Mechanistic redundancy and hierarchy of aging mechanisms: implications for strategies to extend healthspan and biomarker integration.

Aging involves a network of interrelated biological processes that differ in causality and impact. This review proposes a hierarchical framework of primary, secondary, and tertiary drivers of human aging while emphasizing the extensive feedback loops and mechanistic redundancy. Primary mechanisms include molecular damage, particularly genomic and mitochondrial DNA damage, and mutation accumulation that cumulatively result in genomic instability, and telomere attrition, which represents a separate primary driver. Although rarely recognized as an independent aging mechanism, female sex hormone decline, particularly the abrupt loss of sex steroid signaling at menopause and earlier perimenopausal changes, may constitute a primary sex-specific driver of human aging as an evolved process that amplifies molecular and physiological deterioration. Mechanisms acting as both primary and secondary include damage to molecules other than DNA including protein damage with loss of proteostasis and lipid damage, which may arise directly from molecular insults or emerge as downstream consequences of DNA damage and other primary mechanisms, while also feeding back to accelerate upstream deterioration. Secondary mechanisms comprise cellular senescence, impaired macroautophagy, deregulated nutrient sensing, epigenetic alterations, mitochondrial dysfunction, and altered intercellular communication. These processes emerge downstream of initial damage and further reciprocally reinforce it. Tertiary mechanisms of aging comprise stem cell exhaustion, chronic inflammation, and dysbiosis, which represent the system-level deterioration exacerbating molecular dysfunction. This hierarchical network-based model suggests that many hallmarks of aging may represent manifestations of redundant upstream molecular insults. This review focuses on primary mechanisms as the causative drivers of aging and proposes that the strategy to extend healthspan may require preventive approaches targeting distinct redundant primary mechanisms. Complex preventive interventions that simultaneously reduce molecular damage, slow telomere attrition, and compensate for estrogen depletion may delay the initiation and amplification of secondary and tertiary aging mechanisms. This framework supports coordinated multi-target strategies for healthspan extension and underscores the need for validated biomarkers that reflect these upstream processes as part of an integrated preventive approach.