From Athletic Performance to Functional Ageing: Shared Genetic Architecture, Redox-Inflammatory Pathways and Functional Reserve Across the Life Course—A Narrative Review

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Major Revisions Required
1-While the authors discuss epigenetic memory of exercise (Section 5.7), there is a notable gap regarding epigenetic clocks (e.g., GrimAge, PhenoAge) and their relationship to physical performance and GMDs. Given the growing literature linking DNA methylation-based age acceleration to frailty, sarcopenia, and physical function, this omission is significant. The authors briefly mention GrimAge (reference 118) but do not integrate this into their framework or discuss how exercise may reverse epigenetic age.
2-Section 7 discusses favourable and antagonistic pleiotropy but remains somewhat superficial. The concept of antagonistic pleiotropy is particularly relevant to this framework and deserves more detailed treatment. The authors mention mTOR as a conceptual example but do not explore other potential trade-offs (e.g., inflammation, IGF-1 signalling, or telomere dynamics).
3-The manuscript does not adequately address potential sex differences in the genetic architecture of performance and GMDs. Given that sarcopenia and frailty prevalence differ between men and women, and that genetic associations often show sex-specific effects, this is a significant oversight.
4-While the authors mention the exposome (reference 53), the discussion remains somewhat abstract. The manuscript would benefit from more concrete examples of how environmental factors (e.g., occupational physical activity, socioeconomic status, air pollution, built environment) interact with genetic predisposition to influence functional trajectories.
5-As a narrative review, the manuscript lacks a systematic approach to evidence synthesis. The authors acknowledge this limitation (Section 10), but the lack of formal criteria for study selection, quality assessment, or evidence grading makes it difficult to assess the strength of the conclusions.
6-    The abbreviation GMDs (geriatric motor dysfunctions) is introduced but not consistently used throughout the manuscript. Consider defining it early and using it consistently.
7-    The term "dynamenia" (page 4, line 108) is uncommon. Consider defining it or using more widely recognised terminology.
8-    Figure 1 (Life-course model) is well conceptualised but could benefit from additional detail, such as indicating where genetic, environmental, and lifestyle factors exert their influence along the trajectory.
9-    Figure 3 is comprehensive but dense. Consider splitting into two figures (e.g., one for molecular pathways and one for systemic/organ-level pathways) to improve readability.
10-    A small number of references appear to be outdated or superseded by more recent meta-analyses. For example, the ACTN3 meta-analysis by Tharabenjasin et al. (2019) could be supplemented with more recent findings.
11-    Consider including more references from the last two years (2024-2026) to demonstrate currency, particularly in the rapidly evolving fields of GWAS and gut microbiome research.

Author Response

Reviewer 1 — Major Revisions

Comment R1.1 — Epigenetic clocks

"While the authors discuss epigenetic memory of exercise (Section 5.7), there is a notable gap regarding epigenetic clocks (e.g., GrimAge, PhenoAge) and their relationship to physical performance and GMDs. Given the growing literature linking DNA methylation-based age acceleration to frailty, sarcopenia, and physical function, this omission is significant. The authors briefly mention GrimAge (reference 118) but do not integrate this into their framework or discuss how exercise may reverse epigenetic age."

Response. We agree that epigenetic clocks provide an important link between molecular ageing and functional outcomes. Section 5.7 has therefore been substantially expanded beyond exercise-induced epigenetic memory. The revised text describes the progression from first-generation chronological-age estimators, including the Hannum and Horvath clocks, to second-generation healthspan-oriented measures such as PhenoAge and GrimAge and third-generation pace-of-ageing biomarkers such as DunedinPACE. We then synthesise evidence relating epigenetic-age acceleration to frailty trajectories, grip strength, gait speed and overall physical performance in older adults. Studies examining physical activity and structured exercise interventions are also discussed, while emphasising that effect sizes depend on the population, intervention and specific clock analysed. Finally, the section considers the potential translational use of simplified and tissue-accessible methylation models, while acknowledging that their ability to monitor functional reserve requires further validation. Figure 5 incorporates epigenomic regulation into the integrated life-course framework.

Location. Section 5.7, paragraphs beginning “Recent developments in biological age estimation…” and ending with “Taken together, these data support a view in which epigenetic clocks…”, and Figure 5.

 

Comment R1.2 — Antagonistic pleiotropy

"Section 7 discusses favourable and antagonistic pleiotropy but remains somewhat superficial. The concept of antagonistic pleiotropy is particularly relevant to this framework and deserves more detailed treatment. The authors mention mTOR as a conceptual example but do not explore other potential trade-offs (e.g., inflammation, IGF-1 signalling, or telomere dynamics)."

Response. Section 7 has been expanded to provide a more detailed and balanced treatment of antagonistic pleiotropy. Four complementary examples are now discussed: the IGF-1/insulin/mTOR axis, in which growth-promoting signalling may have different consequences when chronically activated in later life; telomere biology, which illustrates the balance between regenerative capacity and proliferative risk; redox-inflammatory signalling as a hormetic trade-off between acute adaptation and chronic dysregulation; and mTORC1 as an intracellular integrator of growth, autophagy and cellular ageing. We also explicitly acknowledge that direct human evidence linking individual performance-associated variants to increased late-life GMD risk remains limited.

Location. Section 7, paragraphs beginning “Antagonistic pleiotropy, Williams’ evolutionary principle…” and ending with “Direct human evidence that specific performance-enhancing variants…”.

 

Comment R1.3 — Sex differences

"The manuscript does not adequately address potential sex differences in the genetic architecture of performance and GMDs. Given that sarcopenia and frailty prevalence differ between men and women, and that genetic associations often show sex-specific effects, this is a significant oversight."

Response. A dedicated paragraph has been added at the end of Section 4 to address sex as a modifier of skeletal-muscle biology, athletic performance and GMD epidemiology. The revised text discusses sex differences in absolute muscle mass and strength, muscle metabolism, fibre characteristics and the prevalence of sarcopenia and frailty, while noting that estimates depend strongly on the diagnostic definition and sex-specific thresholds. It also incorporates sex-stratified GWAS and polygenic-score findings and discusses the influence of sex hormones and the menopausal transition on muscle-protein turnover, satellite-cell activity and neuromuscular function. The section concludes by highlighting the need for more sex-stratified genomic and intervention studies.

Location. Section 4, final paragraph beginning “Furthermore, there are also sex differences in relation to the development of GMDs…”.

 

Comment R1.4 — Exposome with concrete examples

"While the authors mention the exposome (reference 53), the discussion remains somewhat abstract. The manuscript would benefit from more concrete examples of how environmental factors (e.g., occupational physical activity, socioeconomic status, air pollution, built environment) interact with genetic predisposition to influence functional trajectories."

Response. Section 7 now provides concrete examples of how life-course exposures may modify functional trajectories. The revised discussion includes the physical-activity paradox associated with prolonged occupational activity and limited recovery; socioeconomic influences on access to nutrition, safe exercise environments and healthcare; ambient and indoor air pollution; characteristics of the built environment; and the potential contributions of sleep, psychosocial stress and circadian disruption. These examples are integrated with evidence on gene–environment interaction and are presented as cumulative and interacting influences rather than isolated determinants. The review by Pandics and colleagues is used to frame the broader relationship between environmental exposures and unhealthy ageing.

Location. Section 7, paragraph beginning “The exposome, defined as the totality of environmental exposures across the life course…”.

 

Comment R1.5 — Lack of systematic approach

"As a narrative review, the manuscript lacks a systematic approach to evidence synthesis. The authors acknowledge this limitation (Section 10), but the lack of formal criteria for study selection, quality assessment, or evidence grading makes it difficult to assess the strength of the conclusions."

Response. We have added a dedicated methodological paragraph explaining why a narrative review was selected. The revised text clarifies that the objective was conceptual and mechanistic integration rather than quantitative estimation, that the relevant fields use highly heterogeneous terminology and study designs, and that the principal constructs are theoretical and life-course oriented. We also describe the measures used to mitigate the limitations of narrative synthesis, including structured conceptual search blocks, explicit prioritisation criteria, appraisal of methodological robustness and transparent acknowledgment that no formal risk-of-bias assessment or evidence-grading system was applied.

Location. Section 2, new paragraph "A narrative review methodology was deliberately chosen…".

 

Comment R1.6 — Consistent use of GMDs

"The abbreviation GMDs (geriatric motor dysfunctions) is introduced but not consistently used throughout the manuscript. Consider defining it early and using it consistently."

Response. The abbreviation GMDs is now defined at first use in the Introduction and is used consistently when referring collectively to the relevant phenotypes. The revised definition clarifies that GMDs is a heuristic umbrella concept proposed in this review for sarcopenia, dynapenia, lower-limb weakness and the motor component of physical frailty, rather than an established diagnostic category. The individual diagnostic terms are retained when a cited study concerns a specific phenotype.

Location. Introduction, paragraph beginning “The concept of functional reserve…”, immediately before Figure 1.

 

Comment R1.7 — "Dynamenia" terminology

"The term 'dynamenia' (page 4, line 108) is uncommon. Consider defining it or using more widely recognised terminology."

Response. We confirm that the intended term was “dynapenia”, rather than “dynamenia”. To ensure clarity for readers outside geriatric muscle research, dynapenia is now defined at first use as the age-related loss of muscle strength that occurs independently of the loss of muscle mass and is presented as a distinct functional phenotype within the broader GMD framework.

Location. Section 2, first paragraph, within the conceptual block describing age-related functional-decline phenotypes.

 

Comment R1.8 — Figure 1 detail

"Figure 1 (Life-course model) is well conceptualised but could benefit from additional detail, such as indicating where genetic, environmental, and lifestyle factors exert their influence along the trajectory."

Response. Figure 1 has been redesigned to indicate how the relative influence of different determinants may change across the life course. The revised figure shows that genetic architecture contributes substantially to peak-capacity potential; physical activity, exercise and nutrition influence peak development and maintenance; and accumulated environmental exposures and comorbidities increasingly affect the rate of decline in later life. The lower panel distinguishes factors predominantly influencing peak-capacity attainment from those increasingly affecting functional decline, while the revised legend clarifies that these effects overlap and interact throughout the life course.

Location. Figure 1 and its revised legend in the Introduction.

 

Comment R1.9 — Figure 3 splitting

"Figure 3 is comprehensive but dense. Consider splitting into two figures (e.g., one for molecular pathways and one for systemic/organ-level pathways) to improve readability."

Response. The previous dense pathway figure has been divided into two complementary figures to improve readability. Figure 3 summarises molecular and cellular pathways, including mitochondrial function and redox homeostasis, anabolic–catabolic balance, inflammageing and immunometabolism, satellite-cell function, mechanotransduction and epigenetic memory. Figure 4 presents systemic and organ-level interfaces, including neuromuscular integrity, myokine/exerkine-mediated muscle–organ communication and the gut–muscle axis. Both figures use the same five-column structure to facilitate direct comparison between athletic-performance functions, GMD-related alterations and their integrative interpretation.

Location. Figures 3 and 4, presented in Section 5.7 immediately after the overview of the biological pathways.

 

Comment R1.10 — ACTN3 updated meta-analyses

"A small number of references appear to be outdated or superseded by more recent meta-analyses. For example, the ACTN3 meta-analysis by Tharabenjasin et al. (2019) could be supplemented with more recent findings."

Response. The ACTN3 discussion has been updated with three recent systematic reviews and meta-analyses. The revised paragraph now complements the earlier evidence with Chelly et al. on ACTN3 R577X and athlete status, Silvino et al. on the distribution of ACTN3 genotypes in Brazilian populations, and Ferreira et al. on multiple candidate polymorphisms and sporting performance. The text emphasises that ACTN3 may have a modest population-level association with power-oriented athlete status but is insufficient for individual talent identification and must be interpreted within a polygenic framework.

Location. Section 4, opening paragraph on ACE and ACTN3

 

Comment R1.11 — More 2024–2026 references

"Consider including more references from the last two years (2024-2026) to demonstrate currency, particularly in the rapidly evolving fields of GWAS and gut microbiome research."

Response. The literature has been updated throughout the manuscript, with particular attention to studies published between 2023 and 2026. Recent evidence has been incorporated in relation to GWAS and polygenic scores, sarcopenia-related traits, sex-stratified genetic analyses, mitochondrial quality control, anabolic resistance, IL-6 signalling, mechanotransduction, myokines and muscle–brain communication, epigenetic ageing, the gut–muscle axis, antagonistic pleiotropy and environmental exposures. Foundational studies have been retained where they provide the original conceptual or mechanistic basis.

Location. Sections 4–7 and the revised References section.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for submitting your manuscript to Biomedicines. After careful consideration, we feel that it has merit but does not fully meet Biomedicines publication criteria as it currently stands. The shortcomings of this paper needs to be worked out before it can be considered for publication. Therefore, we invite you to resubmit a revised version of the manuscript that addresses the points raised during the review process.

 

The manuscript titled “From Athletic Performance to Functional Ageing: Shared Genetic Architecture, Redox-Inflammatory Pathways and Functional Reserve across the Life Course—A Narrative Review” demonstrated how the relationship between athletic performance and age-related changes can be understood as a continuum of muscle function throughout the life course. The variants and pathways that influence strength, power, endurance or trainability do not disappear with age: they are expressed in a different physiological context, characterized by reduced reserve capacity, comorbidity, inflammageing, neuromuscular changes, deterioration of satellite cells and cumulative exposure to physical activity or inactivity.

 

The topic is relevant; the explanations is not comprehensive. There are several areas in the manuscript that require substantial revisions before the manuscript can be considered for publication.

1. The rationale for conducting this narrative review would be strengthened by explicitly identifying unresolved questions in the literature and explaining how the present review addresses these gaps.
2. The review aims to cover functional reserve, pleiotropy, polygenic influences, and life-course trajectories. Given the breadth of these topics, the authors should clearly define the boundaries of the review and explain how these concepts are interconnected.
3. The proposed framework suggesting that athletic performance and geriatric motor dysfunction represent different manifestations of common biological systems is intriguing but currently speculative. The introduction should provide preliminary evidence supporting this hypothesis.
4. The authors should clearly justify why a narrative review methodology was chosen instead of a systematic or scoping review.
5. The authors should provide a schematic figure illustrating the proposed biological pathways, shared genetic architecture, and functional reserve trajectory across the lifespan which would strengthen the manuscript.
6. The authors should provide a clear operational definition of “functional reserve” and discuss how it can be measured clinically and experimentally.
7. The authors must discuss the emerging role of polygenic risk scores (PRS) and their potential utility and limitations in predicting functional decline, frailty, or physical performance trajectories.
8. The authors should explicitly discuss limitations regarding causality and potential confounding factors. The authors should discuss limitations in ethnic diversity and implications for generalizability.
9. Multiple mechanisms are discussed but their interrelationships are not fully integrated. The authors should provide a comprehensive mechanistic model linking these pathways would improve coherence.
10. The HERITAGE study is mentioned, but the section would benefit from additional evidence linking genetic determinants of exercise performance (e.g., genes involved in mitochondrial function, muscle structure, inflammation, or neuromuscular signaling) with frailty, sarcopenia, or mobility decline.
11. The authors should consider explicitly discussing how genetic variants associated with exercise responsiveness, muscle quality, neuromuscular function, and recovery may contribute to resilience against GMDs across the life course.
12. The authors must provide a schematic or conceptual model illustrating the progression from candidate genes to polygenic and systems-biology approaches could improve readability.
13. The section “Key biological pathways: The mechanisms behind the overlap” would benefit from greater conciseness, stronger integration across pathways, clearer distinction between established and emerging evidence, and enhanced focus on translational and clinical implications. These revisions would improve readability while preserving its substantial scientific value.
14. Inadequate and obsolete literature survey. It discusses findings in relation to some of the work in the field but ignores other important work. References: Check the currentness of your references, especially focusing on recent advances that might complement your discussion. Ensure that all references are current and relevant. It might also be beneficial to include more recent studies that have explored to contextualize your findings within the broader research landscape.
15. There are several grammatical errors and awkward phrasings throughout the manuscript. I suggest a thorough revision of the manuscript for language issues, perhaps with the help of a professional editor.

Comments on the Quality of English Language

1. There are several grammatical errors and awkward phrasings throughout the manuscript. I suggest a thorough revision of the manuscript for language issues, perhaps with the help of a professional editor.

Author Response

Reviewer 2 — Major Revisions

Comment R2.1 — Rationale and unresolved questions

"The rationale for conducting this narrative review would be strengthened by explicitly identifying unresolved questions in the literature and explaining how the present review addresses these gaps."

Response. The Introduction now contains a dedicated paragraph identifying the principal unresolved questions that motivate the review. These include the poorly quantified overlap between the genetic architectures of athletic performance and late-life motor decline, the separation between the exercise-adaptation and sarcopenia/frailty literatures, the incomplete treatment of favourable and antagonistic pleiotropy, and the absence of a coherent life-course framework despite emerging genetic, Mendelian-randomisation and epidemiological evidence. The paragraph explains how the present review addresses these gaps through an integrated genetic, mechanistic and functional-reserve model.

Location. Introduction, paragraph beginning “There are therefore several unresolved issues that require a more integrated approach…”.

 

Comment R2.2 — Scope and interconnection

"The review aims to cover functional reserve, pleiotropy, polygenic influences, and life-course trajectories. Given the breadth of these topics, the authors should clearly define the boundaries of the review and explain how these concepts are interconnected."

Response. The final part of the Introduction now explicitly defines the boundaries of the review and explains how its four core concepts are interconnected. Functional reserve is presented as the phenotypic outcome, pleiotropy as the evolutionary and mechanistic hypothesis, polygenic architecture as the biological substrate, and life-course trajectories as the temporal axis. The scope is restricted to skeletal-muscle-centred motor function and its genetic and environmental modulators, while neurodegenerative, cognitive and exclusively cardiovascular conditions are considered only where they directly intersect with musculoskeletal function.

Location. Final paragraph of the Introduction, beginning “The scope of this review is deliberately restricted…”.

 

Comment R2.3 — Preliminary evidence for the framework

"The proposed framework suggesting that athletic performance and geriatric motor dysfunction represent different manifestations of common biological systems is intriguing but currently speculative. The introduction should provide preliminary evidence supporting this hypothesis."

Response. The Introduction now presents several lines of preliminary evidence supporting the proposed shared-architecture framework. These include Mendelian-randomisation evidence linking grip strength to fracture risk, evidence connecting muscle weakness causally with frailty, longitudinal associations between early-life physical capacity and later health outcomes, and epidemiological observations of lower mortality or greater longevity in selected elite athletic populations. These findings are explicitly framed as supportive but not definitive evidence, thereby providing a rationale for the integrative hypothesis without overstating causality.

Location. Introduction, unresolved-questions paragraph and preceding paragraph on longitudinal and athletic-population evidence.

 

Comment R2.4 — Justification of narrative methodology

"The authors should clearly justify why a narrative review methodology was chosen instead of a systematic or scoping review."

Response. The rationale for selecting a narrative methodology is now explicitly stated in Section 2. The revised paragraph explains that the review seeks to integrate heterogeneous genetic, physiological, geriatric, epigenetic and microbiome evidence into a conceptual framework rather than estimate a single pooled effect. It further explains why a systematic or scoping design would not fully capture the theoretical relationships among functional reserve, pleiotropy and life-course trajectories. The methodological limitations of the narrative approach and the strategies adopted to mitigate them are also described.

Location. Section 2, paragraph beginning “A narrative review methodology was deliberately chosen…”.

 

Comment R2.5 — Schematic figure of the framework

"The authors should provide a schematic figure illustrating the proposed biological pathways, shared genetic architecture, and functional reserve trajectory across the lifespan which would strengthen the manuscript."

Response. To provide a unified representation of the proposed framework, we have added a new integrative schematic that connects genetic architecture and polygenic predisposition with epigenetic regulation, converging molecular and systemic pathways, environmental modifiers and the trajectory from athletic performance to functional reserve and GMDs. The figure also distinguishes fixed genetic influences from modifiable inputs, including exercise, nutrition, microbiota and comorbidity management, and positions these factors along the life course.

Location. Figure 5, inserted after the epigenetic-clocks discussion in Section 5.7.

 

Comment R2.6 — Operational definition of functional reserve

"The authors should provide a clear operational definition of 'functional reserve' and discuss how it can be measured clinically and experimentally."

Response. Section 3 now provides an operational definition of functional reserve and describes three complementary strategies for its measurement. Cross-sectional reserve can be estimated by comparing current function with age- and sex-specific normative values; longitudinal reserve can be evaluated through repeated measurements of strength, gait speed or SPPB and the resulting rate of decline; and resilience-based reserve can be assessed through recovery following a standardised stressor such as illness, surgery or an exercise intervention. Intrinsic-capacity measures, resilience scores and DNA-methylation biomarkers are presented as complementary experimental proxies.

Location. Section 3, paragraph beginning “Conceptually, functional reserve corresponds to the difference…”.

 

Comment R2.7 — Emerging role of PRS

"The authors must discuss the emerging role of polygenic risk scores (PRS) and their potential utility and limitations in predicting functional decline, frailty, or physical performance trajectories."

Response. The PRS discussion in Section 4 has been expanded to address both potential applications and current limitations. The revised text considers the use of PRSs to identify individuals with genetically lower muscle strength or potentially less favourable functional trajectories and discusses their possible role in cohort stratification and clinical-trial enrichment. It also identifies four major limitations: poor transferability across ancestries, modest predictive gain over direct functional tests, limited representation of gene–environment interactions and the risk of deterministic communication. The manuscript therefore frames muscular PRSs primarily as research tools rather than as replacements for clinical functional assessment.

Location. Section 4, expanded paragraph beginning “Polygenic risk scores (PRS) have emerged…”.

 

Comment R2.8 — Causality, confounding and ethnic diversity

"The authors should explicitly discuss limitations regarding causality and potential confounding factors. The authors should discuss limitations in ethnic diversity and implications for generalizability."

Response. Limitations relating to causality, confounding and population transferability are now discussed at several levels. The PRS subsection notes that most discovery cohorts remain predominantly European and that current scores do not adequately capture gene–environment interactions. Section 10 further explains that shared pathways or genetic correlations do not establish that a performance-associated variant protects directly against a GMD and identifies athletic selection, behaviour, cumulative training and environmental exposure as potential confounders. The need for diverse populations, sex-stratified analyses, longitudinal cohorts, Mendelian randomisation and intervention studies is explicitly highlighted.

Location. Section 4, PRS limitations paragraph; Section 10, paragraphs on population transferability and causality.

 

Comment R2.9 — Comprehensive mechanistic model

"Multiple mechanisms are discussed but their interrelationships are not fully integrated. The authors should provide a comprehensive mechanistic model linking these pathways would improve coherence."

Response. The opening of Section 5 has been revised to clarify that the individual mechanisms operate as interacting networks rather than independent pathways. The text now distinguishes relatively established mechanisms from emerging areas and explains how mitochondrial energetics, proteostasis, immune regulation, neuromuscular integrity, mechanotransduction, endocrine communication and epigenetic regulation converge on functional reserve. Figures 3 and 4 organise these mechanisms into molecular/cellular and systemic/organ-level domains, while Figure 5 integrates them with genetic architecture, epigenomic regulation, the exposome and functional outcomes.

Location. Opening paragraphs of Section 5; Figures 3–5.

 

Comment R2.10 — HERITAGE plus additional genetic evidence

"The HERITAGE study is mentioned, but the section would benefit from additional evidence linking genetic determinants of exercise performance (e.g., genes involved in mitochondrial function, muscle structure, inflammation, or neuromuscular signaling) with frailty, sarcopenia, or mobility decline."

Response. The genetic discussion now extends well beyond the HERITAGE study. Section 4 integrates large GWAS of grip strength, muscle weakness and appendicular lean mass, together with Mendelian-randomisation evidence linking strength with fracture risk and weakness with frailty. These studies identify loci involved in sarcomeric organisation, neurological signalling, body composition, mitochondrial biology and immune regulation. Section 5 subsequently maps representative candidate genes and GWAS-identified loci onto molecular, cellular and systemic networks, while Figure 5 situates these findings within the integrated life-course model.

Location. Section 4, GWAS paragraphs; opening of Section 5; Figures 3–5.

 

Comment R2.11 — Genetic variants and resilience against GMDs

"The authors should consider explicitly discussing how genetic variants associated with exercise responsiveness, muscle quality, neuromuscular function, and recovery may contribute to resilience against GMDs across the life course."

Response. The revised manuscript explicitly relates genetic determinants of exercise responsiveness, muscle quality, neuromuscular function and recovery to the maintenance of functional reserve. Section 4 explains how variants influencing hypertrophy, oxidative efficiency, body composition and trainability may alter the capacity to withstand age-related decline, while emphasising that such effects are polygenic and environmentally modulated. Section 5 maps these influences onto mitochondrial, anabolic, neuromuscular, regenerative and mechanotransduction pathways, and Section 7 interprets them through favourable and antagonistic pleiotropy.

Location. Section 4, candidate-gene, GWAS and PRS discussion; Section 5; Section 7; Figure 5.

 

Comment R2.12 — Schematic from candidate genes to systems biology

"The authors must provide a schematic or conceptual model illustrating the progression from candidate genes to polygenic and systems-biology approaches could improve readability."

Response. We have added an integrative schematic illustrating the progression from early candidate-gene research through GWAS and polygenic-risk approaches to epigenetic regulation, interconnected biological pathways and life-course functional outcomes. The model places ACTN3, ACE and PPARGC1A within a broader polygenic and systems-biology framework and shows how fixed genetic architecture interacts with the exposome and modifiable interventions to influence functional reserve and GMD risk.

Location. New Figure 5.

 

Comment R2.13 — Section 5 conciseness and integration

"The section 'Key biological pathways: The mechanisms behind the overlap' would benefit from greater conciseness, stronger integration across pathways, clearer distinction between established and emerging evidence, and enhanced focus on translational and clinical implications."

Response. Section 5 has been reorganised to strengthen integration and distinguish the maturity of the available evidence. The revised opening identifies relatively established mechanisms, including mitochondrial biogenesis, anabolic signalling, proteostasis, chronic inflammation and satellite-cell dysfunction, and separates them from emerging areas such as mitochondria-derived peptides, m⁶A regulation, PIEZO1 signalling, redox-sensitive senescence, microbial metabolites and DNA-methylation biomarkers.

Location. Section 5, second opening paragraph beginning.

 

Comment R2.14 — Recent literature currency

"Inadequate and obsolete literature survey. It discusses findings in relation to some of the work in the field but ignores other important work. References: Check the currentness of your references, especially focusing on recent advances that might complement your discussion."

Response. The revised manuscript incorporates recent evidence in the areas most likely to have changed since the original literature search, including contemporary ACTN3 meta-analyses, mitochondrial dynamics and mitophagy, age-related anabolic responses, causal IL-6 research, mechanosensitive PIEZO channels, myokine and muscle–brain communication, skeletal-muscle epigenetic memory and emerging gut–muscle-axis research. Foundational studies have been retained where they provide the original conceptual or mechanistic basis.

Location. Sections 4–7 and the revised References section.

 

Comment R2.15 — English language

"There are several grammatical errors and awkward phrasings throughout the manuscript. I suggest a thorough revision of the manuscript for language issues, perhaps with the help of a professional editor."

Response. To ensure that the work has been correctly translated and understood, we have decided to have the article reviewed by the publisher via their language review service.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

This is a highly valuable, well-structured manuscript that addresses an innovative topic backed by a solid biological foundation and fluid prose.

However, it requires some conceptual and formal refinements to reach an impeccable standard for publication:

The concepts of oxidative stress, chronic inflammation (inflammaging), and redox pathways are repeated almost identically across multiple sections: Mitochondrial Function (5.1), Inflammaging (5.3), Myokines (5.6), and finally in the Conclusions.

Streamline these repetitions. For example, in the myokines section (5.6), focus strictly on the endocrine/paracrine aspects and refer the reader back to sections 5.1 or 5.3 for the detailed molecular loop of the redox-inflammatory axis.

When discussing functional decline, the text occasionally groups endurance performance and power/strength performance into a single biological category. However, aging affects Type II fibers (power) asymmetric compared to Type I fibers (endurance).

Clarify further in Sections 3 or 4 that while the genetic architecture of strength overlaps more heavily with the prevention of sarcopenia and falls (Type II fibers), the metabolic-mitochondrial pathways of endurance primarily mediate cardiorespiratory resilience and overall longevity.

The acronym GMDs (Geriatric Motor Dysfunctions) is introduced as an umbrella term for sarcopenia, frailty, and lower-limb weakness. While it is an excellent conceptual synthesis, it is not clear whether this is an established term validated in existing literature or a novel proposal introduced ex novo by the authors in this paper.

If this is a term proposed by the authors, it should be explicitly stated in the introduction (e.g., "Here, we propose the term..."). If it is an established term, please provide the original reference.

There is a noticeable technical error regarding the bibliography: the text cites references up to [139] (e.g., lines 853-855 in the nutrition section), but the References list at the end of the document abruptly stops at reference 86.

Verify and complete the bibliographic list, ensuring that all 139 citations are present, accurate, and correctly formatted.

 

Author Response

Reviewer 3 — Minor Revisions

Comment R3.1 — Repetition of redox/inflammageing concepts

"The concepts of oxidative stress, chronic inflammation (inflammaging), and redox pathways are repeated almost identically across multiple sections: Mitochondrial Function (5.1), Inflammaging (5.3), Myokines (5.6), and finally in the Conclusions. Streamline these repetitions. For example, in the myokines section (5.6), focus strictly on the endocrine/paracrine aspects and refer the reader back to sections 5.1 or 5.3 for the detailed molecular loop of the redox-inflammatory axis."

Response. The Conclusions have been revised to avoid repeating the full ROS–NF-κB–NLRP3–SASP cascade and now refer readers to Sections 5.1 and 5.3 for the molecular details of the redox-inflammatory axis. Section 5.6 retains only the aspects required to explain how muscle-derived endocrine and paracrine signals influence systemic redox homeostasis and inter-organ communication. An explicit cross-reference has also been added to distinguish this systemic perspective from the detailed molecular mechanisms presented earlier.

Location. End of Section 5.6; second paragraph of Section 11, Conclusions.

 

Comment R3.2 — Fibre-type asymmetry (Type I vs Type II)

"When discussing functional decline, the text occasionally groups endurance performance and power/strength performance into a single biological category. However, aging affects Type II fibers (power) asymmetric compared to Type I fibers (endurance). Clarify further in Sections 3 or 4 that while the genetic architecture of strength overlaps more heavily with the prevention of sarcopenia and falls (Type II fibers), the metabolic-mitochondrial pathways of endurance primarily mediate cardiorespiratory resilience and overall longevity."

Response. Section 3 now explicitly distinguishes the biological translation of endurance from that of strength and power. The new paragraph explains the preferential age-related atrophy and denervation of Type II fibres and relates strength/power biology to sarcopenia, mobility limitation, fall risk, sarcomeric integrity, motor-unit remodelling and mechanotransduction. In contrast, Type I fibre and mitochondrial–oxidative biology are linked more closely to cardiorespiratory resilience, endurance and systemic metabolic health. The corresponding implications for resistance/power and endurance training are also stated.

Location. Section 3, paragraph beginning “Importantly, endurance performance and strength/power performance should not be treated as biologically equivalent…”.

 

Comment R3.3 — GMDs as novel or established term

"The acronym GMDs (Geriatric Motor Dysfunctions) is introduced as an umbrella term for sarcopenia, frailty, and lower-limb weakness. While it is an excellent conceptual synthesis, it is not clear whether this is an established term validated in existing literature or a novel proposal introduced ex novo by the authors in this paper. If this is a term proposed by the authors, it should be explicitly stated in the introduction (e.g., 'Here, we propose the term...'). If it is an established term, please provide the original reference."

Response. We confirm that GMDs is a novel umbrella term introduced by the authors for the purposes of this review and is not presented as an established diagnostic category. The Introduction now states explicitly that sarcopenia, dynapenia, lower-limb weakness and the motor component of frailty are grouped under this term as a conceptual synthesis. It also notes that, to our knowledge, no existing consensus term encompasses these overlapping motor phenotypes.

Location. Introduction, paragraph introducing functional reserve and GMDs immediately before Figure 1.

 

Comment R3.4 — Reference list ending at [86]

"There is a noticeable technical error regarding the bibliography: the text cites references up to [139] (e.g., lines 853-855 in the nutrition section), but the References list at the end of the document abruptly stops at reference 86. Verify and complete the bibliographic list, ensuring that all 139 citations are present, accurate, and correctly formatted."

Response. We appreciate the Reviewer’s careful observation. The complete reference list has been reconstructed and cross-checked against the in-text citations in the revised manuscript. The references now run consecutively from [1] to [176] and include the sources introduced in the expanded discussions of PRSs, sex differences, epigenetic clocks, the gut–muscle axis, antagonistic pleiotropy and the exposome. A final automated and manual check will be performed following the last Zotero refresh to verify that there are no missing entries, duplicated references, uncited bibliography items or in-text citations without a corresponding reference.

Location. Complete References section, references 1–176.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The authors have adequately addressed the comments and revised the manuscript accordingly. The responses are satisfactory and acceptable.