction of CLSV-6 is appropriate, but it appears suddenly. Add a clearer lead-in explaining the gap it addresses.

Response: We agree and have added some additional “lead-in’ discussion.

 

Phrases like “intrinsically linked,” “is achieved by,” or “confirming its causal role” are too definitive. Much of the evidence (especially in humans) is associative, not causal. Recommend softening to “associated with,” “supports,” “suggest.

Response: The above observations are correct and we have incorporated the suggestions throughout the manuscript where appropriate.

 

You repeatedly refer to CLSV-6 as if it is an established biological framework rather than a proposed model.

Response: It is changed to refer as proposed model.

 

 Clarify earlier and consistently that this is a conceptual framework introduced in this review, not an empirically validated system

Response: We agree and have reworded passages accordingly.

 

Statements about interferon signaling, microbiome composition, and inflammasome suppression are presented as universal across bats.

Response: You are correct, bats are a very large group of mammals with many different species that are quite varied.  We are checking the wording to make sure this is clear.

 

The transition from bat biology to human dietary strategies remains conceptually appealing but mechanistically under-supported.

Response: This is true and we hope that some of the added content makes that clear.

 

Ensure consistent use of:

• IFN-α vs IFNα
• mtDNA vs mt DNA
• IL-1β formatting

Mechanisms like S358 STING mutation, PYHIN loss, and constitutive IFN-α are presented as broadly representative of bats.

Response: A complete loss of the PYHIN gene family does appear to be a characteristic of the Order Chiroptera. Mutations affecting STING mutations are also common among bats. Of course with approximately 1500 species of bats it is difficult to say that something is common to the group as a whole, so we will try to qualify he language some.

 

Claims implying causation (e.g., RNASEH2C, senescent cell clearance) are not fully supported in humans.

• Improved compared to earlier sections, but still:
• The leap from evolutionary adaptations → dietary modulation remains somewhat optimistic.
• Needs clearer acknowledgment of magnitude differences (genetic vs. nutritional effects).

 Claims like “suppress cytosolic DNA sensing and STING signaling” or “consistently integrate with all six CLSV-6 mechanisms” are too strong.

Response: We find to be the evidence for most of this to be quite compelling, but you are correct that it does not reach the level to support a statement that suggests it is fully established. Therefore, we have softened the language.

 

Human evidence is often indirect or context-dependent.

Response: We agree it and revised it.

 

Phrases like “centenarians converge toward this configuration” and “CLSV-6 provides an operational blueprint” remain too strong.

Response: We have tried to soften the language, we felt like the statement of “converge toward” is quite qualified. It suggests a direction toward which humans may be more “bat-like”.

 

Damage vs. inflammation,” “immune quality vs. intensity,” and “six mechanisms” are repeated multiple times.

Response: Since these are core concepts of this manuscript, they deserve to be repeated, but perhaps it was excessive so we have addressed this.

 

Dose–Response and Adherence

• Well addressed.
• Could be strengthened by:
• Mentioning long-term compliance issues in dietary trials
• Acknowledging confounding lifestyle factors

Response: We have added this to the conclusions.

 

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The Authors carefully addressed all comments. 

The Review is improved.  It can be published. 

Reviewer 2 Report

Comments and Suggestions for Authors

ِaccept in the present form