Background: Population aging is driving a convergent rise in three disorders historically managed in isolation: cardiovascular disease, neurocognitive decline, and osteoporotic bone loss. Accumulating mechanistic data indicate that these systems are coupled through shared regulators of calcium trafficking, inflammation resolution, vascular integrity, and inflammaging, supporting the concept of an integrated "Heart-Brain-Bone" axis. Three lipid-soluble nutrients-long-chain omega-3 polyunsaturated fatty acids (EPA/DHA), vitamin D3 (cholecalciferol), and vitamin K2 (menaquinone-7 [MK-7])-act on overlapping nodes of this network. Methods: We conducted a structured narrative review of mechanistic, observational, and randomized controlled trial (RCT) evidence, grading the strength of support for each claim. Results: Vitamin K2-dependent gamma-carboxylation of matrix Gla protein (MGP) and osteocalcin is proposed to reciprocally direct calcium away from the arterial wall and toward the bone matrix, offering a candidate mechanistic resolution of the "calcium paradox" associated with isolated vitamin D3 supplementation; EPA/DHA-derived specialized pro-resolving mediators may support resolution of endothelial and neuronal inflammation; and bone-, vascular-, and brain-derived signals (osteocalcin, FGF23, the neurovascular unit) interconnect the three organs. Human clinical evidence, however, is heterogeneous and formulation- and population-dependent: cardiovascular omega-3 RCTs are discordant (REDUCE-IT, which used icosapent ethyl [an EPA ethyl ester], positive; VITAL/STRENGTH/ASCEND null, predominantly in lower-risk or replete cohorts), cognitive trials are largely null or subgroup-dependent (MAPT, DO-HEALTH), and MK-7 improves surrogate bone and calcification biomarkers, with only a single recent hard-endpoint coronary calcification RCT (VitaK-CAC). Conclusions: The combined use of long-chain omega-3, vitamin D3, and MK-7 is mechanistically rational and hypothesis-generating rather than clinically established; benefit appears most plausible in individuals with elevated risk or demonstrable nutritional insufficiency, and least in replete, low-risk populations. Findings should be interpreted within a broader healthy-aging context that includes lifestyle and psychosocial factors. Adequately powered factorial RCTs stratified by baseline Omega-3 Index, 25(OH)D, and vitamin K status, with prespecified mechanistic biomarkers and hard endpoints, are required.

Background: Population aging is driving a convergent rise in three disorders historically managed in isolation: cardiovascular disease, neurocognitive decline, and osteoporotic bone loss. Mechanistic data indicate that these systems are coupled through shared regulators of calcium trafficking, inflammation resolution, vascular integrity, and inflammaging. On this basis, a “Heart–Brain–Bone” axis has been proposed; it should be understood as an integrative conceptual framework that organizes evidence drawn from three separate studies, not as a validated physiological entity with agreed diagnostic criteria or demonstrated modifiability. Three lipid-soluble nutrients—long-chain omega-3 polyunsaturated fatty acids (EPA/DHA), vitamin D3 (cholecalciferol), and vitamin K2 (menaquinone-7 [MK-7])—act on overlapping nodes of this network. Methods: We performed a structured narrative review. PubMed/MEDLINE, Embase, the Cochrane Library, and Web of Science were searched from database inception to 25 June 2026 using predefined term blocks for each nutrient, each organ domain, and each candidate mechanism, and the search was updated on 7 August 2026. Records were screened against prespecified inclusion and exclusion criteria by two authors independently, with disagreements resolved by a third. The strength of evidence for each nutrient–organ relationship was graded with an explicitly defined four-level scheme ((−) to (+++)) applied separately to preclinical, observational, randomized and meta-analytic evidence. Results: Vitamin K2-dependent gamma-carboxylation of matrix Gla protein (MGP) and osteocalcin has been proposed to influence whether calcium is incorporated into the bone matrix or deposited in the arterial wall, offering a candidate mechanistic account of the “calcium paradox” associated with isolated vitamin D3 supplementation; EPA/DHA-derived specialized pro-resolving mediators may support resolution of endothelial and neuronal inflammation; and bone-, vascular- and brain-derived signals (osteocalcin, FGF23, the neurovascular unit) interconnect the three organs. These mechanisms are biologically plausible but remain insufficiently confirmed in humans. The clinical evidence is heterogeneous, formulation- and population-dependent, and comprises positive, neutral and null results: cardiovascular omega-3 trials are discordant (REDUCE-IT, which used icosapent ethyl [an EPA ethyl ester], positive; VITAL/STRENGTH/ASCEND null, predominantly in lower-risk or replete cohorts); cognitive trials are largely null or subgroup-dependent (MAPT, DO-HEALTH, VITAL); and MK-7 improves surrogate bone and calcification biomarkers and slowed coronary artery calcification in one recent randomized imaging trial (VitaK-CAC), whereas combined MK-7 plus vitamin D3 did not slow aortic valve or coronary calcification in AVADEC and MK-7 did not reduce bone loss in early menopausal women. Recognized safety signals include a dose-dependent increase in atrial fibrillation with high-dose omega-3, adverse skeletal effects of high-dose or bolus vitamin D, and clinically relevant interference of even low-dose MK-7 with vitamin K antagonist therapy. Conclusions: No adequately powered randomized trial has demonstrated that the combination of long-chain omega-3, vitamin D3 and MK-7 is superior to its individual components or to placebo for any clinical endpoint. The combined regimen is therefore mechanistically rational and hypothesis-generating rather than clinically established; benefit appears most plausible in individuals with elevated risk or demonstrable nutritional insufficiency, and least in replete, low-risk populations. Findings should be interpreted within a broader healthy-aging context that includes lifestyle and psychosocial factors. Adequately powered factorial randomized controlled trials stratified by baseline Omega-3 index, 25(OH)D and vitamin K status, with prespecified mechanistic biomarkers and hard endpoints, are required.

Background: Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are under investigation as cell-free therapeutic platforms for neurodegeneration and age-related disease, and their biological effects depend partly on cargo composition. Existing MSC-EV cargo studies rarely integrate disease-gene evidence, aging databases, publication-level support and translational annotation. Methods: Using public data only, we assembled documented human MSC-EV cargo from ExoCarta and Vesiclepedia, deduplicated to independent source publications, and retained proteins with support from at least two publications. Each protein was integrated across independent-publication support, neurodegeneration disease-gene evidence (Open Targets), aging/senescence membership (CellAge, GenAge) and protein-interaction centrality (STRING) into a four-component Cargo Prioritization Score (CPS), after a component-correlation analysis. Robustness was assessed by weighting, component and source-study analyses; enrichment used the MSC-EV cargo universe as background; and top candidates received a separate Computational Liability Annotation (LOEUF, oncology association, expression breadth) with structured directionality curation. Results: The reproducible universe comprised 815 proteins derived from 9 source publications; disease-breadth was removed for redundancy with the neurodegeneration score (Spearman ρ=0.93). The ranking was robust to weighting (equal-weight ρ≈0.99) and to removal of any single component (ρ=0.83–0.94), but the eligible universe and several disease-anchored candidates depended strongly on individual source publications: excluding one publication reduced the universe from 815 to 228 proteins. 43 proteins carried joint neurodegeneration and aging evidence, including VCP, PARK7, SQSTM1, SOD1 and APOE, whereas the highest ranks partly reflected abundant, broadly expressed or highly connected proteins (GAPDH, ACTB, ALDOA, EGFR). Conclusions: The framework integrates evidence to prioritize MSC-EV cargo and separately annotates translational directionality and liability. A high CPS does not establish beneficial delivery, and the annotation is not a safety assessment; the output is a translationally annotated, hypothesis-generating candidate set for product-specific experimental validation.