Proposed model for the role of dysfunctional and short telomeres in the pathogenesis of human disease. Aging, bone marrow stress, and genetic factors, such as mutations in telomerase complex genes (TERT, TERC, DKC1, and NOP10), shelterin components (TINF2, TERF1, and TERF2), or in other genes (SBDS and DDX11) produce progressive telomere erosion. Excessive telomere shortening results in defective cell proliferation, senescence, apoptosis, and genomic instability. Environmental factors, such as viruses, drugs, smoking, or asbestos exposure, may contribute to telomere shortening as well as injury to an organ with limited regeneration capacity, thus triggering disease development (aplastic anemia, pulmonary fibrosis, and hepatic cirrhosis). Short telomeres also promote genomic instability, breakage-fusion-bridge cycles, and aneuploidy, which can lead to myelodysplasia (MDS) or leukemia (AML).