A structured narrative review spanning PubMed/MEDLINE and Embase (2010–2026) positions knee osteoarthritis not as a mechanical wear-and-tear condition but as a phenotype-dependent manifestation of joint aging, driven by cellular senescence, inflammaging, mitochondrial dysfunction, synovial inflammation, and impaired vascular remodeling. The analysis evaluates the full therapeutic spectrum: lifestyle modification (weight loss, exercise) shows consistent pain and functional benefits with favorable systemic anti-inflammatory effects; pharmacologic agents and intra-articular corticosteroids act as symptom modulators only; PRP, autologous conditioned serum, and mesenchymal stromal cells remain limited by heterogeneity and absent long-term structural data; genicular artery embolization (GAE) is biologically plausible for hypervascularity-dominant synovitis but lacks consistent sham-controlled validation.
Reframing KOA through a geroscience lens is arguably the most important conceptual shift in musculoskeletal medicine this decade. It aligns KOA with the broader hallmarks-of-aging framework, opening therapeutic targets — senolytics, mitochondrial support, NAD+ precursors — that symptom-focused trials have ignored entirely. Practically, this means clinicians should phenotype patients before selecting therapy: a synovitis-dominant patient may respond to GAE or anti-inflammatory biologics, while a senescence-dominant joint may eventually benefit from dasatinib/quercetin-class interventions. The review's limitation is inherent to its design — narrative reviews cannot resolve inconsistent trial data, and GAE in particular needs adequately powered, sham-controlled RCTs before clinical adoption. Still, this framework is paradigm-shifting in orientation, even if the evidence supporting novel therapies remains early-stage.
