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Biomedical subjects

Suresh I S Rattan

Publications and source records attributed to Suresh I S Rattan.

At least 19 recordsLinked to original sources
PubMed2006

Theories of biological aging: genes, proteins, and free radicals.

Traditional categorization of theories of aging into programmed and stochastic ones is outdated and obsolete. Biological aging is considered to occur mainly during the period of survival beyond the natural or essential lifespan (ELS) in Darwinian terms. Organisms survive to achieve ELS by virtue of genetically determined longevity assuring maintenance and repair systems (MRS). Aging at the molecular level is characterized by the progressive accumulation of molecular damage caused by environmental and metabolically generated free radicals, by spontaneous errors in biochemical reactions, and by nutritional components. Damages in the MRS and other pathways lead to age-related failure of MRS, molecular heterogeneity, cellular dysfunctioning, reduced stress tolerance, diseases and ultimate death. A unified theory of biological aging in terms of failure of homeodynamics comprising of MRS, and involving genes, milieu and chance, is acquiring a definitive shape and wider acceptance. Such a theory also establishes the basis for testing and developing effective means of intervention, prevention and modulation of aging.

Aging↗
PubMed2006

Proteasomal oscillation during mild heat shock in aging human skin fibroblasts.

Augmentation of proteasome machinery is emerging as a significant gerontomodulatory consequence of hormetic stimulation, such as mild heat stress. This study describes the phenomenon we term hormetic proteasomal oscillation, wherein mildly heat-stressed human fibroblasts (41 degrees C, 1 h) display an adaptation response pattern in proteasome activity. Remarkably, such response appears to be diverse in severely heat-stressed or senescent fibroblasts. This proteasomal oscillation, as an innate cellular reaction to heat and aging, however, is independent of 20S proteasome protein levels and nuclear factor-E2-related factor 2 (Nrf2) transactivation.

Adult↗
PubMed2006

Heat-shock protein 70 genes and human longevity: a view from Denmark.

We have studied the association of three single nucleotide polymorphisms (SNPs) present in the three HSP70 (heat-shock protein) genes on 6p21 with human longevity. The availability of biological samples from various population cohorts in Denmark has given us the opportunity to try novel methods of gene association with human longevity. A significant association of one haplotype with male longevity was observed. Furthermore, a significant difference in the survival of the carriers of the different genotypes in females was observed. We also found an age-dependant decline in the ability of peripheral blood mononuclear cells to respond to heat stress in terms of Hsp70 induction.

Adult↗
PubMed2006

Kinetin-induced differentiation of normal human keratinocytes undergoing aging in vitro.

Kinetin (N(6)-furfuryladenine) is a cytokinin growth factor having several anti-aging effects reported for human cells and fruit flies. We have observed that short-term culturing of human keratinocytes in the presence of 40 to 200 microM kinetin results in a significant inhibition of cell growth. Studies were undertaken to analyze the process of differentiation as a reason for growth inhibition. Keratinocytes at different passage levels were treated with fetal calf serum (FCS) and calcium as differentiation-inducing positive controls, with different concentrations of kinetin, and with a combination of kinetin and calcium. The induction and progression of differentiation was monitored by morphological observations and by using several differentiation markers, including keratins (K10 and K14), involucrin, epidermal transglutaminase, and some new keratinocyte-specific antibodies isolated by the phage display method. In young keratinocytes, two days of calcium treatment reduced the K14 level by 78%, and increased the levels of K10 and involucrin by 40% and 29%, respectively. In comparison, 40 microM kinetin had no effect on the K14 level, but increased the K10 level by 28% and that of involucrin by four-fold. The combination of calcium and 40 microM kinetin led to a decrease by 23% in the K14 level, to an increase in the level of K10 by 55%, and to a two-fold rise in the involucrin level. These results suggest that the rate, extent, and quality of differentiation depend on the inducing agent, and that kinetin may be useful in promoting the differentiation of human keratinocytes, especially in the presence of calcium.

Adult↗
PubMed2006

MAP kinases and heat shock-induced hormesis in human fibroblasts during serial passaging in vitro.

Adult human skin fibroblasts were exposed repeatedly to 41 degrees C or 42 degrees C heat shock (HS) for 1 h twice a week during serial passaging throughout their replicative life span. On the basis of longevity curves, cell size, and morphology, we observed that repeated mild heat shock (RMHS) at 41, degrees C had strong anti-aging hormetic effects, including 20% extension of cellular longevity. The basal levels of the MAP kinases JNK1, JNK2, and p38 increased during serial passaging, while that of ERK2 decreased. RMHS further exaggerated these effects, which suggests that age-related changes in MAP kinases may be an adaptive response for better cell survival.

Adult↗
PubMed2006

Curcumin's biphasic hormetic response on proteasome activity and heat-shock protein synthesis in human keratinocytes.

Curcumin (diferuloylmethane), is a component of the yellow powder prepared from the roots of Curcuma longa (Zingiberaceae), also known as tumeric or turmeric. It is widely cultivated and used as a food ingredient in tropical areas of Asia and Central America. Treatment of mid-passage human epidermal keratinocytes with curcumin resulted in a biphasic hormetic dose-response with respect to proteasome activity. Curcumin treatment (up to 1 microM for 24 h) increased chymotrypsin-like activity by 46% compared to that in untreated keratinocytes. However, higher concentrations of curcumin were inhibitory, and at 10 microM the proteasome activity decreased to 46% of its initial value. Furthermore, the preincubation of human keratinocytes at 43 degrees C for 1 h, followed by 24-h treatment with 3 microM curcumin, led to an increase in heat-shock protein (hsp70 and hsp90) levels by 24% and 19%, respectively, and the effect was sustained at concentrations up to 10 microM. On the other hand, the level of the small hsp27 was unaffected by curcumin concentrations of 0.3-1 microM, while it decreased by 34% at 10 microM.

Adult↗
PubMed2006

Preincubation with the proteasome inhibitor MG-132 enhances proteasome activity via the Nrf2 transcription factor in aging human skin fibroblasts.

Strategies that lead to the upregulation of the proteasome are known to elicit beneficial consequences to the organism by countering oxidative stress-associated disorders, such as protein conformational diseases, cancer, and aging. Mild treatment with proteasome inhibitors has been previously demonstrated to stimulate proteasome activity and cellular resistance against oxidative injury. However, the mechanism for this action has not been clearly defined. We examined the role of the nuclear factor-E2-related factor 2 (Nrf2) in fibroblasts, a key transactivator of the antioxidant response pathway, in the regulation of the proteasome by its inhibitor MG-132. Here, we demonstrate that the stimulation of the proteasome by low levels of MG-132 can be abrogated by small interfering RNAs (siRNAs) targeted against Nrf2. Consistently, cells that constitutively express Nrf2 exhibit elevated levels of proteasome activities. We further investigate how its beneficial effects, that is, proteasome stimulation, are manifested in young and replicative-senescent cells. Our data underscore that manipulation of Nrf2 by the administration of pharmacologically low levels of proteasome inhibitors may prove to be an alternatively potent strategy for inducing long-term protective effects against oxidative stress.

Cells, Cultured↗
PubMed2006

Heat shock-induced enhancement of osteoblastic differentiation of hTERT-immortalized mesenchymal stem cells.

Heat shock (HS)-induced stress response in human cells results in a variety of biological effects and is known to induce the transcription of heat-shock proteins, which help the cells to cope with different kinds of stress. We have studied the effects of HS on the differentiation of human mesenchymal stem cells (hMSCs) into osteoblastic cells. As a model for hMSCs we used a telomerase-immortalized hMSC line designated hMSC-TERT. Cells were exposed to 1 h HS at 41 degrees C, 42.5 degrees C, or 44 degrees C prior to incubation in a medium containing either 10(-8) M 1alpha,25-dihydroxy-vitamin-D(3) (calcitriol) or 10(-8) M calcitriol, 50 microg/mL L-ascorbic acid, and 10 mM beta-glycerophosphate followed by an analysis of induction of osteoblast differentiation and the formation of mineralized matrix, respectively. Our results indicate that the exposure of cells to mild heat stress enhances the extent of differentiation of hMSCs by 12% to 42%. These effects are an expression of the phenomenon of mild stress-induced hormesis.

Adult↗
PubMed2006

Phage-displayed antibodies for the detection of glycated proteasome in aging cells.

Accumulation of posttranslationally damaged proteins during aging could explain the decline of cell performance with age. N(epsilon)-carboxymethyllysine (CML) is the major glycation product on damaged proteins, causing dysfunction and cross-linking. The proteasome, a multicatalytic degradation complex, is one of the pathways for eliminating damaged proteins, and thus regulating their accumulation within the cell. However, the proteinase activities of the proteasome decline during aging. This may be due to posttranslational modifications of the subunits forming the proteasome complex. Using phage display technology, we have selected 16 single-chain variable fragments (scFv) recognizing the CML-modified alpha7 subunit of the proteasome. Using one of them, Ab3, we have observed a five-fold increase of CML-alpha7 in old human skin fibroblasts in comparison with young fibroblasts and telomerase-immortalized bone marrow cells (hTERT-BMCs).

Antibodies↗
PubMed2006

Geroprotection by glycerol: insights to its mechanisms and clinical potentials.

Chaperones, particularly the heat-shock proteins, are considered as key players in the maintenance of protein homeostasis and are associated with longevity and cellular immortalization. In this study, we investigated the geroprotective activity of the chemical chaperone glycerol. Glycerol showed significant chaperoning activity in refolding heat-denatured luciferase in vivo and in protecting cells from heat stress-induced cytotoxicity. This was accompanied by decrease in p53, an upregulation of a stress chaperone mortalin/mtHsp70, and an increase in proteasome activity in the presence of oxidative stress.

Aging↗
PubMed2006

Reduced heat shock response in human mononuclear cells during aging and its association with polymorphisms in HSP70 genes.

Age-dependent changes in heat shock response (HSR) were studied in mononuclear cells (monocytes and lymphocytes) collected from young (mean age = 22.6 +/- 1.7 years) and middle-aged (mean age = 56.3 +/- 4.7 years) subjects after 1 hour of heat shock at 42 degrees C. Genotype-specific HSR was measured by genotyping the subjects for 3 single nucleotide polymorphisms, HSPA1A(A-110C), HSPA1B(A1267G), and HSPA1L(T2437C), 1 each in the 3 HSP70 genes. A significant age-related decrease in the induction of Hsp70 occurred after heat shock in both monocytes and lymphocytes. The noninducible and inducible forms of Hsp70 decreased 1.3-fold (P < 0.001) and 1.4-fold (P < 0.001), respectively, in the monocytes with age. In the young subjects, a positive association was found between HSPA1L(T2437C) polymorphism and HSR. CC carriers had a significantly lower induction than TT carriers in both monocytes (P = 0.015) and lymphocytes (P = 0.044). This polymorphism, which is present in the coding region of HSPA1L gene, can affect the chaperoning function of Hsp70. These data consolidate our other observations that the CC genotype is unfavorable for human longevity and provide a functional explanation in terms of variations in HSR.

Adult↗
PubMed2005

At the heart of aging: is it metabolic rate or stability?

Foundational changes in science are rare, but in the field of biogerontology there is a new theory of aging that may shake things up. The conventional wisdom about duration of life is based on an old idea known as the "rate of living" theory, which suggests that aging is caused by the loss of some vital substance. The modern version of this theory is that duration of life is influenced by the relative speed of a species' resting metabolism. However, empirical evidence does not consistently support this hypothesis. In an article published recently by mathematician/biologist Lloyd Demetrius, it is suggested that the most important factor involved in duration of life is not metabolic rate or oxidative stress, but metabolic stability. If Demetrius is correct, his theory will have important implications for intervention research. For example, if the metabolic rate/oxidative stress theory is correct, efforts to intervene in the aging process should be directed at finding ways to reduce metabolic rate, lessen the production of reactive oxygen species (ROS), improve antioxidant defenses, or increase the quantity of antioxidants. If the metabolic stability hypothesis is correct, efforts to intervene in the aging process should be directed at finding ways to increase the stability of the steady state values of ROS, increase the robustness of metabolic networks, or improve the stability of antioxidant enzymes. For now there is reason to believe that Demetrius' theory deserves further consideration - whether it meets the test of a paradigm shift has yet to be determined.

Aging↗
PubMed2005

Gerontomodulatory and youth-preserving effects of zeatin on human skin fibroblasts undergoing aging in vitro.

Our studies have shown that zeatin, (6-[4-hydroxy-3-methyl-but-2-enylamino]adenine), a cytokinin plant growth factor, has gerontomodulatory, youth preserving and anti-aging effects on serially passaged human adult skin fibroblasts undergoing aging in vitro. There were no immediate negative or toxic effects in terms of cell attachment, cell proliferation, cell survival, cytoskeletal organization, and cellular growth by treatment with zeatin concentrations between 1 and 200 microM. During long-term treatment, cells could be maintained throughout their replicative lifespan in the presence of 40, 80, and 200 microM zeatin, but the optimal concentration of zeatin's anti-aging and youth preserving effects was found to be 80 microM. Life-long serial passaging of human skin fibroblasts in the presence of zeatin resulted in the prevention of cell enlargement, reduction of intracellular debris, prevention of actin polymerization, and enhancement of cellular ability to decompose hydrogen peroxide and to cope with ethanol and oxidative stresses. Most importantly, anti-aging and beneficial effects of zeatin were observed without any induction of additional cell proliferation or an increase in the maximum proliferative capacity, thus ruling out any potentially harmful and carcinogenic effects.

Cellular Senescence↗
PubMed2004

Aging, anti-aging, and hormesis.

As a result of almost 50 years of efforts in collecting descriptive data, biogerontologists are now able to construct general principles of aging and to explore possibilities of gerontomodulation. Most of the data indicate that aging is characterized by a stochastic accumulation of molecular damage and a progressive failure of maintenance and repair, and the genes involved in homeodynamic pathways are the most likely candidate virtual gerontogenes. Several approaches are being tried and tested to modulate aging in a wide variety of organisms, but with the ultimate aim of improving the quality of human life in old age. These approaches include gene therapy, hormonal supplementation, nutritional modulation, and intervention by antioxidants and other molecules. A recent approach is that of applying hormesis in aging research and therapy, which is based on the principle of stimulation of maintenance and repair pathways by repeated exposure to mild stress.

Aging↗
PubMed2004

Association between low self-rated health and heterozygosity for -110A > C polymorphism in the promoter region of HSP70-1 in aged Danish twins.

We have studied the possible association between the -110A > C polymorphism in the promoter region of one of the heat shock protein genes HSP70-1 with human longevity in a cohort of aged Danish twins. This cohort includes individuals aged between 70 and 91 years (mean = 75.6 years), who are categorized according to the presence or absence of various diseases and according to the various, age-related parameters for which a genetic component has already been defined. Four hundred DNA samples from the cohort were genotyped using real-time PCR. Aging phenotypes (diseases, physical and cognitive functioning) were compared with regard to genotype. Of all the aging phenotypes studied, self-rated health and relative self-rated health, which represent an individual's overall sense of physical well-being and which have been shown to be both predictors of survival at older ages and better indicators of future survival than objectively measured health status, were associated with the polymorphism. An association was found between low self-rated health and heterozygosity for -110A > C polymorphism in the promoter region of HSP70-1 in aged Danish twins.

Aged↗
PubMed2004

Hormetic mechanisms of anti-aging and rejuvenating effects of repeated mild heat stress on human fibroblasts in vitro.

The phenomenon of hormesis is represented by mild stress-induced stimulation of maintenance and repair pathways, resulting in beneficial effects for cells and organisms. We have reported that repeated mild heat stress (RMHS) has anti-aging hormetic effects on growth and various cellular and biochemical characteristics of human skin fibroblasts undergoing aging in vitro. These effects of RMHS include the maintenance of the stress protein profile, reduction in the accumulation of oxidatively and glycoxidatively damaged proteins, stimulation of the activities of the proteasome and its 11S activator, improvement in cellular resistance to ethanol, hydrogen peroxide, and ultraviolet rays, and increased antioxidative activity of the cells. We have also reported that RMHS prolongs the lifespan of Drosophila. Others have reported anti-aging and life prolonging effects of a wide variety of so-called stressors, such as pro-oxidants, aldehydes, calorie restriction, irradiation, heat shock, and hypergravity. Although molecular mechanisms of hormesis are yet to be elucidated, there are indications that relatively small hormetic effects become biologically amplified, resulting in significant improvement of cellular and organic functions and survival. Hormesis, therefore, can be an effective approach for modulating aging, for preventing or delaying the onset of age-related diseases, and for improving the quality of life in old age.

Cellular Senescence↗