Acute Myeloid Leukemia: Aging and Epigenetics

Acute myeloid leukemia (AML) is an aggressive hematological disorder mainly affecting people of older age. AML initiation is primarily attributed to mutations in crucial cellular regulators such as epigenetic factors, transcription factors, and signaling genes. AML's aggressiveness and responsiveness to treatment depends on the specific cell type where leukemia first arose. Aged hematopoietic cells are often genetically and/or epigenetically altered and, therefore, present with a completely different cellular context for AML development compared to young cells. In this review, we summarize key aspects of AML development, and we focus, in particular, on the contribution of cellular aging to leukemogenesis and on current treatment options for elderly AML patients. Hematological disorders and leukemia grow exponentially with age. So far, with conventional induction therapy, many elderly patients experience a very poor overall survival rate requiring substantial social and medical costs during the relatively few remaining months of life. The global population's age is increasing rapidly without an acceptable equal growth in therapeutic management of AML in the elderly; this is in sharp contrast to the increase in successful therapies for leukemia in younger patients. Therefore, a focus on the understanding of the biology of aging in the hematopoietic system, the development of appropriate research models, and new therapeutic approaches are urged

Understanding intrinsic hematopoietic stem cell aging

Hematopoietic stem cells (HSC) sustain blood production over the entire life-span of an organism. It is of extreme importance that these cells maintain self-renewal and differentiation potential over time in order to preserve homeostasis of the hematopoietic system. Many of the intrinsic aspects of HSC are affected by the aging process resulting in a deterioration in their potential, independently of their microenvironment. Here we review recent findings characterizing most of the intrinsic aspects of aged HSC, ranging from phenotypic to molecular alterations. Historically, DNA damage was thought to be the main cause of HSC aging. However, over recent years, many new findings have defined an increasing number of biological processes that intrinsically change with age in HSC. Epigenetics and chromatin architecture, together with autophagy, proteostasis and metabolic changes, and how they are interconnected, are acquiring growing importance for understanding the intrinsic aging of stem cells. Given the increase in populations of older subjects worldwide, and considering that aging is the primary risk factor for most diseases, understanding HSC aging becomes particularly relevant also in the context of hematologic disorders, such as myelodysplastic syndromes and acute myeloid leukemia. Research on intrinsic mechanisms responsible for HSC aging is providing, and will continue to provide, new potential molecular targets to possibly ameliorate or delay aging of the hematopoietic system and consequently improve the outcome of hematologic disorders in the elderly. The niche-dependent contributions to hematopoietic aging are discussed in another review in this same issue of the Journal

An aged bone marrow niche restrains rejuvenated hematopoietic stem cells

Aging-associated leukemia and aging-associated immune remodeling are in part caused by aging of hematopoietic stem cells (HSCs). An increase in the activity of the small RhoGTPase cell division control protein 42 (Cdc42) within HSCs causes aging of HSCs. Old HSCs, treated ex vivo with a specific inhibitor of Cdc42 activity termed CASIN, stay rejuvenated upon transplantation into young recipients. We determined in this study the influence of an aged niche on the function of ex vivo rejuvenated old HSCs, as the relative contribution of HSCs intrinsic mechanisms vs extrinsic mechanisms (niche) for aging of HSCs still remain unknown. Our results show that an aged niche restrains the function of ex vivo rejuvenated HSCs, which is at least in part linked to a low level of the cytokine osteopontin found in aged niches. The data imply that sustainable rejuvenation of the function of aged HSCs in vivo will need to address the influence of an aged niche on rejuvenated HSCs

Attrition of X Chromosome Inactivation in Aged Hematopoietic Stem Cells

During X chromosome inactivation (XCI), the inactive X chromosome (Xi) is recruited to the nuclear lamina at the nuclear periphery. Beside X chromosome reactivation resulting in a highly penetrant aging-like hematopoietic malignancy, little is known about XCI in aged hematopoietic stem cells (HSCs). Here, we demonstrate that LaminA/C defines a distinct repressive nuclear compartment for XCI in young HSCs, and its reduction in aged HSCs correlates with an impairment in the overall control of XCI. Integrated omics analyses reveal higher variation in gene expression, global hypomethylation, and significantly increased chromatin accessibility on the X chromosome (Chr X) in aged HSCs. In summary, our data support the role of LaminA/C in the establishment of a special repressive compartment for XCI in HSCs, which is impaired upon aging

Male sex pheromone components in Heliconius butterflies released by the androconia affect female choice.

Sex-specific pheromones are known to play an important role in butterfly courtship, and may influence both individual reproductive success and reproductive isolation between species. Extensive ecological, behavioural and genetic studies of Heliconius butterflies have made a substantial contribution to our understanding of speciation. Male pheromones, although long suspected to play an important role, have received relatively little attention in this genus. Here, we combine morphological, chemical and behavioural analyses of male pheromones in the Neotropical butterfly Heliconius melpomene. First, we identify putative androconia that are specialized brush-like scales that lie within the shiny grey region of the male hindwing. We then describe putative male sex pheromone compounds, which are largely confined to the androconial region of the hindwing of mature males, but are absent in immature males and females. Finally, behavioural choice experiments reveal that females of H. melpomene, H. erato and H. timareta strongly discriminate against conspecific males which have their androconial region experimentally blocked. As well as demonstrating the importance of chemical signalling for female mate choice in Heliconius butterflies, the results describe structures involved in release of the pheromone and a list of potential male sex pheromone compounds

Male sex pheromone components in Heliconius butterflies released by the androconia affect female choice

Sex-specific pheromones are known to play an important role in butterfly courtship, and may influence both individual reproductive success and reproductive isolation between species. Extensive ecological, behavioural and genetic studies of Heliconius butterflies have made a substantial contribution to our understanding of speciation. Male pheromones, although long suspected to play an important role, have received relatively little attention in this genus. Here, we combine morphological, chemical and behavioural analyses of male pheromones in the Neotropical butterfly Heliconius melpomene. First, we identify putative androconia that are specialized brush-like scales that lie within the shiny grey region of the male hindwing. We then describe putative male sex pheromone compounds, which are largely confined to the androconial region of the hindwing of mature males, but are absent in immature males and females. Finally, behavioural choice experiments reveal that females of H. melpomene, H. erato and H. timareta strongly discriminate against conspecific males which have their androconial region experimentally blocked. As well as demonstrating the importance of chemical signalling for female mate choice in Heliconius butterflies, the results describe structures involved in release of the pheromone and a list of potential male sex pheromone compounds. © 2017 Darragh et al

Inhibition of Cdc42 activity extends lifespan and decreases circulating inflammatory cytokines in aged female C57BL/6 mice

Cdc42 is a small RhoGTPase regulating multiple functions in eukaryotic cells. The activity of Cdc42 is significantly elevated in several tissues of aged mice, while the Cdc42 gain-of-activity mouse model presents with a premature aging-like phenotype and with decreased lifespan. These data suggest a causal connection between elevated activity of Cdc42, aging, and reduced lifespan. Here, we demonstrate that systemic treatment of aged (75-week-old) female C57BL/6 mice with a Cdc42 activity-specific inhibitor (CASIN) for 4 consecutive days significantly extends average and maximum lifespan. Moreover, aged CASIN-treated animals displayed a youthful level of the aging-associated cytokines IL-1β, IL-1α, and INFγ in serum and a significantly younger epigenetic clock as based on DNA methylation levels in blood cells. Overall, our data show that systemic administration of CASIN to reduce Cdc42 activity in aged mice extends murine lifespan

Can Urban Air Mobility become reality? Opportunities, challenges and selected research results

Urban Air Mobility (UAM) is a new air transportation system for passengers and cargo in urban environments, enabled by new technologies and integrated into multimodal transportation systems. The vision of UAM comprises the mass use in urban and suburban environments, complementing existing transportation systems and contributing to the decarbonization of the transport sector. Initial attempts to create a market for urban air transportation in the last century failed due to lack of profitability and community acceptance. Technological advances in numerous fields over the past few decades have led to a renewed interest in urban air transportation. UAM is expected to benefit users and to also have a positive impact on the economy by creating new markets and employment opportunities for manufacturing and operation of UAM vehicles and the construction of related ground infrastructure. However, there are also concerns about noise, safety and security, privacy and environmental impacts. Therefore, the UAM system needs to be designed carefully to become safe, affordable, accessible, environmentally friendly, economically viable and thus sustainable. This paper provides an overview of selected key research topics related to UAM and how the German Aerospace Center (DLR) contributed to this research in the project "HorizonUAM - Urban Air Mobility Research at the German Aerospace Center (DLR)". Selected research results that support the realization of the UAM vision are briefly presented.Comment: 20 pages, 7 figures, project HorizonUA

Aging of human hematopoietic stem cells is linked to changes in Cdc42 activity

In this study, we characterize age-related phenotypes of human hematopoietic stem cells (HSC). We report increased frequencies of HSC, hematopoietic progenitor cells and lineage negative cells in the elderly but a decreased frequency of multi-lymphoid progenitors. Aged human HSC further exhibited a delay in initiating division ex vivo though without changes in their division kinetics. The activity of the small RhoGTPase Cdc42 was elevated in aged human hematopoietic cells and we identified a positive correlation between Cdc42 activity and the frequency of HSC upon aging. The frequency of human HSC polar for polarity proteins was, similar to the mouse, decreased upon aging, while inhibition of Cdc42 activity via the specific pharmacological inhibitor of Cdc42 activity, CASIN, resulted in re-polarization of aged human HSC with respect to Cdc42. Elevated activity of Cdc42 in aged HSC thus contributed to age-related changes in HSC. Xenotransplant, using NBSGW mice as recipients, showed elevated chimerism in recipients of aged compared to young HSC. Aged HSC treated with CASIN ex vivo displayed an engraftment profile similar to recipients of young HSC. Taken together, our work reveals strong evidence for a role of elevated Cdc42 activity in driving aging of human HSC, and similar to mice, this presents a likely possibility for attenuation of aging in human HSC

The global EPTO database: Worldwide occurrences of aquatic insects

Motivation: Aquatic insects comprise 64% of freshwater animal diversity and are widely used as bioindicators to assess water quality impairment and freshwater eco-system health, as well as to test ecological hypotheses. Despite their importance, a comprehensive, global database of aquatic insect occurrences for mapping freshwater biodiversity in macroecological studies and applied freshwater research is missing. We aim to fill this gap and present the Global EPTO Database, which includes world-wide geo- referenced aquatic insect occurrence records for four major taxa groups: Ephemeroptera, Plecoptera, Trichoptera and Odonata (EPTO).Main type of variables contained: A total of 8,368,467 occurrence records globally, of which 8,319,689 (99%) are publicly available. The records are attributed to the cor-responding drainage basin and sub-catchment based on the Hydrography90m dataset and are accompanied by the elevation value, the freshwater ecoregion and the pro-tection status of their location. Spatial location and grain: The database covers the global extent, with 86% of the observation records having coordinates with at least four decimal digits (11.1 m preci-sion at the equator) in the World Geodetic System 1984 (WGS84) coordinate refer-ence system.Time period and grain: Sampling years span from 1951 to 2021. Ninety- nine percent of the records have information on the year of the observation, 95% on the year and month, while 94% have a complete date. In the case of seven sub-datasets, exact dates can be retrieved upon communication with the data contributors. Major taxa and level of measurement: Ephemeroptera, Plecoptera, Trichoptera and Odonata, standardized at the genus taxonomic level. We provide species names for 7,727,980 (93%) records without further taxonomic verification.Software format: The entire tab-separated value (.csv) database can be downloaded and visualized at https://glowabio.org/project/epto_database/ . Fifty individual data-sets are also available at https://fred.igb-berlin.de, while six datasets have restricted access. For the latter, we share metadata and the contact details of the authors