Exploration of Drug Science

Table 6. Risk-of-bias assessment of human studies (clinical trials and observational cohorts) examining anti-infective drugs in relation to vascular ageing.

Ref #	Study type	Drug/Class	Model/Population	Tools used	Key bias domains (summary)	Overall risk	Ageing effects (biomarkers)
[11]	Clinical	Antibiotics (mixed)	Patients with vascular disease (meta-analysis)	RoB-2	Moderate heterogeneity; unclear blinding; limited reporting.	Some concerns	Mixed outcomes; no consistent biomarker tracking; some ↓ CRP and vascular inflammation.
[136]	Clinical	Azithromycin/Roxithromycin	Senescent fibroblasts (clinical translation)	RoB-2	In vitro-clinical extrapolation; not randomized.	High	↓ SA-β-gal+ cells; ↓ p16/p21 expression in fibroblast biopsies.
[65]	Clinical	Azithromycin	Cystic fibrosis patients	RoB-2	Observational; small cohort; confounding not adjusted.	High	↑ Senescence markers in airway cells (p16, p21, SA-β-gal); systemic spillover likely.
[66]	Clinical	Azithromycin (COVID-19)	COVID-19 patients	RoB-2	Not randomized; strong confounding; small sample.	High	Theoretical ↓ SASP load proposed; not biomarker validated.
[67]	Clinical	Azithromycin	Women with endometriosis	RoB-2	Randomization not reported; allocation concealment unclear.	Some concerns	↓ Lesion progression; signals of ↓ senescence markers (p16, SA-β-gal) in tissue.
[61]	Clinical	VDA (Vit C, Doxycycline, Azithromycin)	Human adipose-derived MSCs	RoB-2	Ex vivo/MSC work; randomization unclear.	High	↓ Senescence gene expression (p16, p21, SASP mediators) in MSCs.
[62]	Clinical	Doxycycline	Endothelial cells from ethanol-exposed humans	RoB-2	Small cohorts; observational; incomplete adjustment.	Some concerns	↓ Inflammageing markers (IL-6, TNF-α); partial ↓ p16/p21 signals in endothelial cells.
[73]	Clinical	ART (Efavirenz/Zidovudine)	HIV⁺ patients under ART	ROBINS-I	Observational; confounding by indication; attrition bias.	Some concerns	↑ ROS, mitochondrial dysfunction, endothelial dysfunction; no direct senescence markers.
[109]	Clinical	Protease inhibitors	HIV⁺ patients	RoB-2	Observational; moderate confounding; incomplete reporting.	Some concerns	↑ Senescence phenotype (reversible); mitochondrial dysfunction.
[111]	Clinical	Protease inhibitors	HIV⁺ patients (vascular biopsies)	RoB-2	Non-randomized; mechanistic endpoints limited.	High	↑ Prelamin A accumulation; ↑ p16/p21; premature vascular senescence.
[112]	Clinical	Viral therapy context	HIV/Viral infections (review translational)	Narrative	Not interventional; observational extrapolation.	Some concerns	↑ Senescence in the viral infection context; drug exposure exacerbates markers.
[114]	Clinical	HAART	HIV⁺ patient endothelial cells	RoB-2	Observational; incomplete adjustment; confounding.	High	↑ Oxidative stress; ↑ endothelial senescence; ↑ monocyte adhesion.
[113]	Clinical	Antivirals	Endothelial cells from patients	RoB-2	High-content imaging assays; small cohorts.	Some concerns	Distinct ↑ senescence signatures across drugs; drug-specific biomarker profiles.
[135]	Clinical	Niclosamide	Ageing/Frailty patients (clinical models)	RoB-2	Early-stage; randomization not clear; limited duration.	Some concerns	↓ mTORC1 hyperactivation; ↓ frailty index; no direct p16/p21/SA-β-gal measured.
[105]	Human genomic analysis/observational mechanistic study	Ganciclovir (antiviral nucleoside analog)	Hematopoietic stem & progenitor cells (HSPCs) from HSCT recipients (n = 12 recipients; 15 expanded clones). Donors = matched controls	ROBINS-I	Selection bias: moderate (recipients selected based on post-transplant samples). Confounding: moderate (immunosuppression, CMV infection, other antivirals). Detection bias: low (whole-genome sequencing, validated pipelines). Reporting bias: low (complete genomic datasets shared). Attrition bias: low (all sequenced samples included).	Moderate	Significant increase in somatic mutation load in recipients exposed to ganciclovir. Mutation burden increased 3–6-fold vs. non-exposed donor HSPCs. Distinct antiviral-associated mutational signature (“Signature GX”) identified. Mutations enriched in T>A and C>A substitutions, consistent with nucleoside-analog misincorporation. Same signature observed in therapy-related cancers in transplant recipients. It indicates genomic instability, a hallmark of aging.
[79]	Clinical	Microbiome-ageing/antibiotic exposure	Human gut microbiome cohorts	ROBINS-I	Observational; confounding not excluded; no specific antibiotics mentioned.	Some concerns	↑ Inflammageing: altered microbiome linked to ↑ systemic senescence load.
[50]	Clinical	Microbiome-sarcopenia/nonspecific antibiotics	Ageing frail patients	ROBINS-I	Observational; small cohorts/antibiotics were used, but no specific class was mentioned.	Some concerns	↑ Frailty; ↓ muscle mass; inflammageing.
[58]	Clinical	Antibiotic exposure	Dysbiosis in the human gut	ROBINS-I	Observational; no blinding.	High	↑ Dysbiosis; ↑ pro-inflammatory tone; indirect vascular ageing.
[59]	Clinical	Antibiotics/Antiviral drugs (nonspecific)	Elderly patients with bacterial infections	ROBINS-I	Observational; moderate confounding.	Some concerns	↑ Susceptibility to infection; ↑ SASP cytokines; ↑ vascular inflammation.
[49]	Clinical	Gut microbiome dysbiosis	CKD patients	ROBINS-I	Observational; no blinding; dietary confounding.	Some concerns	↑ TMAO; ↑ oxidative stress; ↑ arterial stiffness.
[75]	Clinical	Microbiome/CKD	CKD patients	ROBINS-I	Observational; dietary confounding.	Some concerns	↑ TMAO; ↑ endothelial dysfunction.
[69]	Clinical	TMAO/Nonspecific antibiotic	Human cohorts	ROBINS-I	Observational; dietary confounding and lack of mention of the employed antibiotic.	Some concerns	↑ TMAO associated with ↑ arterial stiffness, inflammaging.
[76]	Clinical	Broad spectrum antibiotics/microbiota metabolites	Human cohorts	ROBINS-I	Observational; no blinding.	Some concerns	↑ SASP signaling; microbiota-derived metabolites drive vascular inflammation.
[104]	Clinical	miRNA mimics/inhibitors	COVID-19 patients	RoB-2	Small trials; confounding; not blinded.	High	↓ Viral-induced senescence signaling; ↓ cytokine storm; indirect vascular benefit.
[103]	Clinical	LncRNA antifungal	Patients with candidiasis (biopsy models)	RoB-2	Translational; not blinded.	Some concerns	↓ Fungal burden; ↓ inflammatory senescence response.
[108]	Clinical	Microbiome histone modification/antibiotic treatment	Human hepatology patients	ROBINS-I	Observational; confounding not excluded/exact antibiotic not mentioned.	Some concerns	Irreversible histone acetylation; independent of SCFA; links to epigenetic ageing.
[82]	Clinical	Antivirals	Viral infection patients	RoB-2	Non-randomized; confounding.	High	↑ Stress proteins; mitochondrial strain; senescence pathway engagement.
[143]	Clinical	Antivirals	HIV⁺ patients (old regimens)	ROBINS-I	Observational; incomplete adjustment.	Some concerns	↑ Mitochondrial toxicity; ↑ oxidative stress; indirect senescence induction.
[127]	Clinical	Itraconazole	Endothelial cells from patients	RoB-2	Mechanistic study; no blinding.	Some concerns	↓ mTORC1 activation; ↓ angiogenesis; senescence-modulating pathway engaged.
[128]	Clinical	Itraconazole	Endothelial cells (clinical setting)	RoB-2	Small cohorts; limited blinding.	Some concerns	↓ VEGFR2 glycosylation; ↓ angiogenesis; possible senescence-modulating pathway.
[129]	Clinical	Itraconazole	Endothelial angiogenesis (patients)	RoB-2	Observational, translational; confounding.	Some concerns	↓ Angiogenesis; modulation of senescence pathways.
[131]	Clinical	Amphotericin B	Human endothelial cells	RoB-2	Mechanistic; small sample.	Some concerns	↑ ROS; mitochondrial dysfunction; senescence induction.
[20]	Retrospective cohort (observational)	Multiple systemic antibiotics (all classes aggregated)	2,159,864 adults, age 40–79, Korea; 10-year follow-up	ROBINS-I	Confounding: Infection severity & comorbidities may influence antibiotic use; selection bias: possible immortal-time bias; exposure misclassification: antibiotic days aggregated, no dose/type specificity; outcome bias: relies on hospital records.	Moderate, serious	Long-term antibiotic exposure (≥ 365 days) increased CVD risk: aHR = 1.10 (95% CI 1.07–1.13). No direct vascular aging biomarkers measured; evidence suggests epidemiological association, not mechanistic aging effects.
[21]	Prospective cohort (children)	Systemic antibiotics (various classes)	5-year-old children from the WHISTLER birth cohort (Netherlands)	ROBINS-I	Confounding (infections vs. antibiotic use) Exposure misclassification (prescription ≠ actual ingestion; no class/dose stratification). Outcomes limited to subclinical vascular markers (CIMT, distensibility). Loss to follow-up/selection bias (children with vascular measurements ≠ full cohort).	Moderate	↑ CIMT: +18.1 µm (3-mo), +10.7 µm (6-mo). ↓ Carotid distensibility: –8.3 mPa^–1 (6-mo).
[145]	Human tissue observational + multiomics analysis	Maraviroc (CCR5 antagonist)	Human skeletal muscle from donors across the age spectrum	ROBINS-I	Tissue: skeletal muscle, not vascular tissue • Senescence mapping in muscle may not reflect vascular cell senescence. • Drug tested for senotherapeutic potential, but not in a vascular context. • Cross-sectional design (aging donors), observational, not longitudinal.	Moderate, high risk/indirect relevance	Identification of senescent cell populations; heterogenous SASP profiles; epigenomic alterations in aged muscle; evidence that blocking SASP-receptor interactions (via Maraviroc) can modulate senescence-associated pathology.
[100]	Clinical/Observational	Aminoglycosides (geneticin/G418, hygromycin B, streptomycin); rifamycin (rifampicin); β-lactams (amoxicillin, ampicillin, cefepime, cefuroxime)	Human-derived glioma cell lines and fibroblast	Narrative	In-vitro model; cancer cell lines; short exposure duration; no organism-level ageing outcomes; no randomisation/blinding applicable.	Moderate	↑ Alpha satellite DNA transcription (1.5–3-fold); ↓ H3K9me3; ↑ H3K18ac → heterochromatin erosion, epigenetic drift, genome instability (aging hallmarks).

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RoB-2 was applied for interventional trials, and ROBINS-I for observational studies. Ageing biomarkers reported included SA-β-gal activity, p16/p21 expression, mitochondrial dysfunction, oxidative stress, prelamin A accumulation, TMAO levels, and frailty indices (n = 36). ↑: increased/upregulated/elevated, ↓: decreased/downregulated/reduced. ART: antiretroviral therapy; CIMT: carotid intima-media thickness; HAART: highly active ART; ROS: reactive oxygen species; SASP: senescence-associated secretory phenotype; SCFA: short-chain fatty acid; TMAO: trimethylamine N-oxide; mTORC1: mechanistic target of rapamycin complex 1.

Declarations

Acknowledgments

The authors thank Lusaka Apex Medical University, School of Health Sciences, and Faculty of Medicine, for their academic and institutional support towards the completion of this manuscript.

Author contributions

CWS: Conceptualization, Writing—original draft, Writing—review & editing. JM: Data curation, Resources, Writing—review & editing. SKD: Methodology, Writing—review & editing, Supervision. AC: Data curation, Visualization, Writing—review & editing. LS: Validation, Resources, Writing—review & editing. KM: Investigation, Formal analysis, Writing—review & editing. All authors read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

The dataset used during the study is available from the corresponding author upon request.

Funding

No funding was received for this manuscript.

Copyright

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