Aging is a major risk factor for many types of cancer, and the molecular mechanisms implicated in aging, progeria syndromes, and cancer pathogenesis display considerable similarities. Maintaining redox homeostasis, efficient signal transduction, and mitochondrial metabolism is essential for genome integrity and for preventing progression to cellular senescence or tumorigenesis. NAD+ is a central signaling molecule involved in these and other cellular processes implicated in age-related diseases and cancer. Growing evidence implicates NAD+ decline as a major feature of accelerated aging progeria syndromes and normal aging. Administration of NAD+ precursors such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) offer promising therapeutic strategies to improve health, progeria comorbidities, and cancer therapies. This review summarizes insights from the study of aging and progeria syndromes and discusses the implications and therapeutic potential of the underlying molecular mechanisms involved in aging and how they may contribute to tumorigenesis.

The biology of aging is an area of intense research, and many questions remain about how and why cell and organismal functions decline over time. In mammalian cells, genomic instability and mitochondrial dysfunction are thought to be among the primary drivers of cellular aging. This review focuses on the interrelationship between genomic instability and mitochondrial dysfunction in mammalian cells and its relevance to age‐related functional decline at the molecular and cellular level. The importance of oxidative stress and key DNA damage response pathways in cellular aging is discussed, with a special focus on poly (ADP‐ribose) polymerase 1, whose persistent activation depletes cellular energy reserves, leading to mitochondrial dysfunction, loss of energy homeostasis, and altered cellular metabolism. Elucidation of the relationship between genomic instability, mitochondrial dysfunction, and the signaling pathways that connect these pathways/processes are keys to the future of research on human aging. An important component of mitochondrial health preservation is mitophagy, and this and other areas that are particularly ripe for future investigation will be discussed.

Key Points Tolerance of oxidative DNA lesions ensures the genomic and functional integrity of hematopoietic stem and precursor cells. Endogenous DNA damage–induced replication stress is associated with mitochondrial dysfunction.