Exercise, Cellular Senescence, and Cancer: Novel Perspectives on Functional Aging Through Block Strength Training in Older Adults—A Narrative Review

Round 1

Reviewer 1 Report (Previous Reviewer 3)

Comments and Suggestions for Authors

The authors have carefully revised the manuscript in response to the comments raised during the previous round of peer review. After examining the revised version and the authors’ responses, I find that the manuscript has been substantially improved. The authors have adequately addressed the concerns raised by the reviewers, and the revisions have enhanced the overall clarity, structure, and scientific rigor of the study.The revised manuscript demonstrates clear improvements compared with the previous version. The authors have clarified several aspects of the methodology, strengthened the discussion, and improved the presentation of the study. The responses provided in the point-by-point reply are appropriate and satisfactorily address the reviewers’ comments.Overall, the manuscript now presents the research in a clearer and more coherent manner, and the revisions have improved both readability and scientific quality.In my opinion, the manuscript has been sufficiently improved and now meets the standards required for publication.I therefore recommend acceptance of the manuscript for publication in Biomedicines.

Author Response

We sincerely thank the reviewer for the thorough evaluation and positive feedback. We appreciate your recognition of the improvements made in response to the previous comments. Your insights have greatly contributed to strengthening the quality, clarity, and scientific rigor of the manuscript. We are pleased that the revised version meets the standards for publication and are grateful for your recommendation for acceptance.

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

Overall Evaluation
This manuscript addresses a timely and conceptually relevant topic by attempting to integrate cellular senescence, exercise physiology, and cancer biology within the context of aging, with a particular emphasis on BST. The narrative is well-structured and demonstrates strong conceptual ambition, especially in linking molecular mechanisms with functional outcomes. However, the manuscript is limited by a substantial imbalance between speculative interpretation and empirical evidence, particularly regarding BST-specific mechanisms and clinical relevance. The methodological transparency is insufficient for a narrative review making translational claims, and several sections overinterpret indirect evidence. Strengthening the evidentiary hierarchy, moderating speculative conclusions, and improving methodological clarity would significantly enhance the scientific rigor and credibility of the manuscript.

Major Comments

Abstract
• The abstract suggests a mechanistic and preventive role of BST in cancer without direct supporting evidence—can the authors more clearly distinguish hypothesis from established findings?
The abstract focuses excessively on general and well-established effects of exercise rather than the central topic such as cancer. Reading this version of the abstract does not provide sufficient insight into the main focus of the manuscript.
• The concluding statements imply translational applicability; would a more cautious wording better reflect the current level of evidence?
• The nature of the review (narrative vs. systematic) is not explicitly stated—should this be clarified for transparency?

Introduction
• The transition from general exercise benefits to the specific focus on BST is abrupt—what is the clear scientific rationale for prioritizing BST over other resistance training models?
It should be kept in mind that the main focus of the manuscript is BST, not exercise in general or resistance training broadly.
• The manuscript claims novelty in linking BST with senescence pathways—how does this differ from existing literature on resistance training and aging biology?

Methods
• The literature search is described as “focused” but lacks reproducible detail—what were the exact search strings, Boolean operators, and date of last search?
• Study selection is based on “conceptual relevance”—how was this operationalized to minimize selection bias?
• There is no description of screening procedures or study inclusion flow—could a structured summary (e.g., table or flow diagram) improve transparency?
• No quality or risk-of-bias assessment is reported—how do the authors account for heterogeneity in study quality?
• The manuscript combines preclinical, observational, and interventional evidence—should these be stratified more explicitly in the methodology?

Narrative Synthesis
• The manuscript frequently interprets reductions in circulating biomarkers (e.g., p16INK4a, SASP factors) as reductions in senescent cell burden—how do the authors justify this inference given alternative explanations (e.g., immune cell redistribution)?
• The central role of BST is not supported by direct mechanistic or clinical evidence—should the authors explicitly state that conclusions are extrapolated from general resistance training literature?
• The manuscript emphasizes hormesis and adaptive stress models—how specifically does BST differ from other resistance training modalities in this context?
• The manuscript suggests potential oncology applications—are these claims premature without direct intervention studies in cancer populations?
There is limited discussion of practical limitations such as adherence, heterogeneity of response, or clinical contraindications—should these be incorporated?
Given the limited data available on the specific topic of the manuscript, a dedicated limitations section should be added at the end of the manuscript (before the conclusion).
• The argument for BST as a “precision” intervention is interesting but underdeveloped—can this concept be more rigorously defined?
In Section 7, which represents the final part of the manuscript and should provide a synthesis aligned with the main objective, there is no specific emphasis on BST, and the discussion shifts toward exercise as a general concept. This section should be revised to maintain a clear focus on BST rather than exercise in general.

Conclusion
• The conclusion implies that BST may influence cancer-related outcomes—should this be reframed as a hypothesis requiring validation?
• The strength of the conclusions appears to exceed the available evidence—can the authors better align conclusions with the limitations discussed?
• The need for future mechanistic and clinical trials is mentioned but could be more explicitly emphasized as the primary takeaway.

Minor Comments

Abstract
• The phrase “biologically informed intervention” is vague and could be defined more precisely.
• Some sentences are dense and could benefit from simplification for clarity.

Methods
• The time frame of the literature search is broad—clarify whether any updates were performed prior to submission.
• Language restrictions (if any) are not reported.

Narrative Synthesis
• Some claims regarding telomere biology could be expressed more cautiously.
• The distinction between “myokines” and “exerkines” could be clarified more succinctly.
• The discussion would benefit from a clearer synthesis rather than reiteration of earlier sections.

 

Author Response

Reviewer 2

This manuscript addresses a timely and conceptually relevant topic by attempting to integrate cellular senescence, exercise physiology, and cancer biology within the context of aging, with a particular emphasis on BST. The narrative is well-structured and demonstrates strong conceptual ambition, especially in linking molecular mechanisms with functional outcomes. However, the manuscript is limited by a substantial imbalance between speculative interpretation and empirical evidence, particularly regarding BST-specific mechanisms and clinical relevance. The methodological transparency is insufficient for a narrative review making translational claims, and several sections overinterpret indirect evidence. Strengthening the evidentiary hierarchy, moderating speculative conclusions, and improving methodological clarity would significantly enhance the scientific rigor and credibility of the manuscript.

Major Comments

Abstract

• The abstract suggests a mechanistic and preventive role of BST in cancer without direct supporting evidence—can the authors more clearly distinguish hypothesis from established findings?

Response: We appreciate this valuable comment. The final paragraph about BTS and suggested clinical and mechanistic evidences was changed and mentioned by an hypothesis.

“We hypothesized that the exercise in block as a targeted, biologically informed inter-vention highlights the potential of BST to promote functional aging and healthy. In the case of cancer biology, and the environment near to tumour, the relationship between aging mechanisms in older adults and controlled exercise effects are currently in ad-vance, but mechanistic trials are still lacking. Finally, we purpose a novel training method, structured and personalized, that could impact different clinical outcomes in older patients with cancer.”

Page 1, Lines 38-44

 

• The abstract focuses excessively on general and well-established effects of exercise rather than the central topic such as cancer. Reading this version of the abstract does not provide sufficient insight into the main focus of the manuscript.

Response: We appreciate this valuable comment. We added the focus of the review to the effect of exercise on cancer and its respective outcomes.

In the case of cancer biology, and the enviroment near to tumour, the relationship be-tween aging mechanisms in older adults and controlled exercise effects are currently in advance, but mechanistic trials are still lacking. Finally, we purpose a novel training method, structured and personalized, that could be impact in diferents clinical outcomes in older patients with cancer

Page 1, Lines 40-45.

• 
  The concluding statements imply translational applicability; would a more cautious wording better reflect the current level of evidence?

Response: We appreciate this valuable comment. We added a following paragraph that reflect a more cautious mention of mechanistic and translational studies.

Beyond its effects on physical function, a structured and personalized training could plausibly contribute to regulate some biological processes to aging. Moreover, mecha-nistic and clinical evidence of BST remains to be established.

Page1, Lines 36-39.

 

• The nature of the review (narrative vs. systematic) is not explicitly stated—should this be clarified for transparency?

Response:  We appreciate this valuable comment. In this revised version of MS, the titled was modified, and added a: ”Narrative Review”, in the final of paragraph.

“Exercise, Cellular Senescence, and Cancer: Novel Perspectives on Functional Aging through Block Strength Training in Older Adults —A narrative review.”

Introduction
• The transition from general exercise benefits to the specific focus on BST is abrupt—what is the clear scientific rationale for prioritizing BST over other resistance training models?

Response: We appreciate this valuable comment. We added other models of PA and their implications in quality of Life and frailty optimization.

Regarding the type of physical activity, strength training has been described as having a significant benefit in reducing frailty and sarcopenia events in cancer patients (Galvao, 2018). In terms of outcomes, the perception of quality of life has an impact on symptom improvement (Albini, 2025). Furthermore, structured physical activity that combines strength and aerobic exercise has beneficial effects on reducing frailty (Dieli-Conwright, 2018).

Galvão, D.A.; Taaffe, D.R.; Spry, N.; Cormie, P.; Joseph, D.; Chambers, S.K.; Chee, R.; Peddle-Mcintyre, C.J.; Hart, N.H.; Baumann, F.T.; et al. Exercise Preserves Physical Function in Prostate Cancer Patients with Bone Metastases. Med. Sci. Sports Exerc. 2017, 50, 393, doi:10.1249/MSS.0000000000001454.

Albini, A.; La Vecchia, C.; Magnoni, F.; Garrone, O.; Morelli, D.; Janssens, J.P.; Maskens, A.; Rennert, G.; Galimberti, V.; Corso, G. Physical Activity and Exercise Health Benefits: Cancer Prevention, Interception, and Survival. Eur. J. Cancer Prev. 2025, 34, 24–39, doi:10.1097/CEJ.0000000000000898.

Gell, N.M.; Bae, M.; Patel, K. V.; Schmitz, K.; Dittus, K.; Toth, M. Physical Function in Older Adults with and without a Cancer History: Findings from the National Health and Aging Trends Study. J. Am. Geriatr. Soc. 2023, 71, 3498–3507, doi:10.1111/JGS.18508.

Page 2, Lines, 96-101.

• 
  It should be kept in mind that the main focus of the manuscript is BST, not exercise in general or resistance training broadly.

Response: We appreciate this valuable comment. For this pupose we added the following paragraph.

This work attempts to substantiate the hypothesis of the likely beneficial effect of BST in cancer patients. However, the description of the effects of general physical activity or resistance training already demonstrates its role as a precursor to these strategies for optimizing physical capacity in cancer patients.

We added a following paragraph: “This work attempts to substantiate the hypothesis of the likely beneficial effect of "BTS" in cancer patients”.

Page 3, Lines, 113-114.

• 
  The manuscript claims novelty in linking BST with senescence pathways—how does this differ from existing literature on resistance training and aging biology?

Response: We appreciate this valuable comment. We changed this sentence for …

This work attempts to substantiate the hypothesis of the likely beneficial effect of "BTS" in cancer patients.

These novel associations between BTS and clinical effectiveness in training may provide the basis for future intervention protocols in older patients.

Page 3, Lines 115- 116. 

 

Methods
• The literature search is described as “focused” but lacks reproducible detail—what were the exact search strings, Boolean operators, and date of last search?

Response: We appreciate this comment. As clarified in the manuscript, this is a narrative review rather than a systematic review. The methodology was structured according to the SANRA (Scale for the Assessment of Narrative Review Articles) framework, which emphasizes conceptual integration and clarity over exhaustive reproducibility. While the search was intentionally focused to synthesize key biological mechanisms and translational insights, it did not follow a PRISMA-based protocol. However, we have now specified that the final literature search was completed on February 28, 2026, and used combinations of key terms such as “cellular senescence,” “resistance training,” “older adults,” and “cancer” across PubMed, Scopus, and Web of Science, as described in the revised Methods section.

• 
  Study selection is based on “conceptual relevance”—how was this operationalized to minimize selection bias?

Response: Thank you for this important observation. As this is a narrative review, the selection process prioritized studies that offered conceptual integration across the domains of exercise biology, cellular senescence, sarcopenia, and cancer risk in older adults.

• 
  There is no description of screening procedures or study inclusion flow—could a structured summary (e.g., table or flow diagram) improve transparency?

Response: Thank you for this observation. However, we would like to clarify that this is a narrative review, not a systematic review. Therefore, we did not apply formal screening procedures or study inclusion flow diagrams, as typically required in systematic methodologies. Instead, we followed the SANRA (Scale for the Assessment of Narrative Review Articles) guidelines, which emphasize conceptual integration, clarity, and evidence synthesis without requiring reproducibility criteria such as flowcharts. The focus was on integrating diverse lines of evidence under a theoretical framework, rather than exhaustively capturing all existing studies.

• 
  No quality or risk-of-bias assessment is reported—how do the authors account for heterogeneity in study quality?

Response: Thank you for your comment. As this is a narrative review rather than a systematic one, we did not conduct a formal risk-of-bias assessment. Instead, we adhered to the SANRA (Scale for the Assessment of Narrative Review Articles) criteria to guide the selection and interpretation of the literature. These criteria emphasize the use of high-quality sources, conceptual relevance, and scientific rigor appropriate for narrative synthesis.

• 
  The manuscript combines preclinical, observational, and interventional evidence—should these be stratified more explicitly in the methodology?

Response: We appreciate this insightful observation. Given that this work is a narrative review, our goal was to provide an integrative and conceptually driven synthesis of the literature rather than a stratified or hierarchical analysis. The inclusion of preclinical, observational, and interventional studies was intentional to reflect the multidimensional nature of the topic. We followed the SANRA (Scale for the Assessment of Narrative Review Articles) criteria to ensure clarity, relevance, and scientific coherence throughout the manuscript. While stratification is essential in systematic reviews, narrative reviews allow greater flexibility to build conceptual links across different levels of evidence.

Narrative Synthesis
• The manuscript frequently interprets reductions in circulating biomarkers (e.g., p16INK4a, SASP factors) as reductions in senescent cell burden—how do the authors justify this inference given alternative explanations (e.g., immune cell redistribution)?

Response: We appreciate the reviewer’s comment and agree that individual circulating biomarkers, such as IL-6 or p16^INK4a alone, cannot be interpreted as definitive indicators of senescent cell burden. Importantly, our interpretation is not based on single markers, but rather on the integrated behavior of a panel of senescence-associated biomarkers, including cell cycle regulators and SASP-related factors.

We acknowledge, however, that even when considered together, circulating biomarkers reflect systemic senescence-associated signaling rather than a direct quantification of senescent cell burden. These signals may be influenced by multiple mechanisms, including immune cell redistribution, changes in secretory activity, and modulation of inflammatory pathways.

Therefore, we have revised the manuscript to clarify that the combined biomarker profile should be interpreted as a proxy of senescence-related biological processes, rather than a direct measure of senescent cell accumulation.

“However, whether these reductions reflect a true decrease in senescent cell burden or are driven by changes in immune cell composition, altered secretory activity, or systemic inflammatory modulation remains to be elucidated. Therefore, circulating biomarkers should be interpreted as indicators of senescence-associated systemic signalling rather than direct measures of senescent cell accumulation.”

Page 7, 275-280

• 
  The central role of BST is not supported by direct mechanistic or clinical evidence—should the authors explicitly state that conclusions are extrapolated from general resistance training literature?

Response: We thank the reviewer for this insightful comment. We agree that direct mechanistic and clinical evidence specifically addressing block strength training (BST) in the context of cellular senescence and cancer-related outcomes remains limited.

In this review, our intention is not to present BST as an evidence-proven intervention in this specific biological context, but rather as a structured and biologically plausible framework derived from established resistance training literature. The mechanistic interpretations discussed are therefore extrapolated from broader evidence on resistance training adaptations, including effects on inflammation, muscle function, and senescence-associated biomarkers.

To address this point, we have revised the manuscript to explicitly clarify that the proposed role of BST should be interpreted as a hypothesis-generating and translational framework, rather than as a directly validated intervention in this domain.

“Although direct mechanistic and clinical evidence specifically addressing BST in the context of cellular senescence and cancer remains limited, this model is presented here as a biologically plausible and hypothesis generating framework grounded in established resistance training literature.”

Page 3, line 107-110

“Importantly, the proposed biological effects of BST discussed in this section are extrapolated from broader resistance training literature and should not be interpreted as BST-specific mechanistic evidence”

Page 10, Line 421-423

“Importantly, these findings derive from the broader resistance training literature and not from BST-specific interventions and therefore should be interpreted as biologically plausible rather than directly demonstrated mechanisms.”

Page 41. Line 429-431

• 
  The manuscript emphasizes hormesis and adaptive stress models—how specifically does BST differ from other resistance training modalities in this context?

Response: We thank the reviewer. We agree that hormesis is a general property of exercise and not specific to BST. The distinction of BST lies not in unique molecular mechanisms, but in the structured temporal sequencing of training stimuli (strength, power, endurance). This organization may allow more precise dosing of stress–recovery cycles and reduce overlapping adaptive signals compared to non-periodized or concurrent training. We have clarified this point in the revised manuscript.

“Importantly, BST does not rely on unique molecular mechanisms but on the structured sequencing of training stimuli, which may allow more precise hormetic dosing compared to non-periodized or concurrent models.”

Page 11. Line 464-467

• 
  The manuscript suggests potential oncology applications—are these claims premature without direct intervention studies in cancer populations?

Response: We appreciate the reviewer’s insightful comment. A following paragraph at final of the BTS was replaced…

Accordingly, while BST principles appear compatible with current exercise-oncology recommendations, their specific validation in frail older adults with active cancer remains an important priority for future controlled trials.

By this paragraph…. In the case of cancer patients, it is widely demonstrated that PA intervention reduces complications during chemotherapy or in the long term. Therefore, theoretically, structured training should have clinical effects in this type of patient, as previously described by the authors (Jofré, 2025).

Lines 567-571.

• 
  There is limited discussion of practical limitations such as adherence, heterogeneity of response, or clinical contraindications—should these be incorporated?

Response: Thanks for the value opinion. We added a Limitations in a new Point 8.

Despite the theoretical, biological, and functional benefits of block strength training (BST), its implementation in older adults with cancer faces critical limitations that must be considered. First, there are specific contraindications related to treatment toxicity, such as the presence of severe peripheral neuropathy or chemotherapy-induced cardiotoxicity, which can compromise safety during high-intensity exercise. Furthermore, there is marked heterogeneity in exercise response, where factors such as reduced anabolic sensitivity and age-related mitochondrial dysfunction can cause molecular and strength adaptations to vary significantly among individuals. Finally, poor adherence to exercise presents a major challenge, exacerbated by symptoms such as cancer-related fatigue and reduced physiological reserve, requiring highly individualized and closely monitored programs to ensure long-term sustainability.

Page 16, Lines 646-657.

• 
  Given the limited data available on the specific topic of the manuscript, a dedicated limitations section should be added at the end of the manuscript (before the conclusion).

Response: Thanks for the value opinion. We added a Limitations in a new Point 8.

• 
  The argument for BST as a “precision” intervention is interesting but underdeveloped—can this concept be more rigorously defined?

Response: We thank the reviewer for this valuable comment, which helps strengthen the conceptual clarity of the manuscript. We agree that the characterization of BST as a “precision-based” intervention required a more explicit definition. In the revised version, we have incorporated a more rigorous formulation of this concept, defining precision as the ability to align external training variables with individual physiological and perceptual responses, allowing for adaptive and individualized regulation of the training stimulus. This definition is directly linked to the operational components of the model, including the manipulation of load, volume, movement velocity, and repetitions in reserve (RIR). This addition reinforces the conceptual foundation of BST as a programming strategy oriented toward individualized stimulus regulation while maintaining coherence with the overall structure of the manuscript.

• 
  In Section 7, which represents the final part of the manuscript and should provide a synthesis aligned with the main objective, there is no specific emphasis on BST, and the discussion shifts toward exercise as a general concept. This section should be revised to maintain a clear focus on BST rather than exercise in general.

Response: We thank the reviewer for this valuable comment, which helps improve the alignment between this section and the central objective of the manuscript. We agree that Section 7 required a stronger emphasis on BST. In the revised version, we have incorporated a closing statement that explicitly reframes the section from a BST perspective, highlighting it as a structured framework through which exercise-induced adaptations may be organized in accordance with age-related functional and biological demands. This modification preserves the conceptual integration with the broader exercise literature while ensuring that BST remains the central interpretative axis of the section.

 

Conclusion
• The conclusion implies that BST may influence cancer-related outcomes—should this be reframed as a hypothesis requiring validation?

Response: We thank the reviewer for this valuable comment, which helps ensure alignment between the interpretation of the findings and the level of available evidence. We agree on the importance of avoiding causal or translational interpretations in the absence of direct evidence. In the revised manuscript, the conclusion has been explicitly reframed to present the potential effects of BST on cancer-related outcomes as a hypothesis-driven and speculative approach that requires validation through dedicated mechanistic and clinical studies. In this context, more cautious language has been incorporated, emphasizing that these associations remain hypothetical and should be confirmed in future research.

Page 16, Lines 661-673.

• 
  The strength of the conclusions appears to exceed the available evidence—can the authors better align conclusions with the limitations discussed?

Response: We thank the reviewer for this valuable comment, which helps improve the consistency between the conclusions and the level of available evidence. We agree on the importance of avoiding overinterpretation of the findings. In the revised manuscript, we have adjusted the tone of the conclusion to better align with the limitations discussed throughout the text. Specifically, more cautious language has been incorporated, emphasizing that the biological effects of BST remain speculative and that the proposed associations should be interpreted as hypotheses requiring validation through dedicated mechanistic and clinical studies. As a result, the conclusion is now fully consistent with the level of evidence presented in the manuscript.

• 
  The need for future mechanistic and clinical trials is mentioned but could be more explicitly emphasized as the primary takeaway.

Response: We thank the reviewer for this valuable comment, which helps strengthen the main takeaway of the manuscript. While the need for future studies was already acknowledged, we have now explicitly emphasized this point in the conclusion. Specifically, a final statement has been added to highlight the advancement of mechanistic and clinical research as a primary priority to validate the translational potential of BST in this context.

 

Minor Comments

Abstract
• The phrase “biologically informed intervention” is vague and could be defined more precisely.

Response: We thank the reviewer for this comment. We have revised the abstract to clarify the term “biologically informed intervention” by specifying its physiological basis and simplified several sentences to improve clarity and readability.

• 
  Some sentences are dense and could benefit from simplification for clarity.

Response: We thank the reviewer for this comment. The abstract has been revised to improve clarity by simplifying sentence structure and reducing complexity.

Methods
• The time frame of the literature search is broad—clarify whether any updates were performed prior to submission.

Response: We thank the reviewer for this comment. We have clarified the time frame of the literature search by specifying that it covered studies published between 2000 and 2025, and that the search was updated prior to manuscript submission to ensure inclusion of the most recent available evidence.

“published between 2000 and 2025. The search was updated prior to manuscript submission to ensure inclusion of the most recent available evidence.”

Page 3. Lines 123-125.

• 
  Language restrictions (if any) are not reported.

Response: We thank the reviewer for this comment. We have clarified the language criteria applied during study selection by specifying that only articles published in English were considered.

“Only articles published in English were considered”

Page 3, Lines 129-130.

 

Narrative Synthesis
• Some claims regarding telomere biology could be expressed more cautiously.

Response: We thank the reviewer for this comment. We have revised the statements on telomere biology to adopt a more cautious tone, avoiding causal interpretations and emphasizing the associative nature of the available evidence.

Page 7. Line 281-282.

• 
  The distinction between “myokines” and “exerkines” could be clarified more succinctly.

Response: We thank the reviewer for this comment. We have clarified the distinction between “myokines” and “exerkines” by simplifying the definition and improving conciseness in the revised manuscript.

“Myokines are signaling molecules released specifically by skeletal muscle during contraction, whereas exerkines refer to a broader group of exercise-induced factors derived from multiple tissues, including muscle, adipose tissue, and other organs.”

Page 7. Line 307-309.

• 
  The discussion would benefit from a clearer synthesis rather than reiteration of earlier sections.

Response: We thank the reviewer for this comment. As this is a narrative review, interpretative synthesis is integrated throughout each section rather than presented in a separate discussion. The manuscript is intentionally structured to progressively link concepts and provide hypothesis-driven integration across sections, rather than reiterating content. Therefore, we believe that the current organization already reflects a continuous synthesis of the evidence.

Round 2

Reviewer 2 Report (New Reviewer)

Comments and Suggestions for Authors

The authors have addressed my comments satisfactorily, and in my opinion the manuscript is now suitable for acceptance.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The authors developed an interesting study for the reader Biomedicines (MDPI).  This study aimed to framing physical exercise as a targeted and biologically informed intervention highlights the potential of block strength training to promote functional ageing and to contribute to cancer prevention by modulating fundamental mechanisms of ageing in older women.

I leave some comments and considerations:

- The authors clearly present the problem addressed by the study, supporting it with statistical data that emphasise the importance of oncology-related research in older adults, particularly in women, given the context of frailty.

- The relevance of the study is conveyed through a concise yet detailed description of the general benefits of physical exercise in preventing a large proportion of the functional declines typically associated with ageing, thereby reducing the burden of chronic diseases in this population. However, the authors could further specify the effects of resistance/strength training programmes on these variables and in this population.

- The chapter on “cellular senescence in ageing and cancer” is structured in an organised manner and uses clear language, enabling the reader to understand the role of senescent cells in inflammaging and in cellular immune surveillance, which strongly contributes to the development of chronic diseases, including cancer. The SASP phenotype of senescent cells is well explained, with reference to multiple processes associated with cancer initiation and progression.

- The authors discuss the benefits of physical exercise for the immune system, namely its potential to slow multiple aspects of biological ageing, including chronic inflammation and the accumulation of senescent cells, through broad systemic and cellular adaptations; the reduction of cellular senescence markers; and the preservation of telomere length and telomerase activity, thereby preventing replicative cellular senescence. They also highlight the reduction of chronic low-grade inflammation (inflammaging) through a decrease in pro-inflammatory SASP factors, as well as the beneficial effects of muscle contraction, which stimulates the production of substances exerting systemic effects on inflammation, tissue regeneration, and immune modulation.

- The authors succinctly describe what sarcopenia is and its causes, particularly in older women. They also refer to its role in the development of other conditions, namely those related to multifactorial cardiovascular disease risk and the immune system (chronic inflammation, oxidative stress, and immune impairment).

- They discuss muscular power, underscoring its importance for activities of daily living, and highlight the relevance of resistance/strength training in older adults. However, the authors could strengthen this section by including concrete examples and references to published scientific evidence, particularly intervention studies.

- The authors describe the specific characteristics of block strength training and reinforce its relevance by drawing on previously published scientific studies. They conclude with a reflective link between physical exercise, cellular senescence, and oncological outcomes.

- The authors provide clear and highly explanatory figures, which make the manuscript more interactive and engaging.

- It would be worthwhile for the authors to add a paragraph describing the type of study and the strategies used to gather and synthesise this information.

- The work is innovative, interesting, and, in my opinion, well developed. Congratulations.

Author Response

Reviewer 1.

The authors developed an interesting study for the reader Biomedicines (MDPI).  This study aimed to framing physical exercise as a targeted and biologically informed intervention highlights the potential of block strength training to promote functional ageing and to contribute to cancer prevention by modulating fundamental mechanisms of ageing in older women.

I leave some comments and considerations:

- The authors clearly present the problem addressed by the study, supporting it with statistical data that emphasise the importance of oncology-related research in older adults, particularly in women, given the context of frailty.

Response: Thank you for this comment. The main aim of this narrative review is to frame structured resistance training—particularly BST—as a biologically informed strategy to preserve functional capacity in older adults, a population in which frailty and reduced physiological reserve increase vulnerability to cancer-related adverse outcomes.

- The relevance of the study is conveyed through a concise yet detailed description of the general benefits of physical exercise in preventing a large proportion of the functional declines typically associated with ageing, thereby reducing the burden of chronic diseases in this population. However, the authors could further specify the effects of resistance/strength training programmes on these variables and in this population.

Response: We appreciate this valuable comment. Regarding the type of training and effects in older patients, resistance protocols not only improve physical parameters but also directly impact at the quality of life (QoL):

• Preservation of independence: It allows women to maintain physical, mental, and social functioning regardless of their chronological age (An, 2020).
• Compression of morbidity: It helps reduce the approximately 9-year gap between life expectancy and healthy life expectancy, preventing later years from being spent with functional limitations (Schroeder, 2019).
• Reduced Disease Burden: Consistently active individuals have significantly lower risks of cardiovascular disease (27-33% lower), cancer, and other fatal, debilitating illnesses, which are the primary causes of the gap. (Jung, 2024).

We added this paragraph in the main text, Page 9 Lines, 374-382

References.

An HY, Chen W, Wang CW, Yang HF, Huang WT, Fan SY. The Relationships between Physical Activity and Life Satisfaction and Happiness among Young, Middle-Aged, and Older Adults. Int J Environ Res Public Health. 2020 Jul 4;17(13):4817. doi: 10.3390/ijerph17134817.

Schroeder EC, Franke WD, Sharp RL, Lee DC. Comparative effectiveness of aerobic, resistance, and combined training on cardiovascular disease risk factors: A randomized controlled trial. PLoS One. 2019 Jan 7;14(1):e0210292. doi: 10.1371/journal.pone.0210292.

Jung W, Cho IY, Jung J, Cho MH, Koo HY, Park YM, Han K, Shin DW. Changes in Physical Activity and Cardiovascular Disease Risk in Cancer Survivors: A Nationwide Cohort Study. JACC CardioOncol. 2024 Dec 3;6(6):879-889. doi: 10.1016/j.jaccao.2024.09.013.

- The chapter on “cellular senescence in ageing and cancer” is structured in an organised manner and uses clear language, enabling the reader to understand the role of senescent cells in inflammaging and in cellular immune surveillance, which strongly contributes to the development of chronic diseases, including cancer. The SASP phenotype of senescent cells is well explained, with reference to multiple processes associated with cancer initiation and progression.

Response: We appreciate this valuable comment. In context to highlight this concept, we added the following paragraph: “This biological process strongly contributes to the development of chronic diseases, including cancer [Calcinotto, 2019]”.

Calcinotto A, Kohli J, Zagato E, Pellegrini L, Demaria M, Alimonti A. Cellular Senescence: Aging, Cancer, and Injury. Physiol Rev. 2019 Apr 1;99(2):1047-1078. doi: 10.1152/physrev.00020.2018.

Page 3, Lines 125-126.

- The authors discuss the benefits of physical exercise for the immune system, namely its potential to slow multiple aspects of biological ageing, including chronic inflammation and the accumulation of senescent cells, through broad systemic and cellular adaptations; the reduction of cellular senescence markers; and the preservation of telomere length and telomerase activity, thereby preventing replicative cellular senescence. They also highlight the reduction of chronic low-grade inflammation (inflammaging) through a decrease in pro-inflammatory SASP factors, as well as the beneficial effects of muscle contraction, which stimulates the production of substances exerting systemic effects on inflammation, tissue regeneration, and immune modulation.

Response: We appreciate this valuable comment. We added the following paragraph to highlighted this interaction.

“These signaling molecules, were defined as “exerkines”—encompassing peptides, lipids, nucleic acids, and extracellular vesicles released not only by muscle but also by the heart, liver, and adipose tissue in response to exertion—orchestrate interorgan communication that transcends local motor function [Bilski, 2025]. This complex network constitutes a key molecular mechanism for promoting healthy longevity and preventing cancer, acting by mitigating chronic inflammation (inflammaging), optimizing immune surveillance, and regulating cellular senescence profiles.”

Page 7, Lines 285- 294. 

Reference.

Bilski J, Szlachcic A, Ptak-Belowska A, Brzozowski T. Physical Activity, Exerkines, and Their Role in Cancer Cachexia. Int J Mol Sci. 2025 Aug 19;26(16):8011. doi: 10.3390/ijms26168011.

- The authors succinctly describe what sarcopenia is and its causes, particularly in older women. They also refer to its role in the development of other conditions, namely those related to multifactorial cardiovascular disease risk and the immune system (chronic inflammation, oxidative stress, and immune impairment).

Response: We appreciate this valuable comment. We added the following paragraph about clinical meta-analysis of the effects of exercise training in older adults.

Also, clinical evidence in some meta-analysis showed that in older adults with sarcopenia, high or moderate certainty evidence showed that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life in older adults of both sexes [Shen, 2023].

Pages, 8-9 Lines 359-363.

- They discuss muscular power, underscoring its importance for activities of daily living, and highlight the relevance of resistance/strength training in older adults. However, the authors could strengthen this section by including concrete examples and references to published scientific evidence, particularly intervention studies.

Response: We thank the reviewer for this valuable observation. We added the following paragraph:

“Intervention studies have demonstrated that muscle power training is not only feasible but particularly effective for enhancing functional performance in older adults. For instance, explosive or high-velocity resistance training protocols have been shown to significantly improve rapid force production, muscle power, and functional outcomes such as chair-rise performance and gait speed in older individuals (De Vos et al., 2005; Caserotti et al., 2008). More recent research has further explored structured training strategies aimed at optimizing skeletal muscle performance in aging populations, such as the DART (Developmental Adaptations in Response to Training) randomized trial framework (Tavoian et al., 2019). In addition, large-scale meta-analytic evidence indicates that resistance training interventions consistently improve physical performance, muscle strength, and functional capacity in older adults (Radaelli et al., 2025). Together, these findings support the prioritization of muscle power development in aging populations to preserve autonomy and mitigate frailty risk.”

Page 9, Lines 362- 366. 

De Vos, N.J.; Singh, N.A.; Ross, D.A.; Stavrinos, T.M.; Orr, R.; Singh, M.A.F. Optimal Load for Increasing Muscle Power during Explosive Resistance Training in Older Adults. J. Gerontol. A Biol. Sci. Med. Sci. 2005, 60, 638–647, doi:10.1093/GERONA/60.5.638.

Caserotti, P.; Aagaard, P.; Buttrup Larsen, J.; Puggaard, L. Explosive Heavy-Resistance Training in Old and Very Old Adults: Changes in Rapid Muscle Force, Strength and Power. Scand. J. Med. Sci. Sports 2008, 18, 773–782, doi:10.1111/j.1600-0838.2007.00732.x.

Tavoian, D.; Russ, D.W.; Law, T.D.; Simon, J.E.; Chase, P.J.; Guseman, E.H.; Clark, B.C. A Randomized Clinical Trial Comparing Three Different Exer-cise Strategies for Optimizing Aerobic Capacity and Skeletal Muscle Performance in Older Adults: Protocol for the DART Study. Front. Med. (Lau-sanne). 2019, 6, 482058, doi:10.3389/fmed.2019.00236.

Radaelli, R.; Rech, A.; Molinari, T.; Markarian, A.M.; Petropoulou, M.; Granacher, U.; Hortobágyi, T.; Lopez, P. Effects of Resistance Training Volume on Physical Function, Lean Body Mass and Lower-Body Muscle Hypertrophy and Strength in Older Adults: A Systematic Review and Network Me-ta-Analysis of 151 Randomised Trials. Sports Med. 2025, 55, 167–192, doi:10.1007/s40279-024-02123-z.

- The authors describe the specific characteristics of block strength training and reinforce its relevance by drawing on previously published scientific studies. They conclude with a reflective link between physical exercise, cellular senescence, and oncological outcomes.

Response: We appreciate this valuable comment. The main contribution of this narrative review is the association between physical exercise (BTS), cellular senescence mechanisms, and oncological outcomes, such as quality of life.

- The authors provide clear and highly explanatory figures, which make the manuscript more interactive and engaging.

Response: We appreciate this valuable comment. In the corrected version, some figures were optimized, while others were simplified to facilitate the understanding of some pathophysiological and clinical processes.

- It would be worthwhile for the authors to add a paragraph describing the type of study and the strategies used to gather and synthesise this information.

Response: Thank you for this helpful suggestion. We have added a paragraph in the “Methodological Considerations” section clarifying the type of study (narrative review) and describing the literature search strategy, selection approach, and narrative synthesis procedures used to gather and integrate the evidence.

- The work is innovative, interesting, and, in my opinion, well developed. Congratulations

Response: We appreciate this valuable comment.

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript does not clearly specify the type of review conducted (e.g., narrative, systematic, or scoping), nor does it outline the literature search strategy (databases searched, keywords used, time frame, or inclusion/exclusion criteria). This lack of methodological transparency limits reproducibility and weakens the overall rigor of the review.

 

Although the title explicitly focuses on older women, numerous statements throughout the manuscript are supported by studies that include male or mixed-sex populations. Presenting these findings as women-specific creates a conceptual inconsistency that should be addressed, explicitly qualified, or appropriately contextualized.

 

In several sections, conclusions and interpretations are drawn from meta-analyses that include both male and female participants without sex-disaggregated analyses. Consequently, generalizing these findings specifically to women is methodologically unjustified.

 

The manuscript attributes potential effects of block strength training (BST) on cellular aging, inflammaging, and immune competence without presenting direct empirical evidence specific to BST. These claims appear to extend beyond the currently available data and should either be framed more cautiously or clearly identified as hypothetical or speculative.

 

Some statements combine multiple concepts and references within a single sentence, making it unclear which citation supports which specific claim. Greater clarity and precision in aligning references with the statements they support is needed.

 

In certain sections, the language implies causal biological modulation (e.g., “modulate,” “attenuate”) despite the presence of only associative or indirect evidence. A more cautious and appropriately qualified terminology is recommended.

 

Figure legends, particularly those accompanying conceptual figures, are overly detailed and reiterate information already presented in the main text. The legends should be concise and primarily descriptive rather than explanatory.

 

Detailed corrections, clarifications, and suggested revisions addressing these concerns have been provided as in-text comments throughout the manuscript.

Comments for author File: Comments.pdf

Author Response

Reviewer 2.

- The manuscript does not clearly specify the type of review conducted (e.g., narrative, systematic, or scoping), nor does it outline the literature search strategy (databases searched, keywords used, time frame, or inclusion/exclusion criteria). This lack of methodological transparency limits reproducibility and weakens the overall rigor of the review.

Response: Thank you for this important comment. We agree that clearer methodological transparency strengthens the rigor and reproducibility of the manuscript. We have revised the “Methodological Considerations” section to explicitly specify the type of review (narrative review), detail the databases searched, keywords used, time frame, inclusion criteria, and the narrative synthesis strategy employed. Although this review was not designed as a systematic or scoping review, we have clarified the focused search strategy and the conceptual criteria used to select and integrate the evidence.

Page 3, Lines 103-121.

- Although the title explicitly focuses on older women, numerous statements throughout the manuscript are supported by studies that include male or mixed-sex populations. Presenting these findings as women-specific creates a conceptual inconsistency that should be addressed, explicitly qualified, or appropriately contextualized.

 Response: We appreciate this valuable comment. We have changed and generalized the title of the review to refer to older adults in general, regardless of gender, since, based on the fundamental mechanisms, we do not distinguish by sex.

For example, we added a following paragraph:

“Also, clinical evidence in some meta-analysis showed that in older adults with sarcopenia, high or moderate certainty evidence showed that resistance exercise with or without nutrition and the combination of resistance exercise with aerobic and balance training were the most effective interventions for improving quality of life in older adults of both sexes [Shen, 2023].”

Page, 8-9 Lines 359-363.

- In several sections, conclusions and interpretations are drawn from meta-analyses that include both male and female participants without sex-disaggregated analyses. Consequently, generalizing these findings specifically to women is methodologically unjustified.

 Response: We thank the reviewer for this important comment. We agree that much of the mechanistic and interventional evidence cited in this review derives from mixed-sex cohorts without consistent sex-stratified analyses. Accordingly, we have revised the manuscript to avoid women-specific mechanistic generalizations and now frame sex-related considerations as a limitation and a priority for future research. Relevant statements have been adjusted in Section 7.

We added the following paragraph:

“Most mechanistic and interventional evidence cited derives from mixed-sex cohorts without consistent sex-stratified analyses. Therefore, while the clinical focus of this review highlights older women due to their higher frailty burden and cancer-related vulnerability, the biological mechanisms discussed should be interpreted cautiously and not as women-specific. Future research should specifically investigate potential sex-related differences in senescence-related responses to structured resistance training.”

Page 13, lines 517-523

- The manuscript attributes potential effects of block strength training (BST) on cellular aging, inflammaging, and immune competence without presenting direct empirical evidence specific to BST. These claims appear to extend beyond the currently available data and should either be framed more cautiously or clearly identified as hypothetical or speculative.

Response: Thank you for this insightful comment. We agree that the previous version of the manuscript could be interpreted as attributing direct biological effects of block strength training (BST) on cellular aging, inflammaging, and immune competence without sufficient empirical evidence specific to this training model.

In response, we have thoroughly revised the relevant sections of the manuscript. The entire section discussing BST and its potential biological effects has been rewritten to clearly distinguish between established evidence derived from resistance training studies and mechanistic hypotheses specific to BST. Claims that extend beyond currently available data are now explicitly framed as biologically plausible but hypothetical, and the need for future mechanistic and clinical studies is clearly emphasized.

We appreciate this comment, which has strengthened the scientific precision and balance of the manuscript.

Page 10, lines 383; Page 11-12, and Page 13, Lines 483-512.

- Some statements combine multiple concepts and references within a single sentence, making it unclear which citation supports which specific claim. Greater clarity and precision in aligning references with the statements they support is needed.

Response: We carefully revised the manuscript to improve precision in the association between specific claims and their supporting citations. In particular:

We divided several complex sentences that previously combined multiple biological mechanisms or clinical outcomes under broad citation ranges, separating them into discrete statements with individually matched references (notably in the Introduction, Sections 2 and 3).

In the discussion of SASP-related mechanisms (Section 3), we reassigned references to ensure that processes such as extracellular matrix remodeling, epithelial–mesenchymal transition, immune evasion, and telomere dysfunction are now supported by distinct and directly relevant citations rather than grouped ranges.

“In particular, enzymes such as matrix metalloproteinases (MMPs) secreted by senescent cells degrade and remodel the extracellular matrix [26,40], weakening normal tissue architecture and creating space for tumor expansion and invasion within the tumor microenvironment” [41].

Page 5, Lines 193-199.

“Moreover, the SASP interferes with antitumor immune responses through the chronic release of inflammatory mediators that exhaust cytotoxic lymphocytes and NK cells [42,44]. In parallel, SASP components such as GDF15 and pro‑inflammatory cytokines can skew or divert macrophages and other innate immune cells toward immunosuppressive phenotypes, thereby facilitating tumor immune escape [45,46]”

Page 5, Lines 199-204

In Section 7 (exercise and cancer outcomes), we reorganized epidemiological, mechanistic, and clinical trial evidence into clearly differentiated statements, each with appropriately aligned references. We also corrected mismatches between citations and specific claims where necessary.

Page 13, Lines 513-534

These revisions improve traceability, transparency, and evidentiary precision throughout the manuscript.

 - In certain sections, the language implies causal biological modulation (e.g., “modulate,” “attenuate”) despite the presence of only associative or indirect evidence. A more cautious and appropriately qualified terminology is recommended.

Response: We thank the reviewer for this valuable comment. In response, we revised the manuscript to ensure that statements implying causal biological modulation were reformulated using appropriately qualified language consistent with the available evidence.

We provide three representative examples of these revisions:

Abstract

Original wording: “Physical exercise has emerged as a potent modulator of aging biology, capable of attenuating inflammation and limiting the accumulation or activity of senescent cells.”

Revised wording: We removed deterministic phrasing and adjusted related sections to emphasize associative and plausibly mechanistic interpretations rather than direct causal effects.

Page 1, Lines 26-28.

Section 4 (Exercise and senescence biomarkers)

Original wording: “This provides in vivo evidence that exercise can mitigate cellular senescence by reducing existing senescent cells.”

Revised wording: “This provides in vivo evidence that exercise can reduce circulating senescence-associated biomarkers; whether this reflects reduced senescent cell burden versus changes in immune cell composition or SASP signalling remains to be clarified.”

This explicitly acknowledges mechanistic uncertainty.

Page 7, Lines 259-261.

Section 6 (Concept and Implementation).

Original wording: “BST may modulate key aging-related processes…”

Revised wording: “BST could plausibly affect aging-related processes such as oxidative stress, chronic inflammation, and mitochondrial dysfunction…”

Page 12, Lines 477-478.

Also, this sentence was complemented with the brief description of the findings and results.

“As a controlled-intensity, full-body training model with sustained exposure across blocks, BST may elicit antioxidant adaptations that help manage exercise-induced oxidative stress. Regular training can increase antioxidant enzyme activity—particularly superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)—in skeletal muscle, thereby improving the capacity to neutralize reactive oxygen species (ROS) generated during repeated high-demand contractions and endurance-like workloads [Powers, 2022]. Such adaptations provide a biologically plausible link between resistance training programming and redox-sensitive pathways relevant to senescence signaling. [Powers, 2022].

 

Powers SK, Goldstein E, Schrager M, Ji LL. Exercise Training and Skeletal Muscle Antioxidant Enzymes: An Update. Antioxidants (Basel). 2022 Dec 25;12(1):39. doi: 10.3390/antiox12010039.

Pages 9-10, Lines 406 -413.

Collectively, these modifications ensure that causal interpretations have been replaced with cautious, evidence-aligned terminology throughout the manuscript.

- Figure legends, particularly those accompanying conceptual figures, are overly detailed and reiterate information already presented in the main text. The legends should be concise and primarily descriptive rather than explanatory.

Response: We thank the reviewer for valuable suggestion. In response, we revised all conceptual figure legends to ensure they are concise and primarily descriptive.

Specifically, we removed extended mechanistic explanations, detailed listings of molecular mediators, and interpretative language that reiterated content already presented in the main text. The revised legends now focus on describing what is shown in each figure, while explanatory context has been retained within the corresponding sections of the manuscript.

These changes improve clarity, reduce redundancy, and align the figure legends with standard journal conventions.

 - Detailed corrections, clarifications, and suggested revisions addressing these concerns have been provided as in-text comments throughout the manuscript

Response: We sincerely thank the reviewer for the detailed corrections, clarifications, and constructive suggestions provided throughout the manuscript. We carefully considered each in-text comment and implemented the recommended revisions accordingly. These modifications were included in this cover letter point-by-point. Also, these have helped to improve the clarity, precision, and overall quality of the manuscript.

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

The proposed link between Block Strength Training (BST) and senescence-associated pathways is innovative and holds significant translational potential. I appreciate the comprehensive background provided on each of these components.

 

However, to strengthen the manuscript and fully realize its potential, several major points require careful revision. My primary recommendations are aimed at enhancing the precision of the claims, solidifying the mechanistic rationale, and improving the clinical translatability of the proposed framework.

 

Major Points for Revision

 

1. Clarifying the Evidence Base and Mechanistic Hypotheses

A central issue is the gap between the core thesis-that BST specifically modulates senescence to benefit older women with/at risk of cancer-and the evidence currently presented. The review extensively cites literature on exercise in general (often aerobic or traditional resistance training) and its effects on senescence biomarkers, but direct evidence linking BST to these biological mechanisms is lacking, as you correctly note on page 15. Furthermore, the clinical studies summarized in Table 2 involve highly heterogeneous populations (e.g., childhood cancer survivors, middle-aged adults with obesity) and interventions (e.g., senolytics, general physical activity), which weakens the direct support for your argument regarding BST in older women.

 

2. Rationalizing and Improving Table 2

Table 2, in its current form, lacks focus. The inclusion of non-exercise interventions (e.g., senolytics) and diverse patient groups dilutes its utility in supporting the review's primary focus on exercise and BST.

 

3. Addressing Safety, Feasibility, and Recent Evidence for BST in Frail Populations

The review appropriately highlights BST's benefits for functional outcomes in community-dwelling older women [92]. However, the translation to older women with cancer-a typically frailer population with potential treatment-related side effects-is not sufficiently addressed. The safety, tolerability, and optimal implementation of a structured, periodized program like BST in this specific cohort are major clinical considerations. Relying on references [91] and [21], which are from 2005 and 2009 respectively, also weakens the argument.

 

4. Deepening the Discussion on Sex-Specific Factors

While the review focuses on older women and mentions menopause, the discussion of how sex differences might influence the core biology (cellular senescence, SASP, immune response to exercise) remains superficial. The manuscript would be significantly strengthened by exploring whether the mechanisms discussed exhibit sexual dimorphism.

 

Minor Points

1. The abbreviation "Burden's disease" appears on page 3 without prior definition. Please clarify or use the full term upon first mention.

 

2. The manuscript contains some minor grammatical errors and typos (e.g., "sonomorphic" likely should be "senomorphic" on page 6). A thorough proofreading is recommended.

Author Response

Reviewer 3.

The proposed link between Block Strength Training (BST) and senescence-associated pathways is innovative and holds significant translational potential. I appreciate the comprehensive background provided on each of these components.

However, to strengthen the manuscript and fully realize its potential, several major points require careful revision. My primary recommendations are aimed at enhancing the precision of the claims, solidifying the mechanistic rationale, and improving the clinical translatability of the proposed framework.

 Major Points for Revision

1. Clarifying the Evidence Base and Mechanistic Hypotheses

A central issue is the gap between the core thesis-that BST specifically modulates senescence to benefit older women with/at risk of cancer-and the evidence currently presented. The review extensively cites literature on exercise in general (often aerobic or traditional resistance training) and its effects on senescence biomarkers, but direct evidence linking BST to these biological mechanisms is lacking, as you correctly note on page 15. Furthermore, the clinical studies summarized in Table 2 involve highly heterogeneous populations (e.g., childhood cancer survivors, middle-aged adults with obesity) and interventions (e.g., senolytics, general physical activity), which weakens the direct support for your argument regarding BST in older women.

 Response: Thank you for this important and conceptually insightful comment. We agree that the previous version of the manuscript did not sufficiently bridge the gap between the central hypothesis and the level of evidence directly supporting BST-specific biological effects.

In response to this comment — together with the other related methodological concerns raised by the reviewers — we have substantially rewritten the entire section addressing the relationship between BST, cellular senescence, and cancer-related mechanisms.

Page 9-13, Lines 383-512

We believe these revisions significantly strengthen the conceptual coherence, scientific caution, and transparency of this narrative review.

2. Rationalizing and Improving Table 2

Table 2, in its current form, lacks focus. The inclusion of non-exercise interventions (e.g., senolytics) and diverse patient groups dilutes its utility in supporting the review's primary focus on exercise and BST.

 Response: We thank the reviewer for this important observation. We agree that Table 2, in its previous form, included heterogeneous populations and non-exercise interventions that diluted its relevance to the primary focus of the review.

To improve coherence and alignment with the manuscript’s central thesis, we have removed Table 2 and integrated the most directly relevant exercise-based evidence into the main text. This revision strengthens the conceptual clarity of the review and avoids overextending the argument regarding BST-specific mechanisms.

3. Addressing Safety, Feasibility, and Recent Evidence for BST in Frail Populations

The review appropriately highlights BST's benefits for functional outcomes in community-dwelling older women [92]. However, the translation to older women with cancer-a typically frailer population with potential treatment-related side effects-is not sufficiently addressed. The safety, tolerability, and optimal implementation of a structured, periodized program like BST in this specific cohort are major clinical considerations. Relying on references [91] and [21], which are from 2005 and 2009 respectively, also weakens the argument.

Response: Thank you for this important comment. We agree that translating BST from community-dwelling older adults to older adults with cancer requires careful consideration of safety, tolerability, and implementation feasibility.

In the revised manuscript, we have strengthened Section 6 by adding a dedicated paragraph explicitly addressing the clinical application of structured resistance training in oncology populations. This addition discusses cancer-related fatigue, anemia, peripheral neuropathy, cardiotoxicity, and reduced physiological reserve as relevant factors influencing program design and progression. We also emphasize the need for individualized dosing, clinical supervision, and adaptation according to treatment phase and symptom burden.

Furthermore, we incorporated contemporary exercise-oncology guidelines to support the safety and feasibility of supervised resistance training in cancer survivors, while clearly stating that BST-specific validation in frail older adults with active cancer remains to be established in controlled trials.

These revisions enhance the translational rigor of the manuscript and more directly address the reviewer’s concerns regarding safety, feasibility, and contemporary evidence.

Pages 10-13, lines 385 - 523

4. Deepening the Discussion on Sex-Specific Factors

While the review focuses on older women and mentions menopause, the discussion of how sex differences might influence the core biology (cellular senescence, SASP, immune response to exercise) remains superficial. The manuscript would be significantly strengthened by exploring whether the mechanisms discussed exhibit sexual dimorphism.

Response: We thank the reviewer for this thoughtful suggestion. We agree that sex-specific biological differences are highly relevant in the context of aging, senescence, and exercise responses.

While the manuscript adopts a clinical focus on older women due to their higher frailty burden and cancer-related vulnerability, much of the available mechanistic evidence on cellular senescence, SASP signaling, and exercise-induced biological adaptations derives from mixed-sex populations without sex-stratified analyses. At present, there is insufficient direct evidence to comprehensively examine sexual dimorphism in these specific mechanistic pathways within the context of BST.

Clinical epidemiological evidence associates PA with lower cancer incidence and mortality [Moore, 2016; Soares-Miranda, 2017]. For example, active older women have about a 10–20% lower risk of breast cancer compared to their least active peers. Moreover, cancer survivors who exercise tend to have better survival and lower recurrence rates, as shown in breast and colorectal cancer survivor cohorts that added nutritional interventions [Campbell, 2019]. Enough evidence available to conclude that specific doses of aerobic, combined aerobic plus resistance training, and/or only resistance training could improve common cancer-related health outcomes, including anxiety, depressive symptoms, fatigue, physical functioning, and health-related quality of life [Guijarro, 2025]. These full benefits are partly mediated by exercise-induced improvements in body composition, insulin sensitivity, and systemic inflammation that create a less favorable environment for cancer development.

Page 13, Lines 524-534.

To address this point, we have clarified in the revised manuscript that the biological mechanisms discussed are largely derived from studies in older adults irrespective of sex, and we explicitly acknowledge the need for future research investigating potential sex-specific differences in senescence-related responses to structured resistance training.

 Minor Points

1. The abbreviation "Burden's disease" appears on page 3 without prior definition. Please clarify or use the full term upon first mention.

Response: We thank the reviewer for identifying this issue. The term “Burden’s disease” was a typographical error. It has been corrected to “the burden of cancer” in the revised manuscript. We appreciate the reviewer’s careful reading.

Pages 2-3, Lines 95-96.

2. The manuscript contains some minor grammatical errors and typos (e.g., "sonomorphic" likely should be "senomorphic" on page 6). A thorough proofreading is recommended.

Response: We thank the reviewer for carefully identifying minor grammatical errors and typographical issues. We have thoroughly proofread the manuscript and corrected the identified error (“sonomorphic” to “senomorphic”), along with additional minor language inconsistencies throughout the text.

Page 5, Line 224.

 

Author Response File: Author Response.docx