title: The Role of Genome Instability in Frailty: Mitochondria versus Nucleus.
abstract: Late-life aging in humans is often associated with severe frailty. This suggests catastrophic events reaching an undeniable biological threshold in cellular stability and a rapidly diminished homeostasis. The driving force of the syndrome is likely 'genetic instability' or 'genomic instability', a high frequency of mutations and deletions within the genome (both nuclear and mitochondrial DNA) of bodily somatic cells caused by DNA damage and inefficient repair. Reactive oxygen species, calcium deregulation, and iron dyshomeostasis are potential chemical triggers of nucleic acid sequence alterations and chromosomal rearrangements. These include mutations, deletions, translocations, chromosomal inversions, and single- and double-strand DNA breaks. Nuclear damage, such as telomere shortening, also appears to cause an abnormal expression of several proteins, including p53, which leads to impaired mitochondrial biogenesis, mitochondrial permeability transition pore opening, apoptosis, and other biological events. Moreover, mitochondrial DNA damage could produce inaccurate translation and synthesis of proteins important for energy production in the inner mitochondrial membrane. Another cause of genomic instability may be a reduced expression and function of DNA repair genes, especially when stressful events trigger slow responses. With late-life frailty, overall endogenous damage occurs much more frequently and repair is much less efficient, which further accelerates genomic instability.
authors.forename: Arnold Y
authors.initials: AY
authors.lastname: Seo
authors.forename: Christiaan
authors.initials: C
authors.lastname: Leeuwenburgh
mesh_terms: D000369:Aged, 80 and over; D000375:Aging / Q000235:genetics*; D000818:Animals; D017209:Apoptosis; D002908:Chronic Disease / Q000453:epidemiology*; D004249:DNA Damage; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D016330:Frail Elderly; D018507:Gene Expression Regulation, Developmental; D015894:Genome, Human; D054629:Genome, Mitochondrial; D042822:Genomic Instability; D006801:Humans; D063154:Mitochondrial Dynamics; D008957:Models, Genetic; D018384:Oxidative Stress; D012306:Risk; D013312:Stress, Physiological
chemical_list: D045643:DNA Repair Enzymes