T-cell effector pathways in allergic diseases: transcriptional mechanisms and therapeutic targets.

Originally interpreted within the framework of a binary T(H)1/T(H)2 paradigm, our knowledge of the pathogenesis of atopic diseases has broadened to incorporate the contribution of T regulatory cells and the newly described proinflammatory T(H)17 cell lineage. The commitment of peripheral T-cell clones to undergo differentiation into one of those lineages is shaped by self-reinforcing transcriptional circuitries that center on key transcriptional regulators: T-box expressed in T cells (T(H)1), GATA-3 (T(H)2), forkhead box p3 (T regulatory cells), and retinoid-related orphan receptor gammatau/retinoid-related orphan receptor alpha (T(H)17). These circuits function both to establish the respective lineage phenotype and to enable epigenetic changes that maintain those phenotypes long-term.

Nrf2 activation by sulforaphane restores the age-related decrease of T(H)1 immunity: role of dendritic cells.

Background: The decrease in cellular immunity with aging is of considerable public health importance. Recent studies suggest that the redox equilibrium of dendritic cells (DCs) is a key factor in maintaining protective cellular immunity and that a disturbance of this homeostatic mechanism could contribute to immune senescence.

Objectives: We sought (1) to elucidate the role of DC redox equilibrium in the decrease of contact hypersensitivity (CHS) and T(H)1 immunity during aging and (2) to determine how restoration of glutathione (GSH) levels by the Nrf2-mediated antioxidant defense pathway affects this decrease.

Glutathione depletion inhibits dendritic cell maturation and delayed-type hypersensitivity: implications for systemic disease and immunosenescence.

Background: Dendritic cells (DCs) play a key role as antigen-presenting cells in the immune system. There is growing evidence that the redox equilibrium of these cells influences their ability to induce T-cell activation and to regulate the polarity of the immune response. This could affect the outcome of the immune response during systemic diseases and aging.

Gene expression and physiologic responses of the heart to the initiation and withdrawal of caloric restriction.

Aging increases and caloric restriction (CR) decreases morbidity and mortality associated with the cardiovascular system. Using Affymetrix microarrays, we identified changes in heart gene expression induced by aging and CR in male mice. Eight weeks of CR (CR8) reproduced 19% of the long-term CR (LTCR)-related expression changes.

Anti-inflammatory action of dietary fish oil and calorie restriction.

Inflammation, inflammatory mediators, cyclooxygenase (COX)-2, and inducible nitric oxide (iNOS) are all influenced by age-related oxidative status. To investigate the effect of dietary fish oil (FO) and calorie restriction (CR) on oxidative stress-related inflammatory status with age, (NZB/NZW) F1 (B/W) mice were fed for 4 and 9 months either ad libitum or calorie-restricted (60% of ad libitum intake) diets containing 5% corn oil or 5% FO. We measured several key oxidative and inflammatory markers: TBARS, xanthine oxidase (XOD)-derived superoxide generation, and PGE2 and LTB4 production.

The role of phase II antioxidant enzymes in protecting memory T cells from spontaneous apoptosis in young and old mice.

Aging is associated with a functional decline and change in the phenotypic distribution of T cell subsets. The free radical theory of aging is widely promoted as the mechanistic basis for cellular senescence, including the immune system. Although the exact molecular explanation for the role of oxidative stress in cellular senescence is unclear, there is a connection to altered mitochondrial function, both as a contributor and as a target of oxidative stress.

The effect of age and calorie restriction on HIF-1-responsive genes in aged liver.

Hypoxia inducible factor-1 (HIF-1) regulates transactivation of several genes in response to hypoxia condition. We explore hepatic HIF-1 responsive gene regulation during aging and the age-related changes of the HIF-1 related gene activation in young and old rats. Results indicate that the aging process induces the activation of HIF-1alpha, which is accompanied by increased HIF-1 DNA binding.

Suppression of apoptosis by calorie restriction in aged kidney.

Programmed cell death by apoptosis is regarded as an organism's protective mechanism against the accumulation of defective cells. Apoptotic activity is shown to be elevated in most aged tissues, and its intracellular regulation is intricately manipulated by mitochondria. In this study, to determine the progression of apoptosis during aging, we investigated the expression of several key apoptosis-related markers in kidney of 12- and 24-month-old rats.

Temporal linkage between the phenotypic and genomic responses to caloric restriction.

Caloric restriction (CR), the consumption of fewer calories while avoiding malnutrition, decelerates the rate of aging and the development of age-related diseases. CR has been viewed as less effective in older animals and as acting incrementally to slow or prevent age-related changes in gene expression. Here we demonstrate that CR initiated in 19-month-old mice begins within 2 months to increase the mean time to death by 42% and increase mean and maximum lifespans by 4.

Age-associated increase in oxidative stress and nuclear factor kappaB activation are attenuated in rat liver by regular exercise.

The combined effects of aging and regular physical exercise was investigated on the production of reactive oxygen species (ROS), lipid peroxidation, glutathione status, and the activity of nuclear factor-kappaB (NF-kappaB) in rat liver. A group of 24 male F344 rats was divided into the following categories: adult control (18 months), adult exercised (18 months), and aged control (28 months) and aged exercised (28 months). The ROS formation increased as a function of age and exercise training decreased the rate of ROS formation in the two age groups.

Modulation of glutathione and thioredoxin systems by calorie restriction during the aging process.

Accumulating evidence strongly suggests that oxidative stress underlies aging processes and that calorie restriction (CR) retards aging processes, leading to an extended lifespan for various organisms. Recent studies revealed that the anti-aging action of CR depends on its anti-oxidative mechanism. However, at present, the status of glutathione (GSH) and thioredoxin (Trx) system, two major thiol redox systems in animal cells during aging and its modulation by CR has not fully been explored.

Modulation of redox-sensitive transcription factors by calorie restriction during aging.

Oxidative stress is considered to be a major cause of aging and many age-related diseases. Calorie restriction (CR) is known to retard deleterious, age-related processes. Recent studies document that CR retards the aging process by regulating the redox environment through its anti-oxidative properties.

Molecular inflammation hypothesis of aging based on the anti-aging mechanism of calorie restriction.

Accumulating evidence strongly suggests that oxidative stress underlies aging processes. Research provides consistent evidence that calorie restriction (CR) reduces age-related oxidative stress and has anti-inflammatory properties. However, information is lacking on the molecular mechanism that would better define the interrelation of reactive oxygen species and nitrogen species and the pro-inflammatory states of the aging process.

Influence of aging and calorie restriction on MAPKs activity in rat kidney.

Mitogen-activated protein kinases (MAPK), which include the extracellular signal-related kinases (ERK), the c-Jun N-terminal kinases (JNK), and the p38 MAPK, are important regulatory proteins by which a wide variety of extracellular signals are transduced into intracellular sites. Recent studies reported that mitogenic signal transduction in various cell types are exquisitely sensitive to reactive oxygen species (ROS) and the celluar redox status. In the present study, we investigated the activation of MAPK activity by aging and calorie restriction (CR) in rat kidneys isolated from Fischer 344 rats, ages 6, 12, 18, and 24 months fed ad libitum (AL) and CR diets.

Calorie restriction modulates redox-sensitive AP-1 during the aging process.

Oxidative stress is claimed to be a major cause of aging. Recent data suggest that calorie restriction (CR) prolongs life span by its ability to retard aging, possibly by regulating the intracellular redox status through its antioxidative actions. Currently, there is little information showing the influences of age and CR on the redox-sensitive transcription factor activator protein-1 (AP-1).

Molecular exploration of age-related NF-kappaB/IKK downregulation by calorie restriction in rat kidney.

Accumulating evidence strongly suggests that oxidative stress underlies aging processes, and that in a variety of organisms, calorie restriction (CR) retards these processes, thereby extending their lifespan. Recent studies revealed that the anti-aging action of CR depends on its anti-oxidative mechanism. In previous papers, we reported that aging activates the redox-sensitive transcription factor, NF-kappaB, and further reported that age-related NF-kappaB activation correlates with age-related oxidative stress.

NF-kappa B binding activity and cyclooxygenase-2 expression in persistent CCl(4)-treated rat liver injury.

The involvement of NF-kappa B binding activity is known to be important in the mechanism of acute liver injury and in the induction of cyclooxygenase (COX-2). This study was performed to evaluate NF-kappa B binding activity and the expression of COX-2 in chronic liver injury induced by carbon tetrachloride (CCl(4)). Liver tissues from Sprague-Dawley rats were collected at 1, 3, 5, and 7th week after intraperitoneal injection of 0.