A network-based meta-analysis for characterizing the genetic landscape of human aging

Great amounts of omics data are generated in aging research, but their diverse and partly complementary nature requires integrative analysis approaches for investigating aging processes and connections to age-related diseases. To establish a broader picture of the genetic and epigenetic landscape of human aging we performed a large-scale meta-analysis of 6600 human genes by combining 35 datasets that cover aging hallmarks, longevity, changes in DNA methylation and gene expression, and different age-related diseases. To identify biological relationships between aging-associated genes we incorporated them into a protein interaction network and characterized their network neighborhoods. In particular, we computed a comprehensive landscape of more than 1000 human aging clusters, network regions where genes are highly connected and where gene products commonly participate in similar processes. In addition to clusters that capture known aging processes such as nutrient-sensing and mTOR signaling, we present a number of clusters with a putative functional role in linking different aging processes as promising candidates for follow-up studies. To enable their detailed exploration, all datasets and aging clusters are made freely available via an interactive website (https://gemex.eurac.edu/bioinf/age/).     

Shifts in the life history of parasitic wasps correlate with pronounced alterations in early development

Developmental processes have been traditionally viewed to be invariant within higher taxa. However, examples are known whereby closely related species exhibit alterations in early embryogenesis yet appear very similar as adults. Such developmental changes are thought to occur in response to shifts in life history. In insects, the regulation of embryonic development has been intensively studied in model species like Drosophila melanogaster. Previous comparative studies suggest that the developmental processes documented in Drosophila well describe embryogenesis of advanced, holometabolous, insects generally. There have been few attempts, however, to take into account how life history has influenced early development of insects or to characterize early development of species with life histories fundamentally different from flies. Here we compared early development of two species from the same family of parasitic wasps that exhibit very different life histories. Bracon hebetor is an ectoparasite that lays large, yolky eggs on the integument of its host that develop much like the free-living honeybee and Drosophila. In contrast, Aphidius ervi is an endoparasite that lays small and apparently yolk-free eggs that develop in the hemocoel of the host. This wasp exhibits a radically different mode of early development at both the cellular and molecular level from B. hebetor. The developmental changes in A. ervi reflect functional adaptations for its derived life history and argue that departures from the fly paradigm may occur commonly among insects whose eggs develop under conditions different from typical terrestrial species.     

Atherosclerosis and Cardiovascular Diseases in Progeroid Syndromes

Hutchinson–Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the representative genetic progeroid syndromes and have been widely studied in the field of aging research. HGPS is a pediatric disease in which premature aging symptoms appear in early childhood, and death occurs at an average age of 14.5 years, mainly due to cardiovascular disease (CVD). Conversely, WS patients exhibit accelerated aging phenotypes after puberty and die in their 50s due to CVD and malignant tumors. Both diseases are models of human aging, leading to a better understanding of the aging-associated development of CVD. In this review, we discuss the pathogenesis and treatment of atherosclerotic diseases presented by both progeroid syndromes with the latest findings.     

The stationary phase model of aging in yeast for the study of oxidative stress and age-related neurodegeneration

Understanding the biochemical and genetic alterations that occur during the aging of post-mitotic cells is critical for understanding the etiology of abnormalities observed during the aging of the central nervous system (CNS). While many theories for cellular aging exist, the free radical theory of aging has proved useful in explaining multiple aspects of post-mitotic cell aging, including the aging of neuronal cells. It is well established that Saccharomyces cerevisiae are an invaluable model system for exploring the regulation of aging in actively dividing cells, but increasing evidence suggests that the chronological lifespan or stationary phase model of aging in S. cerevisiae may also be useful for understanding the aging process in post-mitotic cells. Interestingly, the stationary phase model of aging in S. cerevisiae recapitulates many pathological alterations observed during neuronal aging, including evidence for increased oxidative stress and proteasome inhibition. Studies using proteins relevant to multiple neurodegenerative conditions (prion, alpha-synuclein, huntingtin) have demonstrated the utility of S. cerevisiae as a model system for understanding the genetic regulation of protein aggregation and cell death. Taken together, these data highlight the potential importance of using S. cerevisiae as a model system with which to explore the molecular basis for neuronal alterations observed in normal brain aging as well as multiple age–related diseases of the CNS.     

自噬调控衰老的研究进展

随着机体老化,组织器官可发生不可逆退行性改变,这些变化与疾病和死亡密切相关。自噬是细胞内一种重要的分解代谢过程,在维持细胞稳态和促进长寿中起重要作用,机体衰老后,其自噬调节能力也随之下降。本文综述了自噬与衰老相关疾病的关系,明确自噬调控衰老的相关分子机制可能为治疗衰老相关疾病提供新的靶点。     

Aging and interstitial lung diseases: unraveling an old forgotten player in the pathogenesis of lung fibrosis

Aging is a natural process characterized by a progressive functional impairment and reduced capacity to respond adaptively to environmental stimuli. Aging is associated with increased susceptibility to a variety of chronic diseases, including type 2 diabetes mellitus, cancer, and neurological diseases. Lung pathologies are not the exception, and the prevalence of several interstitial lung diseases (ILDs), primarily idiopathic pulmonary fibrosis, has been found to increase considerably with age. Although our understanding of the biology of aging has advanced remarkably in the last 2 decades, the molecular mechanisms linking aging to ILD remain unclear. Immunosenescence, oxidative stress, abnormal shortening of telomeres, apoptosis, and epigenetic changes affecting gene expression have been proposed to contribute to the aging process, and aging-associated diseases. Here, we review the emerging concepts highlighting the putative aging-associated abnormalities involved in some human ILDs.     

Neoplastic disease through the human life span

Cancers are different diseases that start andevolve each in its own manner, andtrigger variable responses from the organismdepending upon the neoplastic process under wayand upon the physiopathology of the organism.The clinical incidence of the different cancersis spread through the human life span, withregional differences for each cancer; for manycancers the incidence is increasing at youngerages. More than half of the cancers becomeclinically manifest during the second half ofthe human life span and their frequencyincreases with age, but their natural historystarts way back at earlier ages. The datasuggest that the late manifestation is theresult of the accumulation of events throughtime rather than of aging. Interestingly, latein the human life span the incidence ofneoplastic disease declines. Is this due to thecohort of late survivals naturally resistant tothe development of neoplastic processes, or tothe characteristics of the last ‘window’ of thehuman life span? The evolution of neoplasticdisease is the result of pre- and postnatalaggressions suffered by the organism,individual susceptibility, and developmentalchanges that evolve continuously from thebeginning to the end of the human life span.The identification of the causes of theincidences of the different cancers through thehuman life span will help to understand bothneoplastic disease and aging of the organism.     

Expression of the Hox gene complex in the indirect development of a sea urchin

Hox complex genes control spatial patterning mechanisms in the development of arthropod and vertebrate body plans. Hox genes are all expressed during embryogenesis in these groups, which are all directly developing organisms in that embryogenesis leads at once to formation of major elements of the respective adult body plans. In the maximally indirect development of a large variety of invertebrates, the process of embryogenesis leads only to a free-living, bilaterally organized feeding larva. Maximal indirect development is exemplified in sea urchins. The 5-fold radially symmetric adult body plan of the sea urchin is generated long after embryogenesis is complete, by a separate process occurring within imaginal tissues set aside in the larva. The single Hox gene complex of Strongylocentrotus purpuratus contains 10 genes, and expression of eight of these genes was measured by quantitative methods during both embryonic and larval developmental stages and also in adult tissues. Only two of these genes are used significantly during the entire process of embryogenesis per se, although all are copiously expressed during the stages when the adult body plan is forming in the imaginal rudiment. They are also all expressed in various combinations in adult tissues. Thus, development of a microscopic, free-living organism of bilaterian grade, the larva, does not appear to require expression of the Hox gene cluster as such, whereas development of the adult body plan does. These observations reflect on mechanisms by which bilaterian metazoans might have arisen in Precambrian evolution.     

IGF binding protein 1 is correlated with hypoxia-induced growth reduce and developmental defects in grass carp (Ctenopharyngodon idellus) embryos

The effects of hypoxia on embryonic development and the underlying cellular and molecular mechanisms are poorly understood in teleost fish, although the hypoxic effects on embryonic growth and development have been reported in the zebrafish model. Here, we found that hypoxia caused significant developmental delay and growth retardation during grass carp embryogenesis. Placing the embryos in hypoxic conditions at different developmental stages strongly induced the mRNA expression of insulin-like growth factor-binding protein 1 (IGFBP1), an inhibitory protein that binds to IGF and inhibits its subsequent actions in vivo. Further gain-of-function analysis results provided strong evidence to support the hypothesis that IGFBP1 plays an important role in mediating hypoxic-induced growth and developmental defects. Overexpression of IGFBP1 mRNA reduced the growth rate to a degree that was similar to hypoxia. Additionally, overexpression of IGFBP1 caused significant developmental defects in the formation of midline, somite and hindbrain structures during grass carp embryogenesis. Taken together, our studies suggest that IGFBP1 plays a key role in mediating these hypoxia-induced embryonic growth retardation and developmental delay in grass carp.     

Wolbachia in filarial parasites: Targets for filarial infection and disease control

Lymphatic filariasis and onchocerciasis are debilitating diseases caused by parasitic filarial nematodes. These nematodes have evolved a mutualistic symbiosis with intracellular bacteria of the genus Wolbachia, which are required for nematode embryogenesis and survival. The essential role of these bacteria in the biology of the nematode and their demonstrated involvement in the pathogenesis of filariasis make Wolbachia a promising novel chemotherapeutic target for the control of filarial infection and disease. This article reviews the recent findings, which highlight potential processes that form the basis of the symbiosis, the role of Wolbachia in filarial pathogenesis, and the efficacy of Wolbachia-targeted antibiotic chemotherapy in human trials. Future prospects for the development of an anti-Wolbachia treatment regimen suitable for integration into mass drug administration programs are also discussed.     

The NetAge database: a compendium of networks for longevity,age-related diseases and associated processes

Hundreds of genes and miRNAs have been identified as being involved in the determination of longevity, aging patterns and in the development of age-related diseases (ARDs). The interplay between these genes as well as the role of miRNAs in the context of protein–protein interaction networks has as yet been poorly addressed. This work was undertaken in order to integrate the data accumulated in the field, from a network-based perspective. The results are organized in the NetAge database—an online database and network analysis tools for biogerontological research (). The NetAge database contains gene sets and miRNA-regulated PPI networks for longevity, ARDs and aging-associated processes, and also common signatures (overlapping networks). The database is available through the NetAge website, which provides the necessary bioinformatics tools for searching and browsing the networks, as well as showing network info and statistics. By making these resources available online, we hope to provide the scientific community with a new, network-oriented platform for biogerontological research, and encourage greater participation in the systems biology of aging.     

Aging-related fears and their associations with ideal life expectancy

Fears regarding various aspects tend to stimulate individuals to escape or to avoid the sources of the threat. We concluded that fears associated with the future aging process, like the fear of aging-related diseases, the fear of loneliness in old age, and the fear of death, would stimulate patterns of avoidance when it comes to ideal life expectancy. We expected fear of aging-related diseases and fear of loneliness in old age to be related to lower ideal life expectancies. We expected fear of death to be related to higher ideal life expectancies. In two adult lifespan samples [N₁?=?1065 and N₂?=?591; ages ranging from 18 to 95 years, M (SD)₁?=?58.1 (17.2) years, M (SD)₂?=?52.6 (18.1) years], we were able to support our hypothesis regarding fear of death. We furthermore found significant interactions among the fears, indicating that individuals fearing diseases or loneliness but being unafraid of death opted for the shortest lives. Our results indicate that fears regarding life in very old age might be associated with the wish to avoid this age period; the fear of death was however associated with the wish for particularly long lives, and thus, with distancing oneself from the dreaded event of death. We conclude that fears seem to be associated with how individuals approach old age and with what they wish for in their own future as aged people.

     

Advantages and disadvantages of Caenorhabditis elegans for aging research

The nematode Caenorhabditis elegans has been the organism of choice for most aging research, especially genetic approaches to aging. More than 70 longevity genes have been identified, with more to come, and these genes have been the subjects of intense study. I identify the major reasons for this and discuss limitations of this organism for future progress in research on aging.     

Wnt signaling and aging-related heart disorders

Aging is associated with various heart diseases, and this may be attributable, in part, to the prolonged exposure of the heart to cardiovascular risk factors. However, aging is also associated with heart disorders such as diastolic dysfunction that are not necessarily linked to the risk factors for cardiovascular diseases. Recent studies have demonstrated a mechanistic link between Wnt signaling and premature aging or aging-related phenotypes. As a part of the review series on Wnt signaling and the cardiovascular system, we discuss here the possible involvement of Wnt signaling in aging-associated heart diseases or heart disorders.     

Cu, Zn superoxide dismutase deficiencyaccelerates the time course of an age-related markerin Drosophila melanogaster

In the oxidative stress hypothesis of aging therandom accumulation of oxidative damage over time ispostulated to cause aging. The pace at whichoxidative damage accrues determines the rate of aging,but it is less clear how the accumulation of randomdamage could cause the stereotypic pattern of aging. It has been proposed that oxidative damage induceschanges in gene expression, translating a random inputof damage into a patterned output. In support of thiswe show that in adult Drosophila melanogaster,with a deficiency in the anti-oxidant enzyme Cu, Znsuperoxide dismutase (Sod), an increase in oxidativestress, and a shortened life span, there isacceleration in the normal age-related temporalpattern of wingless gene expression. Theacceleration in the temporal pattern of winglessgene expression is proportional to the shortened lifespan suggesting that the shortened life span of Soddeficient animals is due, not to an abnormalpathological process, but to an increase in the rateof aging.     

Healthy aging: what can we learn from Caenorhabditis elegans?

The microscopic worm Caenorhabditis elegans (C. elegans) is one of the most prominent animal models for aging studies. This is underscored by the fact that most of the genes and interventions that modulate the aging process, such as the insulin/IGF pathway, caloric restriction and mitochondrial signalling, were first identified in this organism. Remarkably, many features of the mammalian aging process are recapitulated in C. elegans: over time, damage to macromolecule accumulates, structural cellular components progressively deteriorate, physiological functions decline, resistance to stress and infections decreases, while morbidity and mortality rates increase. In humans, age represents risk factor number one for most diseases ultimately leading to death in industrialized countries, namely cardiovascular diseases, cancer and neurodegenerative disorders. Genes regulating aging in C. elegans are evolutionarily conserved and their deregulation is often involved in the development of age-associated diseases in humans. It is therefore likely that any intervention that extends C. elegans lifespan will indicate strategies to positively impact on healthy human longevity.