Age-related accumulation of cellular damage and death has been linked to oxidative stress. Calorie restriction (CR) is the most robust, nongenetic intervention that increases lifespan and reduces the rate of aging in a variety of species. Mechanisms responsible for the antiaging effects of CR remain uncertain, but reduction of oxidative stress within mitochondria remains a major focus of research. CR is hypothesized to decrease mitochondrial electron flow and proton leaks to attenuate damage caused by reactive oxygen species. We have focused our research on a related, but different, antiaging mechanism of CR. Specifically, using both in vivo and in vitro analyses, we report that CR reduces oxidative stress at the same time that it stimulates the proliferation of mitochondria through a peroxisome proliferation-activated receptor coactivator 1␣ signaling pathway. Moreover, mitochondria under CR conditions show less oxygen consumption, reduce membrane potential, and generate less reactive oxygen species than controls, but remarkably they are able to maintain their critical ATP production. In effect, CR can induce a peroxisome proliferationactivated receptor coactivator 1␣-dependent increase in mitochondria capable of efficient and balanced bioenergetics to reduce oxidative stress and attenuate age-dependent endogenous oxidative damage.aging ͉ peroxisome proliferation-activated receptor coactivator 1 ͉ reactive oxygen species O ne of the major hypotheses directing gerontological research over several decades is that aging results from the accumulation of macromolecules damaged by oxidative stress and that the major loci of this damage is the mitochondrion (1-4). This hypothesis has been proposed as one explanation of how calorie restriction (CR) in various animal models works so effectively to increase lifespan and stress resistance, reduce susceptibility to chronic disease, and attenuate age-related functional decline (5, 6). Past studies have demonstrated that CR decreases mitochondrial electron and proton leak in mammalian cells and attenuates damage resulting from intracellular oxidative stress (4, 6-9).Mitochondria provide an integrated functional network, many components of which are vulnerable to oxidative stress that can impair cellular function and increase the chance of cell death. Age-related accumulation of cellular damage and death ultimately leads to impaired organ function generating further physiological dysfunction (1, 2). The mitochondrial theory of aging proposes that somatic mutations of mtDNA induced by reactive oxygen species (ROS) are the primary cause of cellular energy decline with complex I being particularly affected by decreasing its rate of electron transport (3).CR is the most robust, nongenetic intervention that increases lifespan and reduces the rate of aging in mammals and other organisms (5, 7). The mechanisms responsible for the antiaging effects of CR remain unknown and likely involve several processes. Results from many different laboratories support that both the activation of c...

A B S T R A C T PurposeAmplifications and mutations in the KIT proto-oncogene in subsets of melanomas provide therapeutic opportunities. Patients and MethodsWe conducted a multicenter phase II trial of imatinib in metastatic mucosal, acral, or chronically sun-damaged (CSD) melanoma with KIT amplifications and/or mutations. Patients received imatinib 400 mg once per day or 400 mg twice per day if there was no initial response. Dose reductions were permitted for treatment-related toxicities. Additional oncogene mutation screening was performed by mass spectroscopy. ResultsTwenty-five patients were enrolled (24 evaluable). Eight patients (33%) had tumors with KIT mutations, 11 (46%) with KIT amplifications, and five (21%) with both. Median follow-up was 10.6 months (range, 3.7 to 27.1 months). Best overall response rate (BORR) was 29% (21% excluding nonconfirmed responses) with a two-stage 95% CI of 13% to 51%. BORR was significantly greater than the hypothesized null of 5% and statistically significantly different by mutation status (7 of 13 or 54% KIT mutated v 0% KIT amplified only). There were no statistical differences in rates of progression or survival by mutation status or by melanoma site. The overall disease control rate was 50% but varied significantly by KIT mutation status (77% mutated v 18% amplified). Four patients harbored pretreatment NRAS mutations, and one patient acquired increased KIT amplification after treatment. ConclusionMelanomas that arise on mucosal, acral, or CSD skin should be assessed for KIT mutations. Imatinib can be effective when tumors harbor KIT mutations, but not if KIT is amplified only. NRAS mutations and KIT copy number gain may be mechanisms of therapeutic resistance to imatinib.