Disease-Aging Network Reveals Significant Roles of Aging Genes in Connecting Genetic Diseases

One of the challenging problems in biology and medicine is exploring the underlying mechanisms of genetic diseases. Recent studies suggest that the relationship between genetic diseases and the aging process is important in understanding the molecular mechanisms of complex diseases. Although some intricate associations have been investigated for a long time, the studies are still in their early stages. In this paper, we construct a human disease-aging network to study the relationship among aging genes and genetic disease genes. Specifically, we integrate human protein-protein interactions (PPIs), disease-gene associations, aging-gene associations, and physiological system–based genetic disease classification information in a single graph-theoretic framework and find that (1) human disease genes are much closer to aging genes than expected by chance; and (2) diseases can be categorized into two types according to their relationships with aging. Type I diseases have their genes significantly close to aging genes, while type II diseases do not. Furthermore, we examine the topological characters of the disease-aging network from a systems perspective. Theoretical results reveal that the genes of type I diseases are in a central position of a PPI network while type II are not; (3) more importantly, we define an asymmetric closeness based on the PPI network to describe relationships between diseases, and find that aging genes make a significant contribution to associations among diseases, especially among type I diseases. In conclusion, the network-based study provides not only evidence for the intricate relationship between the aging process and genetic diseases, but also biological implications for prying into the nature of human diseases

[Article in Russian]

Activity of magnocellular vasopressin (VP) neurons in the human hypothalamus is sex- and age-dependent as judged from the size of the Golgi apparatus, neuronal size and VP mRNA levels. These parameters are significantly higher in young (< or = 50 years old) men than in young women and are markedly increased in postmenopausal women compared to premenopausal women. This data suggest an inhibitory effect of estrogens on metabolic activity of VP neurons in the human supraoptic nucleus (2SON), which is likely to be mediated via estrogen receptor (ER) beta. Estrogens were shown to mediate their inhibitory effect via ER beta. It is expressed to a much higher degree in the SON of young women than in other groups, whereas estrogen receptor alpha, that mediates stimulatory effects of estrogens, is present in a small proportion of SON neurons. In addition, estrogens inhibit p75 neurotrophin receptor expression in VP cells. In conclusion, we discuss the inhibitory role of estrogens in functional activity of human VP neurons, which is most probably mediated directly via ER beta and indirectly by p75 neurotrophin receptor

Increased expression of estrogen receptor alpha and beta in the nucleus basalis of Meynert in Alzheimer's disease

The human nucleus basalis of Meynert (NBM) is severely affected in Alzheimer's disease (AD). Since estrogens may reduce both the risk and severity of AD, possibly by an action on the cholinergic system, we determined whether estrogen receptors are present in the human NBM and what their changes are in normal aging and in AD. ERalpha was expressed to a higher degree than ERbeta and was localized mainly in the cell nucleus, while ERbeta was mainly confined to the cytoplasm. A significant positive correlation between the percentage of ERalpha nuclear positive neurons and age was found in men but not in women, whereas the proportion of ERbeta cytoplasm positive cells increased during aging in both sexes. In AD the proportion of neurons showing nuclear staining for both ERalpha and beta and cytoplasmic staining for ERbeta was markedly increased. The percentage of ERbeta nuclear positive neurons increased in AD only in women but not in men. The ApoE genotype had no effect on ER expression in the NBM in AD. In conclusion, whereas only minor sex- and age-related changes in both ERs were found in the human NBM, a clear upregulation of ERalpha and beta was observed in A

Vasopressin and oxytocin neurons of the human supraoptic and paraventricular nucleus: size changes in relation to age and sex

The hypothalamic supraoptic (SON) and paraventricular (PVN) nuclei consist of arginine vasopressin (AVP)- and oxytocin (OT)-synthesizing neurons that send projections to the neurohypophysis, whereas the PVN also projects to other brain areas. A growing body of evidence in animals suggests the presence of sex differences in the vasopressinergic and oxytocinergic systems. The present study was aimed at determining whether the sizes of AVP and OT neurons in the human SON and PVN show sex differences, as earlier studies demonstrated that a change in neuronal size is a sensitive parameter for activity. The minimal and maximal diameters were determined to estimate the volumes of cell somata and cell nuclei in AVP and OT neurons stained with an antibody against human glycoprotein-(22-39), a part of the AVP precursor, and a monoclonal anti-OT antibody in 15 men and 17 women ranging in age from 29-94 yr. The AVP neurons appeared to be larger in young men than in young women ( 50 yr old) AVP cell size considerably exceeded that in young women. In elderly men AVP neurons were larger than in young men and elderly women, although these differences were not significant. In addition, AVP cell size correlated positively with age in women but not in men. No significant differences were found in the AVP cell nucleus volumes among all four groups studied. Sex differences in the size of the PVN vasopressin neurons were pronounced at the left side (P = 0.048) and absent at the right side (P = 0.368), indicating the presence of functional lateralization in this nucleus. No difference was found in any morphometric parameter of OT neurons in the PVN among the 4 groups studied. Thus, our data demonstrate sex differences in the size of the AVP neurons, and thus in their function, that are age and probably also side dependent and the absence of such changes in OT neurons in the PVN. These data provide a basis for the reported higher AVP plasma levels in men compared to wome

Transcriptional activity of human brain estrogen receptor-α splice variants: evidence for cell type-specific regulation

Estrogen receptor α (ERα) isoforms with complex types of alternative splicing are naturally present in the human brain and may affect canonical receptor signaling. In the present study we investigated transcriptional activity of common ERα splice variants from this group with different molecular defects: MB1 (intron retention), TADDI (small deletion between exons 3 and 4 with an insert), the Δ (deletion) 3(⁎)-7(*)/819 (complete skipping of exons 4, 5 and 6 and partial deletion of exons 3 and 7) and the Δ3-6 (lacking exons 3, 4, 5 and 6) in HeLa and M17 cells upon stimulation with (17β)estradiol or insulin-like growth factor 1 (IGF-1). In HeLa cells, all these splice variants showed the dominant negative function that was more pronounced for the TADDI. In M17 cells the dominant negative variants appeared to be the MB1 and the Δ3-6, whereas TADDI turned out to be a clearly dominant positive variant. In M17 cells mRNA levels of Δ3-6 and Δ3(*)-7(*)/819 variants increased following (17β)estradiol administration. In Hela cells (17β)estradiol up-regulated the IGF-1 receptor mRNA levels in cultures transfected with MB1, TADDI and Δ3(*)-7(*)/819. Our data demonstrate that ERα splice variants show differential levels of the transcriptional activity in a cell type-specific way and that IGF-1 signaling pathways are differentially employed in a cell-type specific manner depending on the level of the discrete ERα splice variants expressed. Functional properties of various ERα splice variants and their cell type-specificity should, thus, be considered as potential confounders of estrogen therapy effects on the brai

Metabolic activity of the human ventromedial nucleus neurons in relation to sex and ageing

The ventromedial nucleus (VMN) in animals is involved in a number of sexually dimorphic behaviors, including reproduction, and is a well-documented target for sex steroids. In rats and in lizards, it is also characterized by the presence of structural sexual dimorphisms. In the present study, we determined whether the metabolic activity of human ventromedial nucleus neurons was sex- or age-related. The size of the immunocytochemically defined Golgi apparatus (GA) and cell profiles were determined as measures for neuronal metabolic activity in 12 male and 16 female control brains sub-divided into four groups with the dividing line being the age of 50. It appeared that the size of the GA relative to cell size was 34% larger in young women ( or = 50 years old) than in young men. In addition, the GA/cell size ratio correlated significantly with age in men and not in women. Our data suggest that androgens play an inhibitory role with respect to the metabolic activity of the human VMN neuron