The damage-independent evolution of ageing by selective destruction

Ageing is currently believed to reflect the accumulation of molecular damage due to energetic costs of maintenance, as proposed in disposable soma theory (DST). Here we have used agent-based modelling to describe an alternative theory by which ageing could undergo positive selection independent of energetic costs. We suggest that the selective advantage of fast-growing mutants might necessitate a mechanism of counterselection we name selective destruction, which removes the faster growing cells from the tissue, preventing the threat of morbidity and mortality they pose. As a result, the survival advantage would shift to the slower cells, allowing them to spread, inducing ageing in the form of a metabolic slowdown. Selective destruction could therefore provide a proximal cause of ageing that is both consistent with the gene expression hallmarks of ageing, and independent of accumulating damage. If true, negligible senescence would acquire a new meaning of increased basal mortality.

Morphological and Physiological Response of Different Lettuce Genotypes to Salt Stress

Salt stress (SS) refers to excessive soluble salt concentrations in the plant root zone. SS also causes cellular water deficits, ion toxicity, and oxidative stress in plants, all of which can cause growth inhibition, molecular damage, and even plant mortality. Lettuce (Lactuca sativa L.) has a threshold electrical conductivity of 1.3–2.0 dS/m. Thus, this research focused on physiological, morphological, and biochemical attributes in multiple lettuce genotypes under SS compared to plants grown under control conditions. The experiment was arranged in a randomized complete block design with four replications. One month after planting, the salt treatment was applied at the rate of 100 millimoles (mM). The 0 mM salt in water treatment was considered the control. A significant effect of SS on different morphological and physiological traits was observed in one-month-old lettuce plants. PI 212099, Buttercrunch-1, and PI 171676 were highly salt-tolerant. Genotypes with high salt tolerance usually had poor growth potential under control conditions. This suggests that the morphological and physiological response of 38 lettuce cultivars towards SS is genotype dependent. Identifying SS’s physiological, morphological, and biochemical attributes in lettuce may help plant-breeders develop salt-tolerant lettuce genotypes.

Health Effects Associated With Pre- and Perinatal Exposure to Arsenic

Inorganic arsenic is a well-established human carcinogen, able to induce genetic and epigenetic alterations. More than 200 million people worldwide are exposed to arsenic concentrations in drinking water exceeding the recommended WHO threshold (10μg/l). Additionally, chronic exposure to levels below this threshold is known to result in long-term health effects in humans. The arsenic-related health effects in humans are associated with its biotransformation process, whereby the resulting metabolites can induce molecular damage that accumulates over time. The effects derived from these alterations include genomic instability associated with oxidative damage, alteration of gene expression (including coding and non-coding RNAs), global and localized epigenetic reprogramming, and histone posttranslational modifications. These alterations directly affect molecular pathways involved in the onset and progression of many conditions that can arise even decades after the exposure occurs. Importantly, arsenic metabolites generated during its biotransformation can also pass through the placental barrier, resulting in fetal exposure to this carcinogen at similar levels to those of the mother. As such, more immediate effects of the arsenic-induced molecular damage can be observed as detrimental effects on fetal development, pregnancy, and birth outcomes. In this review, we focus on the genetic and epigenetic damage associated with exposure to low levels of arsenic, particularly those affecting early developmental stages. We also present how these alterations occurring during early life can impact the development of certain diseases in adult life.

The Hyperfunction Theory: An Emerging Paradigm for the Biology of Aging

The process of senescence (aging) is largely determined by the action of wild-type genes. For most organisms, this does not reflect any adaptive function of senescence, but rather evolutionary effects of declining selection against genes with deleterious effects later in life. To understand aging requires an account of how evolutionary mechanisms give rise to pathogenic gene action and late-life disease, that integrates evolutionary (ultimate) and mechanistic (proximate) causes into a single explanation. A well-supported evolutionary explanation by G.C. Williams argues that senescence can evolve due to pleiotropic effects of alleles with antagonistic effects on fitness and late-life health (antagonistic pleiotropy, AP). What has remained unclear is how gene action gives rise to late-life disease pathophysiology. One ultimate-proximate account is T.B.L. Kirkwood’s disposable soma theory. Based on the hypothesis that stochastic molecular damage causes senescence, this reasons that aging is coupled to reproductive fitness due to preferential investment of resources into reproduction, rather than somatic maintenance. An alternative and more recent ultimate-proximate theory argues that aging is largely caused by programmatic, developmental-type mechanisms. Here ideas about AP and programmatic aging are reviewed, particularly those of M.V. Blagosklonny (the hyperfunction theory) and J.P. de Magalhães (the developmental theory), and their capacity to make sense of diverse experimental findings is described.

Development, validation, and application of the ribosome separation and reconstitution system for protein translation in vitro

Stress-induced molecular damage to ribosomes can impact protein synthesis in cells, but cell-based assays do not provide a clear way to distinguish the effects of ribosome damage from stress responses and damage to other parts of the translation machinery. Here we describe a detailed protocol for the separation of yeast ribosomes from other translational machinery constituents, followed by reconstitution of the translation mixture in vitro. This technique, which we refer to as Ribosome Separation and Reconstitution (RSR), allows chemical modifications of yeast ribosomes without compromising other key translational components. In addition to the characterization of stress-induced ribosome damage, RSR can be applied to a broad range of experimental problems in studies of yeast translation.

Dietary Regulation of Oxidative Stress in Chronic Metabolic Diseases

Oxidative stress is a status of imbalance between oxidants and antioxidants, resulting in molecular damage and interruption of redox signaling in an organism. Indeed, oxidative stress has been associated with many metabolic disorders due to unhealthy dietary patterns and may be alleviated by properly increasing the intake of antioxidants. Thus, it is quite important to adopt a healthy dietary mode to regulate oxidative stress and maintain cell and tissue homeostasis, preventing inflammation and chronic metabolic diseases. This review focuses on the links between dietary nutrients and health, summarizing the role of oxidative stress in ‘unhealthy’ metabolic pathway activities in individuals and how oxidative stress is further regulated by balanced diets.

Thioredoxin reductase controls the capacity of peroxiredoxins to limit mitochondrial H2O2 release

H2O2 performs central roles in signaling at physiological levels, while at elevated levels it causes molecular damage. Mitochondria are major producers of H2O2, which has been implied in regulating diverse processes inside and outside the organelle. However, it still remains unclear whether and how mitochondria in intact cells release H2O2. Here we employed the genetically encoded high-affinity H2O2 sensor HyPer7 in mammalian tissue culture cells to investigate different modes of mitochondrial H2O2 release. We found substantial heterogeneity of HyPer7 dynamics between individual cells, and observed H2O2 released from mitochondria directly at the surface of the organelle and in the bulk cytosol, but not in the nucleus nor on the plasma membrane, pointing to steep gradients emanating from mitochondria. These gradients are controlled by cytosolic peroxiredoxins that act redundantly and are present with a substantial reserve capacity. Furthermore, dynamic adaptation of cytosolic thioredoxin reductase levels during metabolic changes results in improved H2O2 handling and explains previously observed cell-to-cell differences. Thus, our data indicate that H2O2-mediated signaling likely occurs close to mitochondria during specific metabolic conditions.

Localization and Bioreactivity of Cysteine-Rich Secretions in the Marine Gastropod Nucella lapillus

Marine biodiversity has been yielding promising novel bioproducts from venomous animals. Despite the auspices of conotoxins, which originated the paradigmatic painkiller Prialt, the biotechnological potential of gastropod venoms remains to be explored. Marine bioprospecting is expanding towards temperate species like the dogwhelk Nucella lapillus, which is suspected to secrete immobilizing agents through its salivary glands with a relaxing effect on the musculature of its preferential prey, Mytilus sp. This work focused on detecting, localizing, and testing the bioreactivity of cysteine-rich proteins and peptides, whose presence is a signature of animal venoms and poisons. The highest content of thiols was found in crude protein extracts from the digestive gland, which is associated with digestion, followed by the peribuccal mass, where the salivary glands are located. Conversely, the foot and siphon (which the gastropod uses for feeding) are not the main organs involved in toxin secretion. Ex vivo bioassays with Mytilus gill tissue disclosed the differential bioreactivity of crude protein extracts. Secretions from the digestive gland and peribuccal mass caused the most significant molecular damage, with evidence for the induction of apoptosis. These early findings indicate that salivary glands are a promising target for the extraction and characterization of bioactive cysteine-rich proteinaceous toxins from the species.

The Causal Role of Lipoxidative Damage in Mitochondrial Bioenergetic Dysfunction Linked to Alzheimer’s Disease Pathology

Current shreds of evidence point to the entorhinal cortex (EC) as the origin of the Alzheimer’s disease (AD) pathology in the cerebrum. Compared with other cortical areas, the neurons from this brain region possess an inherent selective vulnerability derived from particular oxidative stress conditions that favor increased mitochondrial molecular damage with early bioenergetic involvement. This alteration of energy metabolism is the starting point for subsequent changes in a multitude of cell mechanisms, leading to neuronal dysfunction and, ultimately, cell death. These events are induced by changes that come with age, creating the substrate for the alteration of several neuronal pathways that will evolve toward neurodegeneration and, consequently, the development of AD pathology. In this context, the present review will focus on description of the biological mechanisms that confer vulnerability specifically to neurons of the entorhinal cortex, the changes induced by the aging process in this brain region, and the alterations at the mitochondrial level as the earliest mechanism for the development of AD pathology. Current findings allow us to propose the existence of an altered allostatic mechanism at the entorhinal cortex whose core is made up of mitochondrial oxidative stress, lipid metabolism, and energy production, and which, in a positive loop, evolves to neurodegeneration, laying the basis for the onset and progression of AD pathology.