Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This paper is devoted to the potential use of AI in extending lifespan and healthspan. At one level I think it's important that aging science be more acutely aware of the potential value of AI in detecting and treating disease, and in the potential for lifespan and healthspan extension through the modulation aging. If the paper was devoted entirely to just these concepts without any fanciful notions of achieving radical life extension (which is never defined), I'd have a more favorable view. The main problem as I see it now is that the concepts of disease treatment and aging intervention are mixed together throughout the paper. The authors need to decide whether this paper is devoted to the use of AI in treating diseases; or the use of AI in modulating aging. If both, then these should be logically separated. 

There are multiple references to how AI has already been used in the last decade to influence disease outcomes, but this is presented superficially. The rate of improvement in disease-driven death rates have slowed considerably in the last decade, so if AI is so important, why is this happening? 

The potential use of AI in aging science is at the heart of this manuscript, and while it's okay to speculate about the potential here, it's wildly speculative to even mention notions of radical life extension or radical healthspan extension -- especially when neither concept is defined. Some scientists consider radical life extension as achieving escape velocity where survival time is manufactured at a pace that matches the rising risk of death; others consider radical life extension as achieving a few years of additional life. In my view this speculation does not belong in the paper. While it's fine to speculate that AI should have an impact on lifespan and healthspan, it is not possible to know in advance how much life and health can be created with this technology -- if any. This type of speculation isn't needed to make the point of the potential importance of AI.

Finally, this paper is in desperate need of an editor. On the surface at least, it appears to have been patched together, and my AI detector was pinging as I was readying this. Perhaps I'm wrong here, but at least parts of this appear to have been written using AI. The authors would need to make a declarative statement about this.

Comments on the Quality of English Language

This is a very difficult article to read. The reason is that it appears on the surface to have been written using AI, with numerous errors as if pieces were patched together. If AI was not used to craft this, then the authors did a very poor job of editing. Either way, this paper would require considerable editing before publication should the decision be made to accept it.

Author Response

1.Reviewer 1 Comment 1: The manuscript mixes disease treatment and aging intervention; needs
separation or clarity.
Author`s modification of manuscript in response to Reviewer 1 Comment 1:
We thank the reviewer for this observation. To clarify, our intent is to present both aspects—AI in
disease treatment and in aging modulation—as interconnected but distinct applications. To address
this, we have added a clarifying statement at the end of Part I, noting that the paper covers both
domains, and that examples of disease treatment are provided to illustrate how these approaches
inform strategies for aging modulation. Note that in this passage we have replaced the word
“intervention” with “optimization of healthy aging” since the la?er objective is a more modest goal,
achievable within the limits of current medical practice as opposed to life extension in its various
forms which is viewed by many as overly ambitious, or even fanciful.
2.Reviewer 1 Comment 2: Radical life extension is not defined and appears speculative; should be
removed or clarified.
Author`s modification of manuscript in response to Reviewer 1 Comment 2:
We agree that clarity is needed. We have now defined “radical longevity” in the first paragraph pf
Part I as extending healthy life significantly beyond current averages, while acknowledging that
this is speculative. We have also reduced speculative language in later sections to keep the focus on
healthspan and lifespan extension grounded in current evidence.
3.Reviewer 1 Comment 3: AI has influenced disease outcomes, but death rates have slowed—why?
Author`s modification of manuscript in response to Reviewer 1 Comment 3:
We appreciate this point. We have added a short statement in the conclusions acknowledging that
despite advances in AI and other technologies, improvements in disease mortality have slowed due
to complex, multifactorial causes including lifestyle, access disparities, and chronic inflammatory
disorders. This highlights the importance of AI not as a panacea, but as a complementary tool.
4.Reviewer 1 Comment 4: Article appears to have been wri?en with AI, needs a statement.
Author`s modification of manuscript in response to Reviewer 1 Comment 4:
We confirm that AI-assisted drafting tools familiar to the scientific publication process were used
(e.g., for grammar and reference forma?ing), under the direct supervision and authorship of the
listed investigators. A statement to this effect has been added in the “Author Contributions and
Disclosure” section, per best practice.
5.Reviewer 1 Comment 5: The English is difficult, needs editing.
Author`s modification of manuscript in response to Reviewer 1 Comment 5:
We acknowledge this concern. The manuscript has been carefully re-edited for clarity, consistency,
and concision while retaining the typeset structure. Lead for this task was taken by Dr. Donald
Haines, UK national and graduate of University of Connecticut, USA. Dr. Haines has an extensive
repertoire of scientific publications as primary writer/editor along with newspaper articles and a
chapter in a book.
Minimal Changes to Manuscript (suggested insertions)
Author`s modification of manuscript in response to Reviewer 1`s suggested insertions:
1. Introduction (end of I.1): This insertion has been made in red text.
“This review addresses both the application of AI to disease treatment and to modulation
of aging. While interconnected, these domains are considered separately where
appropriate.”
2. Introduction (I.1 “radical longevity” paragraph):
Define it:
“For the purpose of this report, radical longevity refers to significant extensions of healthspan beyond
current averages, though we recognize that this remains speculative.”
Author response to above recommendation by reviewer 1: The terms radical longevity and
healthspan are described within Section I.1 in the response to Comment 2 by Reviewer 1. Also,
within this portion of the text is the following caveat: “It is here essential to emphasize that
radical longevity is not at the time of this writing, achievable within the limits of technology
based on understanding of the underlying mechanisms of biological aging. Thus consideration
of this concept should avoid speculative language to keep the focus on healthspan and lifespan
extension grounded in current evidence”.
3. Discussion (add sentence after mention of slowed progress):
“Despite technological advances, improvements in disease-driven mortality have slowed in recent
years, reflecting multifactorial influences such as lifestyle, inequities in access, and persistent
chronic inflammatory disorders. This underscores the need to view AI as a complementary, rather
than sole, driver of improved health outcomes.” Author response to above recommendation:
This is discussed within the conclusions section in a paragraph inserted in response to
Comment 3 of Reviewer 1.
4. Author Contributions / Disclosure section (end):
“AI-assisted tools familiar to the scientific publication process were used under direct author
supervision for tasks such as grammar, style, and reference forma?ing. All substantive content was
conceived, wri?en, and critically reviewed by the listed authors.” Author response to above
recommendation: This insertion has been added.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript "Leveraging Artificial Intelligence and Modulation of Oxidative Stressors to Enhance Healthspan: Focus on Cardiovascular Senescence" by D.D. Haines et al., looks as a careful and extended review of AI practical and potential implications in health research of the elderly, not only concerning their focus on oxidative stress. Their extended work is quite impressive.
Apart from many details to check about (the AI 'popularization' of the Intro may be excessive), I was surprised that the major health risk for the elderly does not appear--isolation. The degree of social isolation is a well recognized predictor of the general health state of the old person. Confirmed by prestigious authors: Cacioppo, Putnam, Holt-Lunstad, McPherson, etc.  

Loneliness and its associated mental disorders generate substantial costs for the individual, family, employer, and community, payments ranging from medical bills to sick leave days, to medication expenses, to home care services, to nursing homes. It has already been highlighted by a number of researchers in fields as diverse as social economics, social psychology, mental health and psychiatry, and physiology, not to speak of medical practitioners directly involved in primary care, family care, and geriatric clinics. One of the main concerns is that the increase in the aging population and growing loneliness are putting the sustainability of public healthcare systems at stake. Additionally, all these preexisting problems were magnified by the social impact of the COVID-19 pandemic.

Indeed, the research on aging has come into a new era that marks an inflection point, with unique medical, economic, and societal implications. Thereafter, this kind of systemic, fundamental problems should also be connected with the AI revolution. In the manuscript itself, at least when talking about robotics and lifestyle, there should be room to enter this fundamental aspect with sufficient lenght.

A FEW REFERENCES:

--Holt-Lunstad, J. et al., Advancing social connection as a public health priority in the United States. Am. Psychol. 2017, 72, 517, doi:10.1037/amp0000103.

--Berkman, L.F. Social epidemiology: Social determinants of health in the United States: Are we losing ground? Annu. Rev. Public
Health 2009, 30, 27–41.

Cacioppo, J. et al., Loneliness is a Modern Epidemic in Need of Treatment. 2014, Volume 19, p. 2016. Available online:
https://www. newscientist. com/article/dn26739-loneliness-is-a-modern-epidemic-in-need-of-treatment/ 

 

Author Response

Reviewer 2 Comment 1: Major health risk of social isolation/loneliness not discussed; should be
connected to AI, especially in sections on robotics and lifestyle.
Author`s response to reviewer 2, comment 1:
Indeed, the effects of psychosocial stress on neuroimmune and endocrine function – exacerbating
inflammatory pathologies (including ‘Inflammaging’ is currently underappreciated by healthcare
providers . As veterans of wartime military service and the physical and emotional damage we, the
authors sustained during that period, it is of personal as well as professional interest to myself, Dr.
Mahmoud and Dr. Rose, that public consciousness be raised to possible use of AI systems to mitigate
these horrendous effects. Accordingly, Within the revised manuscript, a discussion of this
phenomenon is included section II.8c. as the author`s response to Reviewer 2 Comment 1.
ADDED CITATIONS: To support statements in this section, major contributors of researchers and
clinicians who characterized this phenomenon, including: Schneiderman et al, 2005, Albasheer et al,
2024, Holt-Lunstad et al, 2022 and Stein et al, 2018, have been cited. Unfortunately, the version of
EndNote available to the writer (Dr. Haines), is incompatible with the EndNote program that Prof.
Arpad Tosaki used for the original manuscript ONLY Dr. Tosaki is able to insert these new
references. He has not responded to requests that he do this. Hence temporarily, Dr. Haines has
listed the references in-text as the full length title, bolded and underlined. Dr Tosaki is familiar
with the style and can easily complete the EndNoting. But if he continues not to reply (today, 5
September 2025 – the deadline, this is problematic).

Reviewer 3 Report

Comments and Suggestions for Authors

The present paper aimed to explore the transformative potentials of artificial intelligence (AI) in promoting healthspan and longevity, emphasizing the importance of AI in inflammaging, aging biomarkers, drug discovery, personalized medicine, analysis and interpretation of genomic data, clinical trials design, proactive health interventions and monitoring victims of war.

Several changes are needed, as follows:

Please explain every abbreviation before using it!

Introduction, lines 68-69: It is not clear what the relationship between hemolytic diseases, oxidative stressors, and Cardiovascular Senescence is. Your paper should be more focused on chronic conditions associated with aging.

I.2. Emerging public availability of AI platforms and I.4. Approach to utilization of AI platforms for solving complex problems can be merged.

I.6. Hypothesis-based approach for use of AI, line 132: “tsk” assignment? Please correct!

1.8. Oxidative Stress, “Inflammaging” and Antioxidant Countermeasures, lines 171-176: Please rephrase without mentioning the position, just the reference number.

I.11. Strategies for use of AI in design of research on hemolytic and other diseases, line 295: “Typically, the investigators?” Please rephrase!

II.8a. Personalized Lifestyle Recommendations Driven by AI, line 700: Please state the reference according to its number.

A few words about AI and gender differences in longevity research, aging biomarkers, drug discovery, elderly care, proactive health interventions, lifestyle, and behavioral interventions would be a benefit. Please mention also vascular aging, since it is known that “a man has the age of his arteries” (Thomas Sydenham).

II.10a. Chronic inflammatory disorders: a consequence of modern warfare, lines 772-775: Just mention the reference in brackets, as a number.

Discussion, line 879: Please state the reference just according to its number.

Author Response

1. Reviewer 3 Comment1: Explain every abbreviation before use.
Author`s response to reviewer 3, comment 1:
We thank the reviewer. All abbreviations (e.g., AI, ML, DL, NLP, MTMC, etc.) have been checked
and expanded at first mention.
2. Reviewer 3 Comment2: Clarify link between hemolytic diseases, oxidative stressors, and
cardiovascular senescence.
Author`s response to reviewer 3, comment 2:
We clarified this in Section I.1 , by adding a brief connecting sentence: hemolytic diseases were
highlighted as an example of oxidative stress–driven pathology, which in turn accelerates
cardiovascular aging, making them a relevant model. Additional consideration of their application
to AI-mediated analysis to disease is given in Section I.10.
3. Reviewer 3 Comment 3: Merge sections I.2 and I.4.
Author`s response to reviewer 3, comment 3:
We have merged I.2 and I.4 into a single section (“I.2. Public Availability and Utilization of AI
Platforms Need for simplicity of operation”) to streamline content. Numbering has been adjusted
accordingly.
Reviewer 3 Comments: Typo “tsk assignment.”
Author`s response to reviewer 3, typo correction
Corrected to “task assignment.”
Reviewer 3 Comment 3:
References should be cited by number only, not by position.
Author`s response to reviewer 3, comment 3
We rephrased the noted sentences to use reference numbers consistently. NOTE TO
BIOMOLECULES REVIEWERS AND EDITORS REGARDING ADDED REFERENCE
FORMATTING: To support statements in section, II.8c, - made in response to Comment 1 by
reviewer 2, major contributors of researchers and clinicians who characterized this phenomenon,
including: Schneiderman et al, 2005, Albasheer et al, 2024, Holt-Lunstad et al, 2022 and Stein et al,
2018, have been cited. Unfortunately, the version of EndNote available to the writer (Dr. Haines),
is incompatible with the EndNote program that Prof. Arpad Tosaki used for the original
manuscript ONLY Dr. Tosaki is able to insert these new references. He has not responded to
requests that he do this. Hence temporarily, Dr. Haines has listed the references in-text as the full
length title, bolded and underlined.
4. Reviewer 3 Comment 4: “Typically, the investigators?” needs rephrasing.
Author`s response to reviewer 3 Comment 4: rephrasing.
Revised for clarity to: “Typically, investigators provide AI with the selected hypothesis…”
5. Reviewer 3 Comment 5: II.8a lifestyle section — reference should be numbered.
Author`s response to reviewer 3 Comment 5:.
Corrected.
6. Reviewer 3 Comment 6: Please add note on gender differences and vascular aging.
Author`s response to reviewer 3 Comment 6:.
We added a short note in the lifestyle/biomarkers section: “It is important to note gender
differences in longevity research, as sex-specific variations influence aging biomarkers, drug
responses, elderly care, and lifestyle interventions. Additionally, vascular aging remains a central
determinant of lifespan, reflecting Sydenham’s maxim that ‘a man has the age of his arteries.’”
7.Reviewer 3 Comment 7: II.10a and Discussion — references should be cited by number only.
Author`s response to reviewer 3 Comment 7:.
Corrected.

Minimal Insertions in Manuscript
1. Introduction (I.1, near hemolytic disease mention):
“Hemolytic diseases are introduced as an example of oxidative stress–driven pathology. Oxidative
damage accelerates cardiovascular tissue decline, thereby linking hemolysis, oxidative stress, and
cardiovascular senescence.”
2. New combined heading:
“I.2 Public Availability and Utilization of AI Platforms” (merge I.2 + I.4).
3. Section II.3 biomarkers / II.8 lifestyle:
“Gender differences should be acknowledged in longevity research, as sex-specific biology influences
biomarker expression, drug responses, and outcomes in elderly care and lifestyle interventions.
Vascular aging is also central, consistent with the classical notion that ‘a man has the age of his
arteries.’”

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The present paper aimed to explore the transformative potentials of artificial intelligence (AI) in promoting healthspan and longevity. 

Most of the suggested changes have been performed.

The only issue to be solved is: References should be cited by number only, not by position. It has not been performed yet for all references.

Author Response

Comment: The only issue to be solved is: References should be cited by number only, not by position. It has not been performed yet for all references.

Answer: Thank you for your professional and careful suggestions. We have reformatted the document in digital format.