NaCT (sodium-coupled citrate transporter) is an Na(+)-coupled citrate transporter identified recently in mammals that mediates the cellular uptake of citrate. It is expressed predominantly in the liver. NaCT is structurally and functionally related to the product of the Indy (I'm not dead yet) gene in Drosophila, the dysfunction of which leads to lifespan extension. Here, we show that NaCT mediates the utilization of extracellular citrate for fat synthesis in human liver cells, and that the process is stimulated by lithium.
Molecular advances of the past decade have led to the discovery of a myriad of 'aging genes' (methuselah, Indy, InR, Chico, superoxide dismutase) that extend Drosophila lifespan by up to 85%. Despite this life extension, these mutants are no longer lived than at least some recently wild-caught strains. Typically, long-lived mutants are identified in relatively short-lived genetic backgrounds, and their effects are rarely tested in genetic backgrounds other than the one in which they were isolated or derived.
A major challenge in current research into aging using model organisms is to establish whether different treatments resulting in slowed aging involve common or distinct mechanisms. Such treatments include gene mutation, dietary restriction (DR), and manipulation of reproduction, gonadal signals and temperature. The principal method used to determine whether these treatments act through common mechanisms is to compare the magnitude of the effect on aging of each treatment separately with that when two are applied simultaneously.
Caloric restriction (CR) and a reduced growth hormone (GH)-insulin-like growth factor (IGF-1) axis are associated with an extension of lifespan across taxa. Evidence is reviewed showing that CR and reduced insulin of GH-IGF-1 axis may exhibit their effects at least partly by their common stimulatory action on autophagy, the cell repair mechanism responsible for the housekeeping of cell membranes and organelles including the free radical generators peroxisomes and mitochondria.
Current models envision replicative senescence to be under dual control by the p53 and retinoblastoma (RB) tumour-suppressor pathways. The role of the p16(INK4a)-RB pathway is controversial, and the function of RB in human cells has not been tested directly. We used targeted homologous recombination to knock out one copy of RB in presenescent human fibroblasts. During entry into senescence, RB+/- cells underwent spontaneous loss of heterozygosity and the resultant RB-/- clones bypassed senescence. The extended lifespan phase was eventually terminated by a crisis-like state.
PURPOSE: To investigate the migratory and contractile behavior of isolated human corneal fibroblasts in fibrillar collagen matrices. METHODS: A telomerase-infected, extended-lifespan human corneal fibroblast cell line (HTK) was transfected by using a vector for enhanced green fluorescent protein (GFP)-alpha-actinin. Cells were plated at low density on top of or within 100-microm-thick fibrillar collagen lattices. After 18 hours to 7 days, time-lapse imaging was performed.
A review of biochemical mechanisms underlying the known approaches to extension of lifespan and/or slowing down of ageing suggests that they all modify balances between generation of active oxygen and carbonyl species and the mechanisms that protect from their damaging effects or repair their consequences. A likely common target of the geroprotector effects of antioxidants, melatonin, and antidiabetic biguanides is the mitochondrial respiratory chain.
Hexavalent chromium (Cr(VI)) is a metal of increasing public health concern, as exposure to it is widespread and it is a well-established cause of human bronchial carcinomas and fibrosarcomas. The water-insoluble Cr(VI) salts are potent carcinogens compared to the water soluble salts; yet the genotoxic mechanisms of both may be mediated by soluble Cr(VI) ions. Currently, these mechanisms are poorly understood.
We hypothesize that many ailments are attributable to dysfunctions of autonomic balance. The autonomic system is a primitive, highly-adaptive response system that allows differential allocation of biologic effort under varying conditions. The autonomic system, however, can execute a response that is inappropriate for the system stressor due to evolutionary displacement. Evolutionary displacement is a situation in which a trait that evolved as an adaptive response to certain conditions now faces a new set of conditions.
Particulate drug carriers offer unique opportunities to improve tumor therapy through several different mechanisms. Liposomes may (1) assist in formulation of poorly-soluble therapeutic agents, (2) provide a slow-release vehicle to achieve pharmacokinetic profiles that maximize the therapeutic index, or (3) behave as long-circulating nano-particulates that can extravasate in the hyperpermeable regions of tumor vasculature. For paclitaxel, liposomes provide an aid to formulation.