HOW TO DELAY AGEING PROCESS.STAY YOUNG AT 65
GOOD LOOKS AT 65
STRONG & HEALTHY AT65
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1.Good Religeous Life
Good Family Life
2..Aerobic Exercises
Walking -30 min
Jogging
Exercise Machines
3..Healthy food
Cholesterol Free
Vegitarian Diet
Less Red Meat
4..Keep Cool
Do not get irritable
5..Meditation
6..Rest & Relaxation
7..Yoga
8..Vitamins & Minerals
VitA
Vit B
Vit C
VitE-Natural better
Selenium
Zinc
9..Ginsen Products
10..Pure,Healthy Environment
Low-CO,SO2,
11. Sex
Safe Sex to be continued
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How old are you now? Well as a matter of facts all people get old, something that all human have to face. Aging is bound to happen. Common aging symptoms that experienced by older people are: changes in hair color, decrease in vision, loss or decrease in hearing, decreased memory, sleep pattern changes, slowly losing sexual drive, sexual dysfunction, menstrual cycle changes, changes in frequency of urination, increase in blood pressure, slower metabolism, wrinkles, fat increase, and lesser bone density. The main reason why these symptoms happen is linked to HGH (Human Growth Hormone) level in your body. The HGH is produced by the pituitary gland located in the brain, and this is the most vital hormone in your body since it regulates the production of all the other hormones. Studies have shown that 600ug level of HGH in a 25 years old men or women can slowly down to 90ug or lesser in 60 years old. The other words, as we age more and more, the HGH levels drop as well. Taking an anti-aging supplements are certainly one of best choice to avoid this degrading process. The anti-aging supplements help more than the vitamins do, because not all vitamins can provide the entire needs of an aging body. This is why seniors or older people should have these anti-aging supplements in their daily routine list. Many doctors today advise HGH supplements for those who want to combat the aging process. This kind of supplements help to increase the level of energy, enhance the strength of immune system, strengthen muscles and bones, improve sleep quality, boost sexual drive and other benefits to health. The good news is, today you may buy a high quality and safe HGH supplements with no side effects without prescription. There are hundreds of new HGH supplements on the market today and many online nutrition stores offer these supplements. With a good study on which HGH supplements that are safe, natural, and affordable -- you will get a high-quality HGH supplement that truly work to overcome your aging symptoms and start enjoying your age gracefully.
THEORY
The AGEing hypothesis of aging was prompted by multiple observations that aged tissues are characterized by the accumulation of a variety of types of AGEs, from CML adducts; to carboxyethyl (CEL) lysine adducts; methylglyoxal; pentosidine; and others (Ahmed et al., 1997 ; Schleicher et al., 1997 ; Odetti et al., 1998 ). In addition to proteins and lipids, evidence exists that DNA may also undergo AGE modification. It is speculated that the modification of DNA has profound implications for both regulatory and perhaps epigenetic components of the aging process (Baynes, 2002 ). The issue of the role of AGEs as a cause and/or biomarker in the maladaptive aspects of the aging process is not a settled issue (Baynes, 2001 ; Kirkland, 2002 ). The intriguing studies of Sell and colleagues suggested, perhaps, at least a little of both. In their experiments, they tested the hypothesis that the longitudinal determination of the rate of glycation/glycoxidation of skin collagen would predict longevities in ad libitum versus caloric-restricted mice. They biopsied C57BL/6Nnia male mice at age 20 months and at natural death. Levels of skin furosine, CML adduct, and pentosidine were determined. Caloric restriction significantly increased life span in these animals versus ad-libitum feeding. In parallel, skin levels of the three types of AGEs were sharply reduced in caloric-restricted fed animals and correlated significantly with longevity (Sell et al., 2000 ). Such considerations may suggest that the levels of skin AGEs are a yardstick for assessing the extent of AGEing in the vasculature.
AGEs, oxidant stress, and inflammation: round and round we go
Top
Abstract
Introduction
AGEs: diabetes, RAGE, and...
AGEs, oxidant stress, and...
AGE and AGEing: an...
Hypotheses and perspectives
How do we break...
Blocking AGEing—to a...
Acknowledgments
References
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A plethora of evidence suggests that AGEs are involved in a vicious cycle of inflammation, generation of ROS, amplified production of AGEs, more inflammation, and so on. In addition to the ligation of RAGE, AGEs may be linked to increased generation of ROS by multiple mechanisms, such as by decreasing activities of superoxide dismutase (SOD) and catalase, diminishing glutathione stores, and activation of Protein Kinase C (Yan and Harding, 1997 ; Obrosova, 2002 ; Jiang et al., 2004 ). The direct link of inflammation to AGE formation was suggested by studies in which the activation of myeloperoxidase (MPO) pathways was shown to directly generate CML-AGEs (Anderson et al., 1999 ). Further evidence for the vicious cycle of oxidative stress begetting AGE and back again was suggested by studies in which malondialdehyde (a lipoperoxidation product) caused secondary oxidative damage to proteins (Traverso et al., 2004 ).
In the context of RAGE, non-AGE ligands for RAGE may accumulate in oxidative/inflammatory settings as well. We hypothesize that although AGEs may be rapidly generated by glucose, ROS, or other acute inflammatory stimuli, a key consequence of this interaction is the migration of inflammatory cells into the initial nidus of stress. What are the alternative ligands of RAGE and what is their biologic context?
S100/calgranulins: extracellular newly-identified RAGErs of RAGE
S100/calgranulins are a family of at least 20 polypeptide members. The principal and prototypic function of these cells involve key intracellular mechanisms linked to calcium binding. The EF-hand, calcium-binding domains of these species place them within this family of molecules. S100/calgranulins may be expressed by a wide array of cell types; in the specific context of inflammation and RAGE, these species may be produced in polymorphonuclear leukocytes, dendritic cells (DC), MP, and lymphocytes (Zimmer et al., 1995 ; Schafer and Heinzmann, 1996 ; Donato, 2001 ). When first identified as signal transduction ligands for RAGE, essentially by the finding that S100A12 (calgranulin C or extracellular newly-identified RAGE binding protein, EN-RAGE) bound RAGE in a saturable and dose-dependent manner on cultured EC, SMC, MP, and lymphocytes (Hofmann et al., 1999 ), a puzzling concept was that S100/calgranulins largely existed as intracellular proteins. Distinct mechanisms were identified by which these molecules may be released by inflammatory cells (Rammes et al., 1997 ; Frosch et al., 2000 ), thereby allowing them to engage the cell surface receptor RAGE in an autocrine and paracrine manner. Indeed, other S100s such as S100B are linked to nervous system stress, and others, such as S100P, are linked to cancer. In this context, RAGE-dependent ligation of S100P increases the proliferation and survival of cancer cells in vitro (Arumugam et al., 2004 ).
The direct evidence linking RAGE to the euglycemic inflammatory response was deduced from the following studies. First, in euglycemic mice, blockade of RAGE suppressed delayed type hypersensitivity in mice sensitized challenged with methylated bovine serum albumin, and decrease colonic inflammation in IL-10 deficient mice (Hofmann et al., 1999 ). Later studies indicated that RAGE blockade suppressed experimental autoimmune encephalomyelitis in mice exposed to encephalitogenic T cells and myelin basic protein and suppressed joint inflammation and destruction in DBA/1 mice sensitized/challenged with bovine type II collagen (Hofmann et al., 2002 ; Yan et al., 2003 ). Important roles for S100/calgranulins in diabetic inflammatory stress are underscored by the observation that S100/calgranulins are increased in diabetic macrovessels and renal cortex in murine models, thus suggesting that these molecules may contribute to the acceleration of perturbation in diabetes (Kislinger et al., 2001 ; Wendt et al., 2003 ).
Amphoterin: from the nucleus to the extracellular space
Amphoterin, also known as high mobility group box 1 (HMGB1), has important functions within the cell as a DNA binding protein. In addition, it is well described that amphoterin may also exist extracellularly and on the surface of cells, especially cells actively involved in migration (Rauvala and Pihlaskari, 1987 ). Our studies have explored this molecule’s interaction with RAGE in the context of neurite outgrowth and tumors (Hori et al., 1995 ; Taguchi et al., 2000 ). The work of Kevin Tracey’s group first implicated amphoterin directly in mechanisms linked to the inflammatory response. Like S100/calgranulins, amphoterin may be released from activated MPs, thereby leading to the propagation of inflammatory responses (Wang et al., 1999 ; Andersson et al., 2000 ). In vivo, the administration of blocking antibodies to amphoterin enhanced the survival of rodents subjected to conditions mimicking that of overwhelming septic shock (Wang et al., 1999 ). These findings support the concept that amphoterin played a role in the generation of inflammatory mediators and was not merely a bystander in immune/inflamed milieu. Studies are underway to elucidate the precise contributions of amphoterin–RAGE as well as the interaction of amphoterin with other binding species, such as toll-like receptor-4 and toll-like receptor-2 (TLR-4 and TLR-2) (Park et al., 2004 ). However, recent studies do suggest that in amphoterin-enriched environments, such as arthritis, RAGE blockade plays important roles (Hofmann et al., 2000 ; Pullerits et al., 2003 ).
The precise role(s) for RAGE and TLR in transducing the inflammatory effects of amphoterin remain to be fully elucidated.
Linking these diverse ligands: RAGE and signal transduction
Experimental evidence supports the premise that RAGE-dependent modulation of gene expression and cellular properties is dependent on signal transduction. The signal transduction pathways downstream of RAGE activation in a wide array of cell types are diverse. Depending on the acuteness/chronicity of ligand stimulation, distinct signaling pathways may be activated. All of the ligands identified to date have been shown to cross compete and bind at the RAGE V-type Ig domain (Hofmann et al., 1999 ). AGEs, S100/calgranulins, and amphoterin may activate cell types intimately involved in macro-/microvascular disease initiation/progression, such as EC, SMC, MP, lymphocytes, neurons, and podocytes. Signaling cascades activated upon ligand–RAGE interaction include pathways such as p21ras, erk1/2 (p44/p42) MAP kinases, p38 and SAPK/JNK MAP kinases, rho GTPases, phosphoinositol-3 kinase, and the JAK/STAT pathway; downstream consequences such as the activation of the key transcription factors, NF-kB and cAmp response element binding protein (CREB) have also been reported (Lander et al., 1997 ; Deora et al., 1998 ; Hofmann et al., 1999 ; Huttunen et al., 1999 , 2002 ; Kislinger et al., 1999 ; Huang et al., 2001 ).
Importantly, ligand stimulated RAGE activation results in the generation of ROS, at least in part via the activation of NADPH oxidase (Wautier et al., 2001 ). Definitive roles for RAGE-mediated activation of NADPH oxidase were demonstrated in studies in NADPH oxidase null mice. Specifically, we found that monocytes retrieved from NADPH oxidase null mice, when compared with wild-type monocytes, failed to display increased generation of tissue factor upon incubation with AGEs (Wautier et al., 1994 ). Studies are underway to delineate if additional mechanisms, distinct from NADPH oxidase, underlie the potent ability of RAGE to generate ROS.
In this context, it is essential to indicate that the cytosolic domain of RAGE is critical for RAGE-dependent signal transduction and modulation of gene expression and cellular phenotype. In studies both in vitro and in vivo, studies have indicated that the deletion of the cytosolic domain of RAGE causes a dominant negative (DN) effect which abrogates ligand-mediated RAGE signaling and function. For example, when DN RAGE is expressed in vivo in SMC, cells of MP lineage, neurons of the central or peripheral nervous system or CD4 lymphocytes, RAGE-mediated signaling is effectively suppressed, thereby strikingly modulating injury-triggered outcomes in diverse settings (Hofmann et al., 1999 ; Kislinger et al., 1999 ; Taguchi et al., 2000 ; Sakaguchi et al., 2003 ; Yan et al., 2003 ; Arancio et al., 2004 ; Rong et al., 2004; Cataldegirmen et al., 2005 ).
Such studies indicate that RAGE is a signal transduction receptor for multiple classes of proinflammatory ligands. Our findings support the premise that the ligand-RAGE axis stimulates EC and other cell types to augment cellular perturbation in a diverse array of disease settings characterized by ligand accumulation.
RAGE and implications for the pathogenesis of type 1 diabetes: nearly full circle
Based on the findings that RAGE appeared to play key roles in euglycemic inflammation, we hypothesized that RAGE might play a role in autoimmune disease, such as that observed in type 1 diabetes. To test this premise, we studied the role of RAGE in a model of adoptive transfer of diabetogenic spleen cells into NOD/SCID mice (Chen et al., 2004 ). Both RAGE and S100 were expressed on islet cells with an inflammatory infiltrate in sections of pancreata from diabetic NOD/SCID mice that had received a transfer of splenocytes, but not from control NOD/SCID mice. In addition to RAGE expression in endocrine cells, other studies demonstrated that RAGE was also expressed at least in a population of T cells (CD4+ and CD8+) and B cells (Chen et al., 2004 ).
To test the potential role of RAGE in mediating autoimmune diabetes in this model, we transferred splenocytes from a diabetic NOD donor into NOD/SCID mice; NOD/SCID mice were treated with either sRAGE or mouse serum albumin. Treatment with sRAGE significantly reduced the rate of transfer of diabetes. By day 36 after transfer, 22 of 24 (92%) control animals but only 2 of 25 (10%) mice treated with sRAGE were diabetic. In parallel, the expression of key cytokines, IL-1beta and TNF-alpha, was significantly reduced in the sRAGE-treated islets compared with vehicle-treated animals. The expression of IL-10 was strikingly increased in sRAGE-treated mice islets, along with increased transforming growth factor (TGF)-beta, compared to vehicle-treated animals (Chen et al., 2004 ).
Further, in the context of our proposed model of AGEs and RAGE triggering a vicious cycle of injury with multiple points of amplification, glucose, AGEs, and oxidative stress augment injury to islets and beta cells (El-Assaad et al., 2003 ; Robertson, 2004 ; Wu et al., 2004 ). Certainly, in the context of islet transplantation, stopping the cycle of AGE generation and oxidative stress, in part via RAGE, may diminish injury to newly transplanted islets.
Interestingly, when preactivated diabetogenic BDC2.5 cells were injected into mice, sRAGE had no effect on preventing diabetes. Such observations require that we "re-open" the issue of potential roles for RAGE in the adaptive immune response. Studies to rigorously address this hypothesis are underway at this time.
Taken together, these findings suggest that it will be critical to dissect each potential component of RAGE-dependent mechanisms in autoimmunity. Specifically, do roles exist for RAGE in both the adaptive immune response and/or the amplification of immune/inflammatory injury in autoimmunity targets such as islets? Will there be beneficial roles for RAGE blockade in attenuating rejection after allogeneic islet transplantation? These concepts must be addressed by instituting RAGE blockade at distinct time points either alone or in combination with classical immunosuppressive agents in experimental models of allogenic islet transplantation. Such studies are underway at this time.
Indeed, AGEs, too may be found on aging lymphocytes (Poggioli et al., 2002 , 2004 ). Although at the very least such modifications may represent "biomarkers" of aging, the more intriguing hypothesis is certainly that AGE-modification of lymphocyte cell surface molecules may either enhance or blunt the impact of antigen presentation on T-cell responses. In this context, recent hints to the implications of AGEing of DC suggest that such glycation may promote DC development but impair their ability to stimulate primary T-cell responses (Price et al., 2004 ). Certainly, altering the imprint of presented antigen may either enhance or suppress proper presentation to the T cell. Likely, such processes depend on the specific site/time/modification in question. Taken together, these observations in lymphocytes and DC suggest that AGE-mediated immune modulation may redirect immune responses in aging and diabetes. The potential links to RAGE in such processes provide for the development of fascinating hypotheses on the role of RAGE in the adaptive immune response.
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