Mosaic loss of Y chromosome (mLOY) is an acquired condition wherein a sizeable proportion of an organ's cells have lost their Y. Large-scale cohort studies have shown that mLOY is age-dependent and a strong risk factor for all-cause mortality and adverse outcomes of age-related diseases. Emerging multi-omics approaches that combine gene expression, epigenetic and mutational profiling of human LOY cell populations at single-cell levels, and contemporary work in in vitro cell and preclinical mouse models have provided important clues into how mLOY mechanistically contributes to disease onset and progression. Despite these advances, what has been missing is a system-level insight into mLOY. By integrating the most recent advances in wide-ranging aspects of mLOY research, we summarize a unified model to understanding the cause and consequence of mLOY at the molecular, cellular, and organismal levels. This model, referred to as the "Unstable Y Cascade model," states that (i) the rise and expansion of LOY result from interaction by the inherently unstable Y, germline genetic and epigenetic variants, and numerous cell-intrinsic and external factors
(ii) LOY initiates genomic, epigenomic, and transcriptomic alterations in X and autosomes, thereafter induces a cascade of tissue-specific cellular alterations that contribute locally to the onset and progression of diseases
and (iii) LOY cells exert paracrine effects to non-LOY cells, thereby amplifying LOY-associated pathological signaling cascades to remote non-LOY cells. This new model has implications in the development of therapeutic interventions that could prevent or delay age-related diseases via mitigating mLOY burden.