Protective Efficacy of Novel Engineered Human ACE2-Fc Fusion Protein Against Pan-SARS-CoV-2 Infection In Vitro and in Vivo.

Enduring occurrence of severe COVID-19 for unvaccinated, aged, or immunocompromised individuals remains an urgent need. Soluble human angiotensin-converting enzyme 2 (ACE2) has been used as a decoy receptor to inhibit SARS-CoV-2 infection, which is limited by moderate affinity. We describe an engineered, high-affinity ACE2 that is consistently effective in tissue cultures in neutralizing all strains tested, including Delta and Omicron.

Applying Artificial Intelligence to Identify Common Targets for Treatment of Asthma, Eczema, and Food Allergy.

Introduction: Allergic disorders are common diseases marked by the abnormal immune response toward foreign antigens that are not pathogens. Often patients with food allergy also suffer from asthma and eczema. Given the similarities of these diseases and a shortage of effective treatments, developing novel therapeutics against common targets of multiple allergies would offer an efficient and cost-effective treatment for patients.

Broad reactivity and enhanced potency of recombinant anti-EGFR × anti-CD3 bispecific antibody-armed activated T cells against solid tumours.

Bispecific antibody (BiAb)-armed activated T cells (BATs) comprise an adoptive T cell therapy platform for treating cancer. Arming activated T cells (ATC) with anti-CD3 x anti-tumour associated antigen (TAA) BiAbs converts ATC into non-major histocompatibility complex (MHC)-restricted anti-tumour cytotoxic T lymphocytes (CTLs). Binding of target antigens via the BiAb bridge enables specific anti-tumour cytotoxicity, Th1 cytokines release, and T cell proliferation.

Antiaging Vaccines Targeting Senescent Cells.

The development of senomorphic drugs to attenuate the senescent phenotype and senolytics to clear pro-inflammatory senescent cells (SCs) to treat aging-associated disorders is being hotly pursued. The effort is complicated by the fact that SCs play a constructive role in some cellular processes such as tissue repair and wound healing. However, concerns about efficacy, which SCs to target, and unwanted side effects have created potential roadblocks.

Stem Cell Rejuvenation by Restoration of Youthful Metabolic Compartmentalization.

Stem cell dysfunction is a hallmark of aging. Much recent study suggests that epigenetic changes play a critical role in the loss of stem cell function with age. However, the underlying mechanisms require elucidation.

Modulation of cGAS-STING Pathway by Nicotinamide Riboside in Alzheimer's Disease.

Numerous studies demonstrate a global decrease in nicotinamide adenine dinucleotide (NAD+) with aging. This decline is associated with the development of several of the hallmarks of aging such as reduced mitophagy and neuroinflammation, processes thought to play a significant role in the progression of Alzheimer's disease (AD). Augmentation of NAD+ by oral administration of a precursor, nicotinamide riboside (NR), reduces senescence of affected cells, attenuates DNA damage and neuroinflammation in the transgenic APP/PS1 murine model of AD.

Response to Hypoxia in Cognitive Decline.

Inflammaging, the increase of proinflammatory processes with increasing age, has multiple mechanisms from increasing numbers of senescent cells secreting cytokines to changes in metabolic processes. Alterations of oxygen metabolism with aging, especially decreased levels of O with age resulting from endocrine and cardiovascular dysfunction as well as desensitization of cellular response to hypoxia, may exacerbate inflammaging, which in turn creates further oxygen metabolic dysfunction. During aging, decline in levels of erythrocyte 2,3-bisphosphoglycerate (2,3-BPG), BPG mutase, and adenosine A2B receptor, a key adenosine signaling receptor that can augment 2,3-BPG expression, may fail to protect sensitive brain tissue from subtly reduced O levels, in turn resulting in increased numbers of activated microglia and secretion of proinflammatory cytokines, ultimately promoting inflammaging and senescence of endothelial cells.

Beneficial Gut Microbiome Remodeled During Intermittent Fasting in Humans.

Intermittent fasting (IF) is the practice of restricting food intake for 12-48 hours per fasting cycle over a prolonged period of time. Previous study shows beneficial health effects such as weight loss and lower risk for cardiometabolic diseases. Although reduced calorie intake may account for some of the observed benefits of IF, exact mechanisms are still unclear.

Rejuvenation Through Oxygen, More or Less.

Modest modulation of oxygen intake, either by inducing mild intermittent hypoxia or hyperoxia appears to induce modest rejuvenative changes in mammals, in part, by activating key regulator hypoxia-induced factor 1a (HIF-1a). Interestingly both lower oxygen and transient higher oxygen levels induce this hypoxia regulator. Hyperbaric oxygen induces HIF-1a by the hyperoxic-hypoxic paradox that results from an overinduction of protective factors under intermittent hyperoxic conditions, leading to a state somewhat similar to that induced by hypoxia.

SUMO Wrestles with Mitophagy to Extend Lifespan.

SUMOylation, a conserved protein post-translational modification that performs multiple functions including regulation of nuclear transport and transcription, is implicated in numerous biological processes including aging. RNAi knockdown of the sole Small Ubiquitin-like MOdifier (SUMO) gene, smo-1, in shortened lifespan, whereas overexpression in the intestine modestly increased lifespan. Smo-1 is required for mitochondrial fission in a tissue-specific manner.

Contribution of Ferroptosis to Aging and Frailty.

Ferroptosis is a recently characterized cell death phenotype resulting from iron-catalyzed peroxidation of polyunsaturated fatty acid phospholipids. Increased dysfunctional iron metabolism is thought to lead to increased levels of iron and ferroptosis, which in turn leads to cell and organismal death at least in the nematode . Drugs that block lipid peroxidation or scavenge intracellular iron extend healthspan and lifespan in independently of other mechanisms such as the (insulin/insulin-like growth factor 1 [IGF-1]) pathway, but unlike many aging mechanisms do not alter temporal scaling across the life cycle of , but rather act at specific late points in the organism's life history, temporarily blocking execution of critical dysfunction that results in listless worms.

Eosinophils and White Fat: Protection from Worms and Inflammaging.

Proinflammatory alterations of white adipose tissue (WAT) with increasing age play an important role in mammalian aging. WAT produced eotaxin-1 (CCL11-C-C motif chemokine ligand 11) and monocyte chemoattractant protein 1 (MCP-1) (CCL2) are elevated in old mammals. Obese and old adipose tissues produce excessive proinflammatory cytokines such as interleukin (IL)-6, CCL2, and IL-1-beta that contribute to inflammaging.

Supplementation with Brush Border Enzyme Alkaline Phosphatase Slows Aging.

Diminished integrity of the intestinal epithelial barrier with advanced age is believed to contribute to aging-associated dysfunction and pathologies in animals. In mammals, diminished gut integrity contributes to inflammaging, the increase in inflammatory processes observed in old age. Recent work suggests that expression of intestinal alkaline phosphatase (IAP) plays a key role in maintaining gut integrity.

The Danger of Being Too Sympathetic: Norepinephrine in Alzheimer's Disease and Graying of Hair.

Although alterations in the sympathetic nervous system (SNS) with age have been reported, and serious degenerative diseases of the autonomic nervous system such as multiple system atrophy are more likely to strike older people, connections between dysregulated adrenergic receptors and age-associated diseases and phenotypes have not been well studied. Two recent reports suggest that SNS may be more closely connected than previously appreciated. First, low nanomolar concentrations of Alzheimer's disease (AD)-associated Aβ42-amyloid oligomers alter signaling by SNS neurotransmitter norepinephrine (NE) to sufficiently activate kinase GSK3β to hyperphosphorylate tau, a key mediator of neurotoxicity in AD.

Increased REST to Optimize Life Span?

Reduced levels of neural activity are associated with a longer life span in the nematode and in mice. Augmented neural activity is associated with a shorter life span. Recent studies show that levels of repressor element 1-silencing transcription factor (REST) increase with normal aging in mice and humans, and reduce neuronal excitation.

Epigenetic Age Reversal by Cell-Extrinsic and Cell-Intrinsic Means.

Reversal of aging by factors or drugs that reprogram adult cells to induced pluripotent stem cells suggests that at least at the cellular level aging may be reversible by resetting somatic cell state to a "ground state." An open question has been whether such rejuvenation is possible in whole organisms, especially in mammals. A related key question is whether rejuvenation can be dissociated from dedifferentiation.

Roads to the Fountain of Youth? Rejuvenating Intestinal Stem Cells.

The intestinal stem cells (ISCs) of old mice and humans exhibit a reduced capacity for regeneration and repair. Compromised intestinal function may play a key role in systemic aging-related changes: not only in the affected gut, but also in the nervous and cardiovascular systems. For example, progression of age-related neurodegenerative diseases such as Alzheimer's and Parkinson's has been linked to increased inflammation from gut microbiota in old mammals, which, in turn, may be linked bidirectionally with reduced ISC function.

Interacting NAD and Cell Senescence Pathways Complicate Antiaging Therapies.

During human aging, decrease of NAD levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells, and neurons. At the same time, the number of senescent cells, associated with damage or stress that secretes proinflammatory factors (SASP or senescence-associated secretory phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models, including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis.

Regulation of S-Nitrosylation in Aging and Senescence.

Nitric oxide signals through several distinct mechanisms, including interaction with the heme group of guanylyl cyclase enzymes resulting in modulation of cGMP levels in the vascular endothelium. Alternatively, reactive nitrogen oxide species can bind cysteine residues in target proteins forming S-nitrosothiols. S-nitrosylation is recognized as an important post-translational modification of dozens of proteins, which plays a key role in cellular homeostasis, metabolism, and various disease states.

Cellular Senescence as the Key Intermediate in Tau-Mediated Neurodegeneration.

Neuroinflammation is thought to play a key role in the progression of neurodegenerative disease such as Alzheimer's disease (AD). Given the apparent nexus of inflammatory disease with the secretory-associated senescence phenotype (SASP) of cellular senescence, two reports found that tau-mediated neurodegeneration involves induction of senescence in astrocytes, microglia, and possibly even neurons. Elimination of senescent cells by pharmacologically induced genetic ablation or by senolytic drugs blocks progression of mutant human tau-mediated neurodegeneration in mice.

Prevention of Senescence in Vasculature Through Quiescence.

Prevention of cell senescence is a potential means to extend healthspan and perhaps lifespan. Agents that increase NAD+ levels, which are diminished with age, may be senopreventive through restoration of SIRT1 and normal mitochondrial activity. The ketone body [Formula: see text]-hydroxybutyrate ([Formula: see text]-HB) prevents senescence by inducing quiescence in endothelial cells.

Mitochondrial-Derived Peptides Exacerbate Senescence.

Mitochondrial-derived peptides (MDPs), encoded by mitochondrial DNA, play a cytoprotective role by helping preserve mitochondrial function and cell viability under stressful conditions. Humanin and its homologs and MOTS-c are two of several MDPs hypothesized to have antiaging activity based on correlative studies. For example, humanin plasma levels are inversely correlated with growth hormone and insulin-like growth factor 1 expression, which may promote accelerated aging.