Does the accumulation of stochastic nuclear DNA damage over time contribute to all aspects of degenerative aging, or only contribute to cancer risk? That is an interesting question, and the answers lack strong proof in one direction or another. The current consensus is that mutational damage to nuclear DNA does indeed contribute to aging, most likely through expansion of such mutations into sizable fractions of a tissue when they occur in stem and progenitor cells. Thus there is some interest in the research community in finding ways to enhance the stability of the genome: better repair, or lower levels of damaging incidents. Given an efficient enough approach that only affects DNA damage and no other aging-related mechanism, it should be possible to use that to obtain strong proof or disproof of the role of nuclear DNA damage in aspects of aging other than cancer risk.
When does the aging process begin? How long can we live? Why do we age? These questions are highly debated with no distinct, definitive answers. Does aging begin when our skin starts to wrinkle, or when our hair commences to turn grey? Or perhaps aging begins after the completion of growth. Aging has also been defined as a shift in an organism's aging reality. The aging reality has been described as a mutually enslaved system of DNA and its environment in which signaling failures within this DNA environment occur over time.
The idea that aging is a random stochastic program is supported by many researchers in the field. The stochastic idea of aging gained traction when the free radical theory of aging was proposed. This theory states that aging occurs due to the natural wear and tear of cellular machinery and biological substances due to exposure to free radicals generated within the cell. Biological systems are constantly fighting a battle with its environment, both internally and externally, to ward off damage. The simple generation of mitochondrial-dependent energy and DNA replication expose cells to damage that must be repaired.
It now seems quite clear that cellular aging is largely dependent on the degree to which genomic instability has affected DNA-dependent processes. Many studies, from yeast to humans, have repeatedly shown that during aging, senescent cells that exit the cell cycle or cease to function harbor large accumulations of DNA mutation, rearrangements, and epigenetic alterations. There are numerous sources of DNA damage, both endogenous and exogenous, that the cell must deal with. It is thought that a somatic cell may receive as many as 100,000 lesions daily. It is not a coincidence that most age-dependent diseases, such as cancer, type II diabetes, and cardiopulmonary and neurodegenerative diseases are associated with increasingly elevated levels of genomic instability that occur over time.
Inside a cell, multiple antagonistic molecular networks are vying for available resources to respond to either stress or nutrients. It should be clear that the opposition of these pathways should not be all or none, as aspects of nutrient availability may be present even in an unfavorable environment. Thus, the question becomes how are nutrient and stress sensing networks regulated? What mediates the end of stress signaling when the stress is gone, or the stalling of the nutrient sensing pathways when the food source is used up? To answer these questions, it is important to identify components that connect stress and nutrient-sensing pathways. The Anaphase Promoting Complex (APC) has come to light as a potential link between the stress and nutrient sensing networks.
The APC is largely known for its role in cell cycle progression, but we and others have identified it as a central player in stress sensing and lifespan determination using the simple brewing yeast eukaryotic model system. Mitosis is a time during the cell cycle when DNA damage can become permanent and lead to further chromosome erosion and genomic instability. The APC is also required for replication-independent chromatin assembly and histone modifications. Considering that replication-independent chromatin assembly is required for DNA repair, we speculate that the APC may be involved in repair of DNA damage incurred during chromosome segregation.
We have reported that the yeast APC prolongs longevity (increased expression of only APC10 increased replicative lifespan), responds to stress, and interacts with multiple conserved stress response pathways. The positioning of the APC at the intersection point of the stress and nutrient sensing pathways confers importance upon this complex, as it may have the potential to protect the cells that come together to form the zygote from the aging process. The potential for aging likely begins for an individual as soon as the germ cells responsible for them are born. It is critical that the repair mechanisms within these cells are functioning optimally. As long as the APC is at its peak function, protection against cellular damage should be high. With continued proper function of the APC through the life of the germ cells and the subsequent offspring, increased healthspan may be possible.