Mitochondrial Changes in Ageing Caenorhabditis elegans – What Do We Learn from Superoxide Dismutase Knockouts?

One of the most popular damage accumulation theories of ageing is the mitochondrial free radical theory of ageing (mFRTA). The mFRTA proposes that ageing is due to the accumulation of unrepaired oxidative damage, in particular damage to mitochondrial DNA (mtDNA). Within the mFRTA, the “vicious cycle” theory further proposes that reactive oxygen species (ROS) promote mtDNA mutations, which then lead to a further increase in ROS production. Recently, data have been published on Caenorhabditis elegans mutants deficient in one or both forms of mitochondrial superoxide dismutase (SOD). Surprisingly, even double mutants, lacking both mitochondrial forms of SOD, show no reduction in lifespan. This has been interpreted as evidence against the mFRTA because it is assumed that these mutants suffer from significantly elevated oxidative damage to their mitochondria. Here, using a novel mtDNA damage assay in conjunction with related, well established damage and metabolic markers, we first investigate the age-dependent mitochondrial decline in a cohort of ageing wild-type nematodes, in particular testing the plausibility of the “vicious cycle” theory. We then apply the methods and insights gained from this investigation to a mutant strain for C. elegans that lacks both forms of mitochondrial SOD. While we show a clear age-dependent, linear increase in oxidative damage in WT nematodes, we find no evidence for autocatalytic damage amplification as proposed by the “vicious cycle” theory. Comparing the SOD mutants with wild-type animals, we further show that oxidative damage levels in the mtDNA of SOD mutants are not significantly different from those in wild-type animals, i.e. even the total loss of mitochondrial SOD did not significantly increase oxidative damage to mtDNA. Possible reasons for this unexpected result and some implications for the mFRTA are discussed

The Function of Saffron and its Constituent in Gastroenterological Tissues

Japan has been moving towards a super aging society, resulting in a rapidly increasing prevalence of lifestyle diseases, including colon cancer. Japanese patients survey by the Ministry of Health, Labour and Welfare reported 235,000 colon cancer patients in 2015, and this number is quickly increasing due to the change of dietary life style from the typical Japanese food to the westernized style food. Although the cancer chemotherapy has been widely developing recently, some natural product support, having wide spectra of bioactivity, however mild, are required. Saffron finds use as folk medicines as well as a flavoring and a coloring agent. Saffron consists of three main chemical components; red color, crocetin glycosides; a bitter taste, picrocrocin; and spicy aroma, safranal. In this chapter, we evaluate the activities of saffron extracts and a major crocetin glycoside, crocin. against colorectal cancer in in vitro and in vivo trials. Saffron crude extracts, which contain approximately 40% of crocin, significantly inhibited the growth of colorectal cancer cell lines HCT-116, HT-29 and SW-480, although crocin did not affect for non-cancer cells. Crocin significantly inhibited the development of colonic adenocarcinomas induced by azoxymethane and dextran sodium sulfate in mice during 18 weeks feeding. The crocin feeding experiment for 4 weeks evidently inhibits the dextran sodium sulfate induced colitis and, then, the clear suppression for the mRNA expression of tumor necrosis factor α, interleukin- (IL-) 1β,IL-6, interferon γ, NF-κB, cyclooxygenase-2, and inducible nitric oxide synthase, and the increase of Nrf2 mRNA expression in the colorectal mucosa occurred. From these results we suggest that crocin can suppress chemically induced colitis and colitis-related colon carcinogenesis in mice mainly through the inhibition of inflammation related cytokines, indicating that saffron and crocin are suitable candidates for the prevention of colitis and inflammation-associated colon carcinogenesis. We further review the supporting phenomena like strong anti-oxidant and anti-inflammation activities of crocin using our previous publications