Age-associated Chronic Diseases Research Articles

Flavonoid glycosides from Japanese Camellia oil cakes and their inhibitory activity against advanced glycation end-products formation

Phytochemical investigation of the oil cakes of Camellia japonica L. seeds resulted in the isolation and structural elucidation of thirteen flavonoid glycosides (1–13), including four novel compounds (6, 10–12). Chemical profiling of the oil cake extract was characterized by HPLC-PDA analysis. The extract and isolated compounds 1–12 exhibited potent inhibitory activities against advanced glycation end-products (AGEs) formation between d-ribose and bovine serum albumin (BSA). The major compound 7 exhibited the most potent inhibitory activity among the isolated compounds. The extract and 7 also inhibited AGEs formation between human serum albumin (HSA) and three intermediates: glycolaldehyde (GA), methyl glyoxal (MGO), and glyoxal (GO). Moreover, extract and compound 7 decreased the GA-HSA enhanced expression of macrophage inflammatory protein-1β (MIP-1β) mRNA in differentiated U937 cells. The extract and its flavonoid glycoside constituents from the oil cakes of C. japonica seeds possessed potential usability as health materials against AGE-associated chronic diseases.

Abstract A06: ‘Accidental discoveries on systematic studies: Role of inflammation in multistep tumorigenesis and angiogenesis in models of allergies

Abstract Among major scientific factors involved in extremely slow progress in cancer research and failed therapies are the lack of understanding of host tissue composition and interactions between resident immune cells and signaling for recruited cells in carcinogenesis. In 1980s experimental models of acute and chronic ocular inflammatory diseases resulted in tumorigenesis and angiogenesis. Analyses of data became accidental discoveries for systematic identification of time-course kinetics of interactions and synergies between host immune cells (e.g., mast, goblet and B cells) and recruiting cells (e.g., eosinophils and TAMs) during acute, intermediate and chronic phases of immune dynamics caused induction of tumor-like lesions in conjunctival-associated lymphoid tissues. The data are the first multiple findings on early events, followed by sequential alterations of immunity toward tissue growth and angiogenesis. In 2008, acute inflammation or effective immunity was defined as the balance between two biologically opposing arms, termed Yin (tumoricidal) and Yang (tumorigenic) properties of immune and non-immune (e.g., vasculature, neurodegenerative and metabolic) responses. Chronic inflammation was hypothesized as loss of balance in Yin and Yang and a common link for genesis of all age-associated chronic diseases or cancer. Future efforts to promote immunity should include systematic understanding of host-pathogen interactions in susceptible tissues. Outcomes are expected to hold real promise in understanding how cancer cells become threat to body and how translate cancer biology into cost-effective drug designs and clinical trials. Note: This abstract was not presented at the conference. Citation Format: Mahin Khatami, Ret. ‘Accidental discoveries on systematic studies: Role of inflammation in multistep tumorigenesis and angiogenesis in models of allergies. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr A06.

Calebin A downregulates osteoclastogenesis through suppression of RANKL signalling

Osteoporosis is a bone disease that is exacerbated by aging and age-associated chronic diseases such as cancer. Cancer-induced bone loss is usually treated with bisphosphonates or denosumab, an antibody against receptor activator of nuclear factor (NF)-κB ligand (RANKL). Because these drugs are expensive and have numerous side effects and high rates of toxicity, safer, more effective, and more affordable therapies for osteoporosis are still needed. We identified a compound, calebin A (CA), derived from turmeric (Curcuma longa) that affects osteoclastogenesis through modulation of the RANKL signalling pathway. The CA's effect on NF-κB activation was examined by electrophoretic mobility shift assay. Using mouse macrophages in vitro model, we found that CA suppressed RANKL-induced osteoclast differentiation of macrophages into osteoclasts, and downregulate RANKL-induced osteoclastogenesis-related marker gene expression, including NFATc-1, TRAP, CTR, and cathepsin K. CA also suppressed the osteoclastogenesis induced by multiple myeloma and breast cancer cells. This effect of CA was correlated with suppression of the phosphorylation and degradation of inhibitor of κB and, thus, inhibition of NF-κB activation. Furthermore, we found that an NF-κB-specific inhibitory peptide blocked RANKL-induced osteoclastogenesis, demonstrating that the NF-κB signalling pathway is mandatory for RANKL-induced osteoclastogenesis. Our results conclusively indicate that CA downmodulates the osteoclastogenesis induced by RANKL and by tumour cells through suppression of NF-κB pathway.

Biochemical Composition of Indian Common Small Pelagic Fishes Indicates Richness in Nutrients Capable of Ameliorating Malnutrition and Age-Associated Disorders

Seafood is an excellent source of metabolically essential proteins, vitamins, trace elements and polyunsaturated fatty acids. There is a rising awareness of the beneficial role of fish and other marine foods in human nutrition. The knowledge regarding the nutritional significance of fish in counteracting the malnutrition and age-associated chronic diseases are relatively scanty. In this present study, an attempt has been made to examine the proximate composition, amino acid profile and fatty acid composition of small pelagic fishes (sardine, mackerel and anchovy) available in Indian south-west coast waters. The biochemical parameters were determined using standard experimental protocols. The low value small pelagic fishes are found to be rich sources of ω-3 Fatty acids [eicosapentaenoic acid (EPA) & docosahexaenoic acid (DHA)], which are very much essential for the development of brain and heart tissues. Sardine and mackerel possess all the essential and non-essential amino acids in a balanced proportion capable of ameliorating the protein deficiency disorders. The non-protein amino acid taurine essential for various physiological functions was also found to be present in rich quantities in small pelagic fishes. Presence of sulphur containing amino acids cysteine and methionine and high histidine content adds functionality to the nutritional value of small pelagic fish protein. Anchovies and sardine are valuable sources of calcium, which can effectively be used to combat calcium deficiency in children. The result of the present study has indicated that small pelagic fishes [sardine, mackerel and anchovy] are potential sources of attenuating malnutrition-related diseases and age-associated disorders.

Posttranscriptional Regulation of the Inflammatory Marker C-Reactive Protein by the RNA-Binding Protein HuR and MicroRNA 637.

C-reactive protein (CRP), an acute-phase plasma protein, is a major component of inflammatory reactions functioning as a mediator of innate immunity. It has been widely used as a validated clinical biomarker of the inflammatory state in trauma, infection, and age-associated chronic diseases, including cancer and cardiovascular disease (CVD). Despite this, the molecular mechanisms that regulate CRP expression are not well understood. Given that the CRP 3' untranslated region (UTR) is long and AU rich, we hypothesized that CRP may be regulated posttranscriptionally by RNA-binding proteins (RBPs) and by microRNAs. Here, we found that the RBP HuR bound directly to the CRP 3' UTR and affected CRP mRNA levels. Through this interaction, HuR selectively increased CRP mRNA stability and promoted CRP translation. Interestingly, treatment with the age-associated inflammatory cytokine interleukin-6 (IL-6) increased binding of HuR to CRP mRNA, and conversely, HuR was required for IL-6-mediated upregulation of CRP expression. In addition, we identified microRNA 637 (miR-637) as a microRNA that potently inhibited CRP expression in competition with HuR. Taken together, we have uncovered an important posttranscriptional mechanism that modulates the expression of the inflammatory marker CRP, which may be utilized in the development of treatments for inflammatory processes that cause CVD and age-related diseases.

Excess body weight increases the burden of age-associated chronic diseases and their associated health care expenditures.

Aging and excessive adiposity are both associated with an increased risk of developing multiple chronic diseases, which drive ever increasing health costs. The main aim of this study was to determine the net (non-estimated) health costs of excessive adiposity and associated age-related chronic diseases. We used a prevalence-based approach that combines accurate data from the Health Search CSD-LPD, an observational dataset with patient records collected by Italian general practitioners and up-to-date health care expenditures data from the SiSSI Project. In this very large study, 557,145 men and women older than 18 years were observed at different points in time between 2004 and 2010. The proportion of younger and older adults reporting no chronic disease decreased with increasing BMI. After adjustment for age, sex, geographic residence, and GPs heterogeneity, a strong J-shaped association was found between BMI and total health care costs, more pronounced in middle-aged and older adults. Relative to normal weight, in the 45-64 age group, the per-capita total cost was 10% higher in overweight individuals, and 27 to 68% greater in patients with obesity and very severe obesity, respectively. The association between BMI and diabetes, hypertension and cardiovascular disease largely explained these elevated costs.

Molecular aspects of renal senescence.

The aging kidney undergoes profound changes that lead to a reduction in stress resistance and impaired repair capacity. In order to improve the outcome of acute and chronic kidney damage, it is instrumental to understand the mechanisms that cause these changes. Cellular senescence has emerged as an important cellular process that contributes to age-associated kidney changes and chronic kidney disease progression. New mechanistic insights into excessive intracellular glucose, advanced glycation end products and endoplasmatic reticulum stress further support the importance of cellular senescence in the development of diabetic nephropathy. As telomere length of leukocytic DNA is increasingly used as a biomarker to estimate senescence in clinical cohort studies, this review also summarizes the literature on telomere length with respect to the kidney and evaluates the strengths and weaknesses of this methodology. Furthermore, novel findings on the relationships among telomeres, senescence and autophagy are discussed. Cellular senescence contributes to the decline in renal function during aging and defective regeneration in kidney diseases. Further insight into the underlying molecular mechanisms of senescence will establish a basis for preventive strategies that improve renal stress resistance and regenerative capacity.

P178. The effect of cognitively challenging tasks on walking in Parkinson’s Patients

Background The interaction between motor and cognitive functions has an important impact on daily activities, is altered during ageing, and particularly affected in age-associated chronic diseases such as Parkinson’s disease (PD). Therefore, this motor-cognitive interaction has been extensively studied e.g. with dual task paradigms. It has become clear that particularly simultaneously performed cognitive secondary tasks with (an additional) motor aspect (such as carrying a glass of water or checking boxes) lead to impaired walking performance, and increase the risk of falls and injuries in PD patients. Yet, a detailed understanding of the changes which occur in PD when performing dual tasks is still lacking. Methods Fourty-four PD patients in off medication and 44 age- and gender-matched healthy controls were included. Dual tasking effects on gait velocity, number of steps, step duration, gait variability, double limb support and stride asymmetry of the primary task as well as velocity of the secondary tasks (subtracting serial sevens and checking boxes) during a 1 min “as fast as possible” walking condition were investigated. Participants wore a portable quantitative gait assessment system with six sensors (Mobility Lab®, APDM, Oregon, USA). Single as well as dual tasking performances were calculated for each group, and compared among groups. Results During the checking boxes task, all six above-mentioned gait parameters deteriorated in both PD patients and controls. Velocity of checking boxes decreased significantly under the dual tasking condition compared to single task also in both groups. During the subtraction task, four gait parameters deteriorated in PD patients but only two in controls. Velocity of serial subtraction decreased significantly only in PD patients but not in controls. Conclusion Dual tasking affects the quality of the performed tasks differently in PD patients and controls, depending on the kind of the secondary task. To study differences of dual tasking performance between PD patients and controls, a more “cognitive” task such as serial subtraction seems more promising than a secondary task that includes substantial motor aspects.

Angiotensin II blockade: how its molecular targets may signal to mitochondria and slow aging. Coincidences with calorie restriction and mTOR inhibition

Caloric restriction (CR), renin angiotensin system blockade (RAS-bl), and rapamycin-mediated mechanistic target of rapamycin (mTOR) inhibition increase survival and retard aging across species. Previously, we have summarized CR and RAS-bl's converging effects, and the mitochondrial function changes associated with their physiological benefits. mTOR inhibition and enhanced sirtuin and KLOTHO signaling contribute to the benefits of CR in aging. mTORC1/mTORC2 complexes contribute to cell growth and metabolic regulation. Prolonged mTORC1 activation may lead to age-related disease progression; thus, rapamycin-mediated mTOR inhibition and CR may extend lifespan and retard aging through mTORC1 interference. Sirtuins by deacetylating histone and transcription-related proteins modulate signaling and survival pathways and mitochondrial functioning. CR regulates several mammalian sirtuins favoring their role in aging regulation. KLOTHO/fibroblast growth factor 23 (FGF23) contribute to control Ca(2+), phosphate, and vitamin D metabolism, and their dysregulation may participate in age-related disease. Here we review how mTOR inhibition extends lifespan, how KLOTHO functions as an aging suppressor, how sirtuins mediate longevity, how vitamin D loss may contribute to age-related disease, and how they relate to mitochondrial function. Also, we discuss how RAS-bl downregulates mTOR and upregulates KLOTHO, sirtuin, and vitamin D receptor expression, suggesting that at least some of RAS-bl benefits in aging are mediated through the modulation of mTOR, KLOTHO, and sirtuin expression and vitamin D signaling, paralleling CR actions in age retardation. Concluding, the available evidence endorses the idea that RAS-bl is among the interventions that may turn out to provide relief to the spreading issue of age-associated chronic disease.

Dry mouth and older people.

Dry mouth is more common among older people than in any other age group. Appropriate definition and accurate measurement of dry mouth is critical for better understanding, monitoring and treatment of the condition. Xerostomia is the symptom(s) of dry mouth; it can be measured using methods ranging from single questions to multi-item summated rating scales. Low salivary flow (known as salivary gland hypofunction, or SGH) must be determined by measuring that flow. The relationship between SGH and xerostomia is not straightforward, but both conditions are common among older people, and they affect sufferers' day-to-day lives in important ways. The major risk factor for dry mouth is the taking of particular medications, and older people take more of those than any other age group, not only for symptomatic relief of various age-associated chronic diseases, but also in order to reduce the likelihood of complications which may arise from those conditions. The greater the number taken, the greater the associated anticholinergic burden, and the more likely it is that the individual will suffer from dry mouth. Since treating dry mouth is such a challenge for clinicians, there is a need for dentists, doctors and pharmacists to work together to prevent it occurring.

RANKL Signaling and Osteoclastogenesis Is Negatively Regulated by Cardamonin

Bone loss/resorption or osteoporosis is a disease that is accelerated with aging and age-associated chronic diseases such as cancer. Bone loss has been linked with human multiple myeloma, breast cancer, and prostate cancer and is usually treated with bisphosphonates, and recently approved denosumab, an antibody against receptor activator of NF-κB ligand (RANKL). Because of the numerous side effects of the currently available drugs, the search continues for safe and effective therapies for bone loss. RANKL, a member of the TNF superfamily, has emerged as a major mediator of bone loss via activation of osteoclastogenesis. We have identified cardamonin, a chalcone isolated from Alpinia katsumadai Hayata that can affect osteoclastogenesis through modulation of RANKL. We found that treatment of monocytes with cardamonin suppressed RANKL-induced NF-κB activation and this suppression correlated with inhibition of IκBα kinase and of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. Furthermore, cardamonin also downregulated RANKL-induced phosphorylation of MAPK including ERK and p38 MAPK. Cardamonin suppressed the RANKL-induced differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. We also found that an inhibitor of NF-κB essential modulator (NEMO) blocked RANKL-induced osteoclastogenesis, indicating a direct link with NF-κB. Finally, osteoclastogenesis induced by human breast cancer cells or human multiple myeloma cells were completely suppressed by cardamonin. Collectively, our results indicate that cardamonin suppresses osteoclastogenesis induced by RANKL and tumor cells by suppressing activation of the NF-κB and MAPK pathway.

Calorie Restriction in the Elderly People

Calorie Restriction in the Elderly People

Abstract B25: Inflammation and cancer: standardizing biomarkers criteria (data elements) as foundation of a database. M-CSF used as prototype to test data elements

Abstract Lack of better understanding, whether inflammation is protective in preventing cancer or it is a cause for promoting cancer, reflected by continuous controversies and debates has significantly slowed down progress in preventing or treating cancer and many age-associated chronic diseases. Consequently, too many expensive and out of focus clinical trials that use potent pro-inflammatory mediators or inhibitors of growth factors (wound healing or tumorigenic) have caused life threatening side-effects such as cachexia, thrombosis, or drug-resistance and cancer-relapse resulting multiple organ failure (MOF) in cancer patients. Such approaches in ‘targeted’ or ‘personalized’ medicine for site-specific cancers that often result in MOF are similar to clinical features of potent pathogens-induced severe inflammatory diseases and MOF in sepsis or meningitis. In 1980's the results of our ‘accidental’ discoveries on experimental models of acute and chronic ocular inflammatory diseases are suggestive of the first evidence for a direct link between inflammation and tumorigenesis and angiogenesis. Analyses of data led to a first publication on inflammation-induced time course kinetics of developmental phases of immune dysfunction that resulted in neovascularzation, tumor growth and angiogenesis in conjunctival-associated lymphoid tissues (1984, 85, 88, 89, 90 a, b, 2005 a, b). Recently, acute inflammation was defined as highly regulated immune responses possessing 2 biologically opposing arms, termed ‘Yin’ (apoptosis or tumoricidal) and ‘Yang’ (wound healing or tumorigenic), capable of precise communications between immune and non-immune systems (e.g., neuroendocrine, vasculature) to protect the body against external and internal foreign elements including killing of cancer cells (cancer or immune surveillance). Unresolved inflammation was proposed as the loss of balance between ‘Yin’ and ‘Yang’ that could lead to expression of exaggerated and mismatched mediators creating immunological chaos or ‘immune tsunami’, and eroding architectural integrity and function of target tissues as the basis for induction and progression of chronic diseases or cancer. This presentation focuses on extension and integration of our ground breaking multidisciplinary data with emphasis on standardizing cancer biomarkers criteria through identifying data elements for nearly all cancer markers as a foundation of a cancer biomarkers database (2005 c). An inflammatory mediator (M-CSF) is used as prototype to tailor data elements (e.g., comparison of its superior sensitivity and specificity with conventional markers such as CA-125) as potential marker for technology development and diagnostic tools. A framework for design of clinical studies will be presented based on hypotheses that: a) Inflammatory mediators are ideal targets for diagnosis and treatment of cancer; b) Inflammation is a common denominator in the genesis of age-associated chronic diseases such as diabetes and cardiovascular complications or cancer; and c) maintenance of balance between ‘Yin’ and ‘Yang’ of acute inflammation is a key for preventing, avoiding or delaying the onset of age-associated chronic diseases or cancer (1999, 2005, 2007, 2008, 2009, 2011, 2012). Citation Format: Mahin Khatami. Inflammation and cancer: Standardizing biomarkers criteria (data elements) as foundation of a database. M-CSF used as prototype to test data elements. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B25.

Role of the Gut Microbiota in Age-Related Chronic Inflammation

Changing demographics have made aging and age-related chronic diseases an enormous and growing biomedical and societal challenge. The biological processes of aging may involve a role for the gut microbiota. Aspects of host physiology such as immune homeostasis and energy balance are profoundly influenced by the microbiota. Immune dysregulation characterizes old age and constitutes a major pathomechanism underlying frailty and age-associated chronic diseases. A growing body of literature implicates age-related perturbations in the gut microbial ecology as contributing to a global inflammatory state in the elderly. A better understanding of the nature and determinants of the host-microbe relationship in old age has the potential to translate into strategies that promote healthy aging and extend life span. This review summarizes our current understanding of the configuration of the age-related gut microbiota and its likely role in determining the immune phenotype in the elderly. It also highlights the specific components of the microbiota that can be targeted to modulate the age-related chronic inflammation.

Developmental programs are kept alive during adulthood by stem cells: The aging aspect

Stem cells are fundamental for life-long preservation of cellular somatic maintenance. Tissue-borne stem cells replenish worn-out critical elements. Provided they remain fit over lifetime, enduring stem cell activities avert the emergence of age-associated chronic degenerative diseases and pathologies.Although experimentally still unclear, it is assumed that stem cells reside in protected niches. Freshly isolated mesenchymal stem cells exhibit donor-specific aberrations, which cannot solely be ascribed to differences in genetic background. Besides inevitably accumulating intrinsic modifications, the systemic environment also impacts on basic properties of mesenchymal stem cells such as their inherent multi-lineage differentiation potential. Chronic systemic aberrations over time comprise unwholesome influences, in particular in terms of regeneration and repair when stem cells recapitulate distinct developmental programs. During or thereafter, stem cells can diversify either because of insufficiently silencing activated building cycles, or by acquiring epigenetic deviations.

Cardamonin inhibits osteoclastogenesis induced by tumor cells through interruption of the signaling pathway activated by receptor activator of NF-κB ligand

Bone loss/resorption or osteoporosis is a disease that is accelerated with aging and age-associated chronic diseases such as cancer. Bone loss has been associated with human multiple myeloma, breast cancer, and prostate cancer and is usually treated with a bisphosphonate. Because of the numerous side effects of the currently available drugs, the search continues for safe and effective therapies for bone loss. Recently, receptor activator of NF-κB ligand (RANKL), a member of the TNF superfamily, has emerged as a major mediator of bone loss via activation of osteoclastogenesis. We have identified cardamonin, a chalcone first isolated from grass cardamom ( Alpinia katsumadai Hayata), that can affect osteoclastogenesis through modulation of RANKL. We found that treatment of monocytes with cardamonin suppressed RANKL-induced NF-κB activation and this suppression correlated with inhibition of IκBα kinase and of phosphorylation and degradation of IκBα, an inhibitor of NF-κB. Cardamonin suppressed the differentiation of monocytes to osteoclasts in a dose-dependent and time-dependent manner. We also found that an NF-κB-specific inhibitory peptide blocked RANKL-induced osteoclastogenesis, indicating a direct link with NF-κB. Finally, osteoclastogenesis induced by human breast cancer cells or human multiple myeloma cells was completely suppressed by cardamonin. Collectively, our results indicate that cardamonin suppresses osteoclastogenesis induced by RANKL and tumor cells by suppressing activation of the NF-κB pathway.

The role of elastin peptides in modulating the immune response in aging and age-related diseases

It is now well accepted that aging is associated with the occurrence of a low-grade inflammation called Inflamm-aging. This leads to the imbalance between the various mediators of the inflammatory response in favour of the pro-inflammatory response represented by pro-inflammatory cytokines and oxidative stress. The question that arises, and is still under investigation, what is the origin of the driving force leading to these changes. One of the current hypotheses is that chronic stimulation of the immune system contributes to the pro-inflammatory shift. The chronic stimulation can be of viral origin such as cytomegalovirus, from tumor antigens or from other sources such as the extracellular matrix, especially from elastin fibres and collagens. Aging and various inflammatory diseases such as atherosclerosis, abdominal aortic aneurysms, chronic obstructive pulmonary diseases (COPD), cancer and type 2 diabetes are characterized by the destruction of elastin fibers and the consequent generation of elastin peptides which are biologically active. This review will describe the putative contribution of elastin peptides to inflamm-aging and extend on their role on immunosenescence, as well as on age-associated chronic inflammatory diseases.

Angiotensin II blockade: a strategy to slow ageing by protecting mitochondria?

Protein and lipid oxidation-mainly by mitochondrial reactive oxygen species (mtROS)-was proposed as a crucial determinant of health and lifespan. Angiotensin II (Ang II) enhances ROS production by activating NAD(P)H oxidase and uncoupling endothelial nitric oxide synthase (NOS). Ang II also stimulates mtROS production, which depresses mitochondrial energy metabolism. In rodents, renin-angiotensin system blockade (RAS blockade) increases survival and prevents age-associated changes. RAS blockade reduces mtROS and enhances mitochondrial content and function. This suggests that Ang II contributes to the ageing process by prompting mitochondrial dysfunction. Since Ang II is a pleiotropic peptide, the age-protecting effects of RAS blockade are expected to involve a variety of other mechanisms. Caloric restriction (CR)-an age-retarding intervention in humans and animals-and RAS blockade display a number of converging effects, i.e. they delay the manifestations of hypertension, diabetes, nephropathy, cardiovascular disease, and cancer; increase body temperature; reduce body weight, plasma glucose, insulin, and insulin-like growth factor-1; ameliorate insulin sensitivity; lower protein, lipid, and DNA oxidation, and mitochondrial H(2)O(2) production; and increase uncoupling protein-2 and sirtuin expression. A number of these overlapping effects involve changes in mitochondrial function. In CR, peroxisome proliferator-activated receptors (PPARs) seem to contribute to age-retardation partly by regulating mitochondrial function. RAS inhibition up-regulates PPARs; therefore, it is feasible that PPAR modulation is pivotal for mitochondrial protection by RAS blockade during rodent ageing. Other potential mechanisms that may underlie RAS blockade's mitochondrial benefits are TGF-β down-regulation and up-regulation of Klotho and sirtuins. In conclusion, the available data suggest that RAS blockade deserves further research efforts to establish its role as a potential tool to mitigate the growing problem of age-associated chronic disease.

Long‐term effects of calorie restriction on serum sex‐hormone concentrations in men

Calorie restriction (CR) slows aging and consistently reduces circulating sex hormones in laboratory animals. However, nothing is known regarding the long-term effects of CR with adequate nutrition on serum sex-hormone concentration in lean healthy humans. In this study, we measured body composition, and serum total testosterone, total 17-beta-estradiol, sex hormone-binding globulin (SHBG), and dehydroepiandrosterone sulfate (DHEA-S) concentrations in 24 men (mean age 51.5 +/- 13 years), who had been practicing CR with adequate nutrition for an average of 7.4 +/- 4.5 years, in 24 age- and body fat-matched endurance runners (EX), and 24 age-matched sedentary controls eating Western diets (WD). We found that both the CR and EX volunteers had significantly lower body fat than the WD volunteers (total body fat, 8.7 +/- 4.2%; 10.5 +/- 4.4%; 23.2 +/- 6.1%, respectively; P = 0.0001). Serum total testosterone and the free androgen index were significantly lower, and SHBG was higher in the CR group than in the EX and WD groups (P < or = 0.001). Serum 17beta-estradiol and the estradiol:SHBG ratio were both significantly lower in the CR and EX groups than in the WD group (P < or = 0.005). Serum DHEA-S concentrations were not different between the three groups. These findings demonstrate that, as in long-lived CR rodents, long-term severe CR reduces serum total and free testosterone and increases SHBG concentrations in humans, independently of adiposity. More studies are needed to understand the role of this CR-mediated reduction in sex hormones in modulating the pathogenesis of age-associated chronic diseases such as cancer and the aging process itself.

Cell autonomous expression of inflammatory genes in biologically aged fibroblasts associated with elevated NF-kappaB activity

BackgroundChronic inflammation is a well-known corollary of the aging process and is believed to significantly contribute to morbidity and mortality of many age-associated chronic diseases. However, the mechanisms that cause age-associated inflammatory changes are not well understood. Particularly, the contribution of cell stress responses to age-associated inflammation in 'non-inflammatory' cells remains poorly defined. The present cross-sectional study focused on differences in molecular signatures indicative of inflammatory states associated with biological aging of human fibroblasts from donors aged 22 to 92 years.ResultsGene expression profiling revealed elevated steady-state transcript levels consistent with a chronic inflammatory state in fibroblast cell-strains obtained from older donors. We also observed enhanced NF-κB DNA binding activity in a subset of strains, and the NF-κB profile correlated with mRNA expression levels characteristic of inflammatory processes, which include transcripts coding for cytokines, chemokines, components of the complement cascade and MHC molecules. This intrinsic low-grade inflammatory state, as it relates to aging, occurs in cultured cells irrespective of the presence of other cell types or the in vivo context.ConclusionOur results are consistent with the view that constitutive activation of inflammatory pathways is a phenomenon prevalent in aged fibroblasts. It is possibly part of a cellular survival process in response to compromised mitochondrial function. Importantly, the inflammatory gene expression signature described here is cell autonomous, i.e. occurs in the absence of prototypical immune or pro-inflammatory cells, growth factors, or other inflammatory mediators.