The Contribution of DNA Interstrand Crosslinks to Aging

摘要: DNA damage is hypothesized to be a driver of aging. In support this, and genetic mutations, resulting from replication that damage, both increase in the nuclear genome as organisms age. Furthermore, long-lived species are relatively resistant genotoxic stress. Conversely, with repair-deficient or instability disorders have decreased lifespans age rapidly, which supports this theory. One main source endogenous reactive oxygen (ROS) generated by mitochondria. While it true ROS can other macromolecules cell, only one repaired rather than replaced, illustrating dire consequences damage. If repair not 100% complete over lifetime, stands reason unrepaired could major contributor aging. Ercc1-/Δ mice deficient multiple pathways therefore suffer more normal mice. As consequence, they prematurely, modeling human progeroid syndrome. This makes them useful vivo system for studying contribution For reason, we challenged chemotherapeutic crosslinking agent determine if promotes aging, an environmental contaminant diet polyunsaturated fatty acids see these promote We found particular class lesions, interstrand crosslinks, accelerate aging associated changes through cytostatic, cytotoxic mechanism. also exposed specialized antioxidant test hypothesis mitochondrial-derived cause Collectively, studies identified genes, influences therapeutics impact lifespan healthspan. total, strongly degenerative These public health significance reveal novel strategies decrease burden, presenting potential opportunities improve quality life old