Putative mechanisms responsible for the decline in cancer prevalence during organism senescence.

Most scientific literature reports that aging favors the development of cancers. Each type of cancer, however, initiates and evolves differently, and their natural history can start much earlier in life before their clinical manifestations. The incidence of cancers is spread throughout human life span, and is the result of pre- and post-natal aggressions, individual susceptibility, developmental changes that evolve continuously throughout an individual's life, and time of exposure to carcinogens. Finally, during human senescence, the incidence declines for all cancers. Frequently, the progression of cancers is also slower in aged individuals. There are several possible explanations for this decline at the tissue, cell, and molecular levels, which are described here in. It is time to ask why some tumors are characteristic of either the young, the aged, or during the time of a decline in the reproductive period, and finally, why the incidence of cancers declines late during senescence of human beings. These questions need to be addressed before the origin of cancers can be understood.

Control of cell replication during aging.

The observation that human fibroblasts have a limited number of cell population doublings in vitro led to the proposal that it is the expression of cellular aging. In vitro, the proliferation of human fibroblasts terminates with a postmitotic cell which was called senescent cell. Due to misinterpreted experiments, the latter was considered the hallmark of cellular aging, although obviously we do not age because our cells stop dividing. The so-called senescent cell has been the core of the investigation on cellular aging and of the theories proposed on the subject. The search for mechanisms responsible for the postmitotic state led to contradictory results, which accumulated when the term cell senescence was used to define the growth arrest due to a variety of causes. The mechanisms believed to be causing these multiple forms of cell senescence multiplied accordingly. This was disregarded claiming that there are multiple pathways to cell senescence. Since it was thought that aging favors malignant transformation, speculations were made to find a relationship between 'cell senescence' and cancers, which led to several paradoxes. The contradictions and paradoxes should be cleared to reestablish logic and order in the field and understand its relevance for human aging.

Diabetes abrogates sex differences and aggravates cardiometabolic risk in postmenopausal women.

BACKGROUND: The aim of this study is to evaluate the effect of gender and menopause in cardiometabolic risk in a type 2 diabetes mellitus (T2DM) population, based on classical and non-traditional markers. METHODS: Seventy four volunteers and 110 T2DM patients were enrolled in the study. Anthropometric data, blood pressure, body mass index (BMI), waist circumference (WC) and the following serum markers were analyzed: glucose, Total-c, TGs, LDL-c, Oxidized-LDL, total HDL-c and large and small HDL-c subpopulations, paraoxonase 1 activity, hsCRP, uric acid, TNF-α, adiponectin and VEGF. RESULTS: Non-diabetic women, compared to men, presented lower glycemia, WC, small HDL-c, uric acid, TNF-α and increased large HDL-c. Diabetes abrogates the protective effect of female gender, since diabetic women showed increased BMI, WC, small HDL-c, VEGF, uric acid, TNF-α and hsCRP, as well as reduced adiponectin, when compared with non-diabetic. In diabetic females, but not in males, WC is directly and significantly associated with TNF-α, VEGF, hsCRP and uric acid; TNF-α is directly associated with VEGF and hsCRP, and inversely with adiponectin. Postmenopausal females presented a worsen cardiometabolic profile, viewed by the increased WC, small HDL-c, VEGF, uric acid, TNF-α and hsCRP. In this population, WC is directly and significantly associated with TNF-α, VEGF, hsCRP; TNF-α is directly associated with VEGF; and uric acid is inversely associated with large HDL-c and hsCRP with adiponectin, also inversely. CONCLUSIONS: Diabetes abrogates the protective effect of gender on non-diabetic women, and postmenopausal diabetic females presented worsen cardiometabolic risk, including a more atherogenic lipid sketch and a pro-inflammatory and pro-angiogenic profile. The classical cardiovascular risk factors (CVRFs) fail to completely explain these differences, which are better clarified using "non-traditional" factors, such as HDL-c subpopulations, rather than total HDL-c content, and markers of inflammation and angiogenesis, namely TNF-α, hsCRP, uric acid and VEGF. Multi-therapeutic intervention, directed to obesity, atherogenic lipid particles and inflammatory mediators is advisory in order to efficiently prevent the serious diabetic cardiovascular complications.

Recto-anal manometric characteristics of type 2 diabetic patients who have sensation of incomplete defecation.

INTRODUCTION: Many diabetic patients report symptoms of incomplete defecation. We aimed to clarify the recto-anal manometric characteristics related to these symptoms. MATERIAL AND METHODS: A questionnaire regarding gastrointestinal symptoms was distributed to 35 diabetics (19 women and 16 men) aged between 39 and 81 years. Nineteen reported incomplete defecation sensation (WS) and 16 did not (NS). Recto-anal manometry was performed for all patients. Data are presented as mean±SD. RESULTS: Resting rectal pressure was 14.4±10.1 mmHg and 8.8±3.9 mmHg, p<.03; first sensation was 61.0±27.8 ml and 83.1±35.7 ml, p<.04; and maximum tolerable volume was 174.2±81.5 ml and 235.0±89.5 ml, p<.04 for WS and NS, respectively. The WS group was further divided into 2 groups according to symptom severity (less severe and very severe). Significant differences were found in resting external anal sphincter pressure (50.4±15.6 and 34.3±17.4, p<.04) and the recto anal inhibitory reflex (48.6±19.8 and 26.3±23.2, p<.03) between the less severe and very severe groups, respectively. CONCLUSIONS: (1) Resting rectal pressure was significantly higher in symptomatic individuals. (2) First sensation and maximum tolerable volume were higher in asymptomatic diabetics. (3) In diabetics with more severe symptoms, the resting external anal sphincter pressures were significantly lower. (4) The degree of relaxation in the recto-anal inhibitory reflex was significantly higher in individuals without complaints.

Esophageal body motility in people with diabetes: comparison with non-diabetic healthy individuals.

AIMS: The aim of this study was to compare esophageal motor characteristics between diabetics and healthy individuals. METHODS: Esophageal manometry was performed in 34 type 2 diabetics and 32 healthy individuals. Waves were evaluated in the 3 thirds of the esophagus (P1=upper, P2=middle, and P3=distal). RESULTS: In diabetics vs. controls, wave distribution was as follows: peristaltic waves, 83.5 ± 22.2% vs. 96.3 ± 4.4%, p<0.002; simultaneous waves, 3.26 ± 5.8% vs. 0.53 ± 1.3%, p<0.01; no transmitted waves, 10.62 ± 20.7% vs. 2.75 ± 3.0%, p<0.002; and retrograde waves, 2.68 ± 4.0% vs. 0.31 ± 1.1%, p<0.03. Wave amplitude was similar between groups. Average upstroke (mmHg/s) in diabetics vs. non-diabetics was P2, 33.8 ± 13.9 vs. 40.2 ± 17.7, p<0.03; and P3, 29.8 ± 15.3 vs. 41.3 ± 14.0, p<0.002. CONCLUSIONS: (1) Simultaneous waves, no transmitted waves, and retrograde esophageal waves were significantly more frequent in diabetics. (2) Average upstroke was significantly lower within the middle and distal esophagus of diabetic individuals. (3) Wave amplitude was similar in both groups.

Cell division and aging of the organism.

The capacity to regenerate cell compartments through cell proliferation is an important characteristic of many developed metazoan tissues. Pre- and post-natal development proceeds through the modifications occurring during cell division. Experiments with cultivated cells showed that cell proliferation originates changes in cell functions and coordinations that contribute to aging and senescence. The implications of the finite cell proliferation to aging of the organism is not the accumulation of cells at the end of their life cycle, but rather the drift in cell function created by cell division. Comparative gerontology shows that the regulation of the length of telomeres has no implications for aging. On the other hand there are interspecies differences in regard to the somatic cell division potential that seem to be related with the "plasticity" of the genome and with longevity, which should be viewed independently of the aging phenomenon. Telomeres may play a role in this plasticity through the regulation of chromosome recombination, and via the latter also in development.

Incidence of subclinical atherosclerosis in asymptomatic type-2 diabetic patients: the potential of multi-slice computed tomography coronary angiography.

BACKGROUND AND OBJECTIVES: Type-2 diabetic patients constitute a high-risk population for atherosclerosis. Primary prevention, although recommended, is not well funded. Our aim was to evaluate the degree of subclinical atherosclerosis, in asymptomatic diabetic patients, using coronary multi-slice computed tomography (MSCT) angiography. METHODS: We prospectively studied 71 diabetic patients without any symptoms or documentation of atherosclerotic disease. Coronary MSCT angiography was performed in all patients and coronary artery calcium score (CACS) was evaluated. The number of diseased coronary segments was determined and classified as obstructive or nonobstructive and fibrolipid or calcified lesions. The mean follow-up was 29.5±6.6 months. Major adverse cardiovascular events were registered. RESULTS: The mean age was 59±10 years, 48% were female patients. The duration of diabetes was 12.5±8.7 years. CACS ranged from 0 to 1293 Agatston units (153±269.1). Image quality was generally good, allowing satisfactory evaluation of most of the coronary artery segments. CACS was 0 in 28 patients, but in nine patients MSCT angiography showed fibrolipid plaques. Obstructive coronary artery disease was present in 26.7% of the patients (5.6% with multivessel disease). During the follow-up period, six major adverse cardiovascular events were detected in patients, five of whom had a CACS more than 100 Agatston units. CONCLUSION: This study shows a high prevalence of silent atherosclerotic lesions in type-2 diabetic patients, reinforcing the importance of risk factor modification even when calcified disease is absent. Coronary MSCT angiography can be performed to identify the atherosclerotic burden and may be an important test in selecting the patients who are benefiting the most from primary prevention.

Cancers and the concept of cell senescence.

The post-mitotic cell reached by normal cell populations after serial divisions has been regarded as the hallmark of cell senescence. It was proposed that this non-dividing cell is a mechanism of protection against malignant transformation and different approaches have been used to induce the post-mitotic state. There are contradictions and paradoxes between the concepts and the data, which are described herein. There are also contradictions between data from different laboratories that attempted to identify the mechanisms leading to the post-mitotic cell. The contradictions are bypassed with the claim that there are different pathways to cell senescence. The contradictions and the differences between the data should be explained before these phenomena can be understood.

Asymmetric distribution of DNA between daughter cells with final symmetry breaking during aging of human fibroblasts.

Human fibroblasts proliferating in vitro go through functional modifications, lose progressively their capacity to divide, and enter finally a post-mitotic state. These events are supposed to reproduce the developmental steps taking place in vivo during aging of the organism. The gradual changes occurring through proliferation are incompatible with an even distribution of the genetic material during cell division. We measured the amount of DNA on pairs of daughter cells at different population doubling levels of human fibroblasts. It was found that at each doubling in a significant fraction of cells, the distribution of DNA between sister cells is asymmetric. The cell system is in a steady state through the different phases of the fibroblast population life span; then during the last mitoses when the cells enter the terminal phase IV there is symmetry breaking with a phase transition, the cells settling into a new state.

Eficiência de Metarhizium anisopliae (Metsch. ) no controle de Mahanarva fimbriolata (Stål) (Hemiptera: Cercopidae) em cana-de-açúcar / Efficiency of Metarhizium anisopliae (Metsch. ) on sugarcane root froghopper Mahanarva fimbriolata (Stål) (Hemiptera: Cercopidae)

Avaliou-se a eficiência de isolados do fungo Metarhizium anisopliae no controle da cigarrinha-das-raízes em cana-de-açúcar, aplicados em quatro doses, uma ou duas vezes ao longo do período de ocorrência da praga. Os ensaios foram conduzidos em três municípios do estado de São Paulo: Guaíra, Iracemápolis e Tarumã. Somente no ensaio conduzido em Tarumã, o fungo mostrou-se eficiente no controle da cigarrinha-das-raízes, reduzindo as populações em até 91,2 por cento, quando aplicado em duas ocasiões, utilizando em cada uma a dose de 1kg/ha de arroz esporulado, na concentração aproximada de 9.10(8)conídeos/g de arroz. A eficiência do fungo em Tarumã foi atribuída às temperaturas mais amenas da região, permitindo o desenvolvimento do ciclo das relações parasito/hospedeiro.

The efficiency of isolates of the fungus Metarhizium anisopliae was evaluated on sugarcane root froghopper, applied at four doses, once or twice during the pest infestation period. The experiments were carried out in three São Paulo State regions: Guaíra, Iracemápolis and Tarumã. Only in the experiment conducted at Tarumã, the fungus was efficient for root froghopper control, reducing the pest population in 91.2 percent, when it was applied twice, using in each application the conidia obtained on 1 kg/ha of rice (9.10(8) conidia/g of rice). The fungus efficiency in Tarumã was attributed to the lower temperatures, favoring the development of the cycle of the relation parasite/host.

Influência da época de aplicação de inseticidas no controle de Mahanarva fimbriolata (Stål) (Hemiptera: Cercopidae), na qualidade e na produtividade da cana-de-açúcar / Influence of time and rate of application of insecticides on Mahanarva fimbriolata (Stål) (Hemiptera: Cercopidae) control and on quality and yield of sugarcane

The objective of this work was to study the effect of insecticides on sugarcane root froghopper mortality and on the technological quality and yield of sugarcane, when they were applied at different times and rates during the froghopper infestation period. Three experiments were carried out under field conditions. Best control was obtained with aldicarb 150G 10kg/ha and carbofuran 100G 25kg/ha, applied in November. When the insecticides were applied in December or January, the efficiency was reduced, especially that of thiamethoxam, probably because the great rain volume after applications contributed to the insecticides leaching, reducing the absorption by the roots. Theinsecticides aldicarb 150G, carbofuran 100G and thiamethoxam 250WG, applied in December, produced the best insect control, higher stalk production and higher sugar yields, in comparison with aplication in January at 40% lower doses. The control of the the root froghopper, made untill December, resulted in yield increase. When the insecticides were applied in January at lower doses, some of them reduced pest infestations, but did not contribute to increase yield, probably because the rootfroghopper had already damaged the plants irreversibly.

Com o objetivo de avaliar a influência da época de aplicação e das doses de inseticidas no controle da cigarrinha das raízes, Mahanarva fimbriolata (Stål), na qualidade e na produtividade da cana-de-açúcar, foram conduzidos três experimentos, em condições de campo. No primeiro ensaio, os melhores resultados de controle foram obtidos com aldicarbe 150G 10 kg/ha e carbofuram 100G 25 kg/ ha, aplicados em novembro. Quando aplicados em dezembro ou janeiro, a eficiência dos inseticidas, especialmente do tiametoxam 250WG 1 kg/ha, diminuiu sensivelmente, provavelmente porque o grande volume de chuvas ocorridas após as aplicações contribuíram para a lixiviação dos produtos, diminuindo a absorção deles pelas raízes. Nos outros dois ensaios, nos quais os inseticidas aldicarbe 150G, carbofuram 100G e tiametoxam 250WG foram aplicados em dezembro, nas doses de 10, 40 e 1kg/ha, respectivamente, ou em janeiro, em doses 40% menores, os melhores resultados de controle e deprodutividade de colmos e de açúcar foram observados nas aplicações feitas em dezembro. O controle de cigarrinha realizado até dezembro resultou em incrementos significativos de produtividade. Embora alguns inseticidas tenham reduzido as populações da cigarrinha, quando aplicados em janeiro e em doses menores, não ocorreram incrementos significativos de produtividade, possivelmente porque a praga já havia danificado irreversivelmente a cultura.

[The biology of conformation in the regulation of the senescent and transformed cell phenotypes]. / La biologie de la conformation dans la régulation des phénotypes cellulaires senescent et transformé.

The cytoskeleton and the cytoplasmic membrane of normal somatic cells are modified during proliferation. The loss of the division potential during serial proliferation is due in part to these structural modifications that induce a decline in the cell conformational flexibility. During viral transformation, the changes in the cytoskeleton and in the affinity of the cell to its matrix and to neighboring cells increase the cell migratory capability, maintaining the conformation flexibility needed for the initiation of the division cycle. We could modulate cell proliferation, transformed phenotype, and differentiation by changing the electric charge of a substratum. Results support the view that the biology of conformation is crucial for the expression of these cell properties.

The decline of the clinical incidence of cancers during human senescence.

Neoplastic growth occurs from the very beginning to the end of the human life span, with a predominant age span for the clinical incidence of each cancer. Most cancers are diagnosed during the second half of human life span, but their natural histories start much earlier than their clinical manifestations. The clinical incidence declines after ages 75-80 years. The histology, the evolution, and the distribution of the frequency of the different cancers during the human life span suggest that neoplastic growth is a dynamic process where new variables are continuously created, the result of the interaction of individual genetics, environmental aggressions, and the developmental stages of the human life span. Data suggest that in many instances tumor growth can be looked upon as a deviation from normal development. Mechanisms are described that can explain the decline of the incidence and the progression during senescence in terms of the changes occurring in the human organism during the last developmental stages.