Background and Objectives Substantial heterogeneity in cognitive aging trajectories has been observed among older adults, with some individuals maintaining exceptional cognitive function (“superagers” or “successful cognitive aging (SCA)”). The biological mechanisms underlying SCA remain unclear. This systematic review synthesizes current evidence on quantifiable SCA biomarkers to address this critical gap. Research Design and Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we systematically searched PubMed, Scopus, PsycINFO, and Web of Science (up to December 2024). After screening 6699 records, 62 studies met the inclusion criteria. Data from included studies were extracted, assessed for risk of bias, and synthesized for integrated findings. Results We identified 34 SCA definitions, categorized them into three types, and analyzed biomarkers across six domains: (1) genetic/epigenetic biomarkers, (2) biofluid biomarkers, (3) histological biomarkers, (4) positron emission tomography (PET) biomarkers, (5) structural magnetic resonance imaging (MRI) biomarkers, and (6) functional neuroimaging biomarkers. Integrated findings suggest SCA is driven by unique multi-domain biological mechanisms (e.g., young DNA methylation age, high von Economo neuron density, and efficient glucose metabolism, etc), not merely resistance to age-related neuropathology such as amyloid-β and tau. Neuroimaging findings highlight the role of brain reserve, maintenance, and compensation on SCA, particularly within a newly defined “cingulate gyrus–medial temporal lobe–frontal cortex” brain signature. Discussion and Implications This systematic review advances our understanding of SCA’s biological substrates, provides theoretical frameworks for future SCA biomarker research, and offers a foundation for future strategies to promote cognitive health in aging populations.
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