ABSTRACT
In this review we discuss the interaction between metabolic stress, mitochondrial dysfunction, and genomic instability. Unrepaired DNA damage in the nucleus resulting from excess accumulation of DNA damages and stalled replication can initiate cellular signaling responses that negatively affect metabolism and mitochondrial function. On the other hand, mitochondrial pathologies can also lead to stress in the nucleus, and cause sensitivity to DNA-damaging agents. These are examples of how hallmarks of cancer and aging are connected and influenced by each other to protect humans from disease.
ABSTRACT
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.
