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Mitochondria may be primary targets of free radical damage associated with aging. We have found that mitochondrial glutathione is markedly oxidized with aging in rats and mice. The oxidized to reduced glutathione ratio rises with aging in the liver, kidney, and brain. The magnitude of these changes is much higher than that previously found in whole cells of any species previously studied. In the liver, this ratio (expressing GSSG as a percent of GSH) changed from 0.77 ± 0.19% (n=5) in young rats to 2.47 ± 1.25% (n = 5) in old ones, i.e., 320% of the controls. In the brain and kidney, values for old rats were, respectively, 600 and 540% higher than those of young rats. A marked oxidation of mitochondrial glutathione also occurred in mice. Aging also caused an increase in 8‐oxo‐7,8‐dihydro‐2'‐dexo) guauosine levels in mtDNA in rats and mice. Oral antioxidant administration protected against both glutathione oxidation and mtDNA damage in rats and mice. Finally, we have found a direct relationship between mtDNA damage and mitochondrial glutathione oxidation. This occurs both in rats (r=0,95) and in mice (r=0.98). This relationship, which has been observed for the first time in these studies, underscores the role of glutathione in the protection against free radical damage that occurs upon aging.—Garcia de la Asuncion, J., Millan, A., Pla, R., Bruseghini, L., Esteras, A., Pallardo, F. V., Sastre, J., ViÑa, J. Mitochrondrial glutathione oxidation correlates with age‐associated oxidative damage to mitochondrial DNA. FASEB J. 10, 333‐338 (1996)

activated species.3 It is well known that fixed, postmitotic Mitochondrial damage may be a major cause of cellucells accumulate different age pigments, especially lipofuscin. lar aging. So far, this hypothesis had only been tested A considerable amount of this pigment may derive from inusing isolated mitochondria. The aim of this study was jured mitochondria. 4 This led us to propose a hypothesis 5 of to investigate the involvement of mitochondria in aging cell aging, according to which senescence is a by-product of using whole liver cells and not isolated mitochondria oxy-radical attack to the mitochondrial genome. only. Using flow cytometry, we found that age is associRecently, several studies have shown changes in mitochonated with a decrease in mitochondrial membrane potendria on aging. Age-related changes in mitochondrial respiratial (30%), an increase in mitochondrial size, and an intory function and in mitochondrial transport systems have crease in mitochondrial peroxide generation (23%).been reported. [6][7][8] All these changes were found in experiments Intracellular peroxide levels were also increased. The using isolated mitochondria. However, these effects could be number of mitochondria per cell and inner mitochoncaused by altered susceptibility of old mitochondria to the drial membrane mass did not change. Gluconeogenesis stress caused by the isolation procedure. Moreover, because from glycerol or fructose (mitochondrial-independent) intact cells were not used, the mitochondrial-cytosolic interdid not change with age, whereas it did from lactate actions were also ignored. This may lead to errors. The iso-(mitochondrial-dependent). The change in the rate of lated hepatocyte is an excellent model for aging studies. 9 This gluconeogenesis was not accompanied by changes in is especially useful when attempting to study aging at the any of the following parameters: phosphoenolpyruvate cellular level, using whole cells. carboxykinase or pyruvate carboxylase activities or miTo our knowledge, no attempts have been made to correlate tochondrial ATP/ADP or cytosolic NADH/NAD / ratios. age-associated changes in physiological functions of intact This was caused by a decreased rate of malate export cells with specific biochemical or molecular changes in mito-(to 20% of the controls) from mitochondria. The impairchondria. The aim of this study was to test whether mitochonment of the mitochondrial malate transporter is postdrial performance is impaired with aging, using intact liver transcriptional because its expression in Xenopus oocells. To this end, we have measured the rate of biochemical cytes using polyadenylated RNA from livers of young or pathways, gluconeogenesis, and ketogenesis, which critically old animals did not change. Ketogenesis from oleate also depend on mitochondrial function. In addition, we have used fell in hepatocytes from old rats. Our results show, for flow cytometry, which allows a noninvasive analysis of indithe first time in intact cells, a correlation between agevidual cells, to study ...

After completing this course, the reader will be able to:1. Use patient age as only one consideration, along with tumor status and comorbidities, in deciding on treatment strategies for elderly colorectal cancer patients.2. Obtain and apply information regarding the medical, functional, mental, and social status of colorectal cancer elderly patients in order to make appropriate therapeutic decisions.This article is available for continuing medical education credit at CME.TheOncologist.com. CME CME ABSTRACTPurpose. To analyze differences in the therapeutic approach to and tumor-related mortality of young and elderly colorectal cancer (CRC) patients. Patients and Methods. This was a descriptive study of a retrospective cohort, based on administrative databases, of all patients with CRC diagnosed or treated in our institution. We extracted data on sociodemographic characteristics, comorbidity, type of cancer, type of treatment received, survival time, and cause of death. We compared differences between a young group (YG) (age <75 years) and an older group (OG) (age >75 years) and assessed the variables associated with receiving different therapeutic options (multivariate analysis) and with survival time (Cox proportional hazards models).Results. The study included 503 patients (YG, 320; OG, 183), with mean ages of 63.1 years in the YG and 81.8 years in the OG. No differences were observed between the groups in degree of differentiation, extension, tumor stage, or comorbidity. After adjustment for gender, comorbidity, and tumor localization and extension, YG patients were more likely than OG patients to receive surgery, radiotherapy, and chemotherapy and less likely to receive palliative care. After a median follow-up of 36.5 months, YG patients had a longer tumor-specific survival time than OG patients (36.41 months vs 26.05 months). After further adjustment, the YG had a lower tumor-specific mortality risk (hazard ratio, 0.66) than the OG.Conclusion. In comparison with younger patients, elderly CRC patients are undertreated, mainly because of their age and not because of their tumor type or comorbidity. Elderly patients have a significantly shorter tumor-specific survival time, partially because of this undertreatment.

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