Therapy-induced senescence through the redox lens.

Therapy-induced senescent tumor cells have emerged as significant drivers of tumor recurrence and disease relapse. Interestingly, reactive oxygen species (ROS) production and its associated redox signaling networks are intertwined with initiation and establishment of therapy-induced senescence. Therapy-induced senescent cells influence neighboring cells and the tumor microenvironment via their bioactive secretome known as the senescence-associated secretory phenotype (SASP). The intracellular effects of ROS are dose and context-dependent. Under normal physiological conditions, ROS is involved in various signalling pathways and cellular processes important for maintenance of cellular homeostasis, such as redox balance, stress response, inflammatory signalling, cell proliferation and cell death among others. However excess ROS accompanied by a pro-oxidant microenvironment can engender oxidative DNA damage, triggering cellular senescence. In this review, we discuss the role of ROS and the redox state dynamics in fine-tuning homeostatic processes that drive therapy-induced cell fate towards senescence establishment, as well as their influence in stimulating inflammatory signalling and SASP production. We also offer insights into interventional strategies, specifically senotherapeutics, that could potentially leverage on modulation of redox and antioxidant pathways. Lastly, we evaluate possible implications of redox rewiring during escape from therapy-induced senescence, an emerging area of research. We envision that examining therapy-induced senescence through the redox lens, integrated with time-resolved single-cell RNA sequencing combined with spatiotemporal multi-omics, could further enhance our understanding of its functional heterogeneity. This could aid identification of targetable signalling nodes to reduce disease relapse, as well as inform strategies for development of broad-spectrum senotherapeutics. Overall, our review aims to delineate redox-driven mechanisms which contribute to the biology of therapy-induced senescence and beyond, while highlighting implications for tumor initiation and recurrence.

Ribosomal protein control of hematopoietic stem cell transformation through direct, non-canonical regulation of metabolism.

We report here that expression of the ribosomal protein, RPL22, is frequently reduced in human myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); reduced RPL22 expression is associated with worse outcomes. Mice null for Rpl22 display characteristics of an MDS-like syndrome and develop leukemia at an accelerated rate. Rpl22-deficient mice also display enhanced hematopoietic stem cell (HSC) self-renewal and obstructed differentiation potential, which arises not from reduced protein synthesis but from increased expression of the Rpl22 target, ALOX12, an upstream regulator of fatty acid oxidation (FAO). The increased FAO mediated by Rpl22-deficiency also persists in leukemia cells and promotes their survival. Altogether, these findings reveal that Rpl22 insufficiency enhances the leukemia potential of HSC via non-canonical de-repression of its target, ALOX12, which enhances FAO, a process that may serve as a therapeutic vulnerability of Rpl22 low MDS and AML leukemia cells. Highlights: RPL22 insufficiency is observed in MDS/AML and is associated with reduced survivalRpl22-deficiency produces an MDS-like syndrome and facilitates leukemogenesisRpl22-deficiency does not impair global protein synthesis by HSCRpl22 controls leukemia cell survival by non-canonical regulation of lipid oxidation eTOC: Rpl22 controls the function and transformation potential of hematopoietic stem cells through effects on ALOX12 expression, a regulator of fatty acid oxidation.

Inflammatory panel cytokines are elevated in the neocortex of late-stage Alzheimer's disease but not Lewy body dementias.

BACKGROUND: Chronically dysregulated neuroinflammation has been implicated in neurodegenerative dementias, with separate studies reporting increased brain levels of inflammatory mediators and gliosis in Alzheimer's disease (AD) as well as in Lewy body dementias (LBD). However, it is unclear whether the nature and extent of neuroinflammatory responses in LBD are comparable to those in AD. In this study, we performed head-to-head measurements of a panel of cytokines in the post-mortem neocortex of AD versus the two major clinical subtypes of LBD, namely, dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD). METHODS: Post-mortem tissues from the mid-temporal cortex (Brodmann area 21) of a cohort of neuropathologically well-defined AD, PDD and DLB patients were processed and measured for a comprehensive range of cytokines (IL-1α, IL-1Ra, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, GM-CSF and FGF-2) using a multiplex immunoassay platform. Associations between inflammation markers and neuropathological measures of neuritic plaques, neurofibrillary tangles as well as Lewy bodies were also performed. RESULTS: We found IL-1α, IFN-γ, GM-CSF and IL-13 to be elevated in the mid-temporal cortex of AD patients. In contrast, none of the measured cytokines were significantly altered in either DLB or PDD. Similar cytokine changes were observed in two other neocortical areas of AD patients. Furthermore, increases of IL-1α, IFN-γ, GM-CSF, IL-10 and IL-13 associated with moderate-to-severe neurofibrillary tangle burden, but not with neuritic plaques or Lewy bodies. Our findings of elevated neocortical pro- and anti-inflammatory cytokines in AD, but not in DLB or PDD, suggest that neuroinflammatory responses are strongly linked to neurofibrillary tangle burden, which is higher in AD compared to LBD. In conclusion, neuroinflammation may not play a prominent role in the pathophysiology of late-stage LBD.

A mechanistic perspective on the health promoting effects of alcohol - A focus on epigenetics modification.

While the detrimental effects of binge drinking are well recognized, low-to-moderate alcohol consumption may be beneficial to health, although the underlying mechanism(s) remains elusive. In this opinion article, we will examine the effects of low dose alcohol consumption from the perspective of epigenetic modulation. Biochemically, alcohol is metabolized into acetate and subsequently to acetyl-coA, which can modulate histone acetylation levels. While elevated levels of acetyl-CoA are detrimental for longevity, we argue that diminished acetyl-CoA also negatively affects fatty acid biosynthesis and histone acetylation, which play a critical role in gene expression and, ultimately, health span. Since mitochondrial function and glucose metabolism, which provide the main source of nucleocytoplasmic acetyl-CoA, are compromised with age, alcohol-derived acetate could be an alternative source of acetyl-CoA to compensate. Hence, the health benefits of low ethanol consumption may be more pronounced after midlife, since mitochondrial function and/or glucose metabolism are diminished in this phase of the life course. Indeed, various clinical alcohol consumption studies concur with this notion, and have shown that a low dose of regular alcohol intake after midlife brings about various health and survival benefits. The requirement for regular alcohol intake may also reflect the transient nature of ethanol-induced histone acetylation. Conversely, ethanol may also stimulate carcinogenesis by inhibiting DNA methylation, as it was shown to reduce various pathways leading to DNA and histone methylation. However, unlike acetylation, where ethanol directly increases the substrate for acetylation, this effect was only observed in the high alcohol exposure cohort. While alcohol-derived acetate may be beneficial for health after midlife, various detrimental effects of alcohol consumption remain, and hence, we do not advocate excessive drinking to increase acetate. This opinion article establishes a possible role of ethanol-derived acetate in achieving homeostasis and sustaining an organism's health span.

Ironing out exercise on immuno-oncological outcomes.

Despite accumulating evidence that supports the beneficial effects of physical exercise in inhibiting cancer progression, whether exercise modulates its effects through systemic and cellular changes in iron metabolism and immune-tumor crosstalk is unknown. Cancer cells have greater metabolic requirements than normal cells, with their survival and proliferation depending largely on iron bioavailability. Although iron is an essential mineral for mitogenesis, it also participates in a form of iron-dependent programmed cell death termed ferroptosis. In this short hypothesis paper, we speculate that modulating iron bioavailability, transport and metabolism with regular exercise can have significant implications for tumor and stromal cells in the tumor microenvironment, by affecting multiple tumor-autonomous and stromal cell responses.

Loss of Ribosomal Protein Paralog Rpl22-like1 Blocks Lymphoid Development without Affecting Protein Synthesis.

Ribosomal proteins are thought to primarily facilitate biogenesis of the ribosome and its ability to synthesize protein. However, in this study, we show that Rpl22-like1 (Rpl22l1) regulates hematopoiesis without affecting ribosome biogenesis or bulk protein synthesis. Conditional loss of murine Rpl22l1 using stage or lineage-restricted Cre drivers impairs development of several hematopoietic lineages. Specifically, Tie2-Cre-mediated ablation of Rpl22l1 in hemogenic endothelium impairs the emergence of embryonic hematopoietic stem cells. Ablation of Rpl22l1 in late fetal liver progenitors impairs the development of B lineage progenitors at the pre-B stage and development of T cells at the CD44-CD25+ double-negative stage. In vivo labeling with O-propargyl-puromycin revealed that protein synthesis at the stages of arrest was not altered, indicating that the ribosome biogenesis and function were not generally compromised. The developmental arrest was associated with p53 activation, suggesting that the arrest may be p53-dependent. Indeed, development of both B and T lymphocytes was rescued by p53 deficiency. p53 induction was not accompanied by DNA damage as indicated by phospho-γH2AX induction or endoplasmic reticulum stress, as measured by phosphorylation of EIF2α, thereby excluding the known likely p53 inducers as causal. Finally, the developmental arrest of T cells was not rescued by elimination of the Rpl22l1 paralog, Rpl22, as we had previously found for the emergence of hematopoietic stem cells. This indicates that Rpl22 and Rpl22l1 play distinct and essential roles in supporting B and T cell development.

Alpha-Ketoglutarate dietary supplementation to improve health in humans.

Alpha-ketoglutarate (AKG) is an intermediate in the Krebs cycle involved in various metabolic and cellular pathways. As an antioxidant, AKG interferes in nitrogen and ammonia balance, and affects epigenetic and immune regulation. These pleiotropic functions of AKG suggest it may also extend human healthspan. Recent studies in worms and mice support this concept. A few studies published in the 1980s and 1990s in humans suggested the potential benefits of AKG in muscle growth, wound healing, and in promoting faster recovery after surgery. So far there are no recently published studies demonstrating the role of AKG in treating aging and age-related diseases; hence, further clinical studies are required to better understand the role of AKG in humans. This review will discuss the regulatory role of AKG in aging, as well as its potential therapeutic use in humans to treat age-related diseases.

Spatio-temporal correlates of gene expression and cortical morphology across lifespan and aging.

Evidence from neuroimaging and genetic studies supports the concept that brain aging mirrors development. However, it is unclear whether mechanisms linking brain development and aging provide new insights to delay aging and potentially reverse it. This study determined biological mechanisms and phenotypic traits underpinning brain alterations across the lifespan and in aging by examining spatio-temporal correlations between gene expression and cortical volumes using datasets d with the age range from 2 to 82 years. We revealed that a large proportion of genes whose expression was associated with cortical volumes across the lifespan were in astrocytes. These genes, which showed up-regulation during development and down-regulation during aging, contributed to fundamental homeostatic functions of astrocytes. Included among these genes were those encoding components of cAMP, Ras, and retrograde endocannabinoid signaling pathways. Genes associated with cortical volumes in the same data aged above 55 years were also enriched for the sphingolipid, renin-angiotensin system (RAS), proteasome, and TGF-ß signaling pathway, which is linked to senescence-associated secretory phenotypes. Neuroticism, drinking, and smoking were the common phenotypic traits in the lifespan and aging, while memory was the unique phenotype associated with aging. These findings provide biological mechanisms mirroring development and aging as well as unique to aging.

A Flexi-PEGDA Upconversion Implant for Wireless Brain Photodynamic Therapy.

Near-infrared (NIR) activatable upconversion nanoparticles (UCNPs) enable wireless-based phototherapies by converting deep-tissue-penetrating NIR to visible light. UCNPs are therefore ideal as wireless transducers for photodynamic therapy (PDT) of deep-sited tumors. However, the retention of unsequestered UCNPs in tissue with minimal options for removal limits their clinical translation. To address this shortcoming, biocompatible UCNPs implants are developed to deliver upconversion photonic properties in a flexible, optical guide design. To enhance its translatability, the UCNPs implant is constructed with an FDA-approved poly(ethylene glycol) diacrylate (PEGDA) core clad with fluorinated ethylene propylene (FEP). The emission spectrum of the UCNPs implant can be tuned to overlap with the absorption spectra of the clinically relevant photosensitizer, 5-aminolevulinic acid (5-ALA). The UCNPs implant can wirelessly transmit upconverted visible light till 8 cm in length and in a bendable manner even when implanted underneath the skin or scalp. With this system, it is demonstrated that NIR-based chronic PDT is achievable in an untethered and noninvasive manner in a mouse xenograft glioblastoma multiforme (GBM) model. It is postulated that such encapsulated UCNPs implants represent a translational shift for wireless deep-tissue phototherapy by enabling sequestration of UCNPs without compromising wireless deep-tissue light delivery.

The quest to slow ageing through drug discovery.

Although death is inevitable, individuals have long sought to alter the course of the ageing process. Indeed, ageing has proved to be modifiable; by intervening in biological systems, such as nutrient sensing, cellular senescence, the systemic environment and the gut microbiome, phenotypes of ageing can be slowed sufficiently to mitigate age-related functional decline. These interventions can also delay the onset of many disabling, chronic diseases, including cancer, cardiovascular disease and neurodegeneration, in animal models. Here, we examine the most promising interventions to slow ageing and group them into two tiers based on the robustness of the preclinical, and some clinical, results, in which the top tier includes rapamycin, senolytics, metformin, acarbose, spermidine, NAD+ enhancers and lithium. We then focus on the potential of the interventions and the feasibility of conducting clinical trials with these agents, with the overall aim of maintaining health for longer before the end of life.

A novel rapamycin analog is highly selective for mTORC1 in vivo.

Rapamycin, an inhibitor of mechanistic Target Of Rapamycin Complex 1 (mTORC1), extends lifespan and shows strong potential for the treatment of age-related diseases. However, rapamycin exerts metabolic and immunological side effects mediated by off-target inhibition of a second mTOR-containing complex, mTOR complex 2. Here, we report the identification of DL001, a FKBP12-dependent rapamycin analog 40x more selective for mTORC1 than rapamycin. DL001 inhibits mTORC1 in cell culture lines and in vivo in C57BL/6J mice, in which DL001 inhibits mTORC1 signaling without impairing glucose homeostasis and with substantially reduced or no side effects on lipid metabolism and the immune system. In cells, DL001 efficiently represses elevated mTORC1 activity and restores normal gene expression to cells lacking a functional tuberous sclerosis complex. Our results demonstrate that highly selective pharmacological inhibition of mTORC1 can be achieved in vivo, and that selective inhibition of mTORC1 significantly reduces the side effects associated with conventional rapalogs.

Mixing old and young: enhancing rejuvenation and accelerating aging.

Donor age and recipient age are factors that influence transplantation outcomes. Aside from age-associated differences in intrinsic graft function and alloimmune responses, the ability of young and old cells to exert either rejuvenating or aging effects extrinsically may also apply to the transplantation of hematopoietic stem cells or solid organ transplants. While the potential for rejuvenation mediated by the transfer of youthful cells is currently being explored for therapeutic applications, aspects that relate to accelerating aging are no less clinically significant. Those effects may be particularly relevant in transplantation with an age discrepancy between donor and recipient. Here, we review recent advances in understanding the mechanisms by which young and old cells modify their environments to promote rejuvenation- or aging-associated phenotypes. We discuss their relevance to clinical transplantation and highlight potential opportunities for therapeutic intervention.

Prelamin A causes aberrant myonuclear arrangement and results in muscle fiber weakness.

Physiological and premature aging are frequently associated with an accumulation of prelamin A, a precursor of lamin A, in the nuclear envelope of various cell types. Here, we aimed to underpin the hitherto unknown mechanisms by which prelamin A alters myonuclear organization and muscle fiber function. By experimentally studying membrane-permeabilized myofibers from various transgenic mouse lines, our results indicate that, in the presence of prelamin A, the abundance of nuclei and myosin content is markedly reduced within muscle fibers. This leads to a concept by which the remaining myonuclei are very distant from each other and are pushed to function beyond their maximum cytoplasmic capacity, ultimately inducing muscle fiber weakness.

A Lipid Transfer Protein Signaling Axis Exerts Dual Control of Cell-Cycle and Membrane Trafficking Systems.

Kes1/Osh4 is a member of the conserved, but functionally enigmatic, oxysterol binding protein-related protein (ORP) superfamily that inhibits phosphatidylinositol transfer protein (Sec14)-dependent membrane trafficking through the trans-Golgi (TGN)/endosomal network. We now report that Kes1, and select other ORPs, execute cell-cycle control activities as functionally non-redundant inhibitors of the G1/S transition when cells confront nutrient-poor environments and promote replicative aging. Kes1-dependent cell-cycle regulation requires the Greatwall/MASTL kinase ortholog Rim15, and is opposed by Sec14 activity in a mechanism independent of Kes1/Sec14 bulk membrane-trafficking functions. Moreover, the data identify Kes1 as a non-histone target for NuA4 through which this lysine acetyltransferase co-modulates membrane-trafficking and cell-cycle activities. We propose the Sec14/Kes1 lipid-exchange protein pair constitutes part of the mechanism for integrating TGN/endosomal lipid signaling with cell-cycle progression and hypothesize that ORPs define a family of stage-specific cell-cycle control factors that execute tumor-suppressor-like functions.

Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse.

Cellular senescence suppresses cancer by irreversibly arresting cell proliferation. Senescent cells acquire a proinflammatory senescence-associated secretory phenotype. Many genotoxic chemotherapies target proliferating cells nonspecifically, often with adverse reactions. In accord with prior work, we show that several chemotherapeutic drugs induce senescence of primary murine and human cells. Using a transgenic mouse that permits tracking and eliminating senescent cells, we show that therapy-induced senescent (TIS) cells persist and contribute to local and systemic inflammation. Eliminating TIS cells reduced several short- and long-term effects of the drugs, including bone marrow suppression, cardiac dysfunction, cancer recurrence, and physical activity and strength. Consistent with our findings in mice, the risk of chemotherapy-induced fatigue was significantly greater in humans with increased expression of a senescence marker in T cells prior to chemotherapy. These findings suggest that senescent cells can cause certain chemotherapy side effects, providing a new target to reduce the toxicity of anticancer treatments. SIGNIFICANCE: Many genotoxic chemotherapies have debilitating side effects and also induce cellular senescence in normal tissues. The senescent cells remain chronically present where they can promote local and systemic inflammation that causes or exacerbates many side effects of the chemotherapy. Cancer Discov; 7(2); 165-76. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 115.

Stem Cell Models: A Guide to Understand and Mitigate Aging?

Aging is studied either on a systemic level using life span and health span of animal models, or on the cellular level using replicative life span of yeast or mammalian cells. While useful in identifying general and conserved pathways of aging, both approaches provide only limited information about cell-type specific causes and mechanisms of aging. Stem cells are the regenerative units of multicellular life, and stem cell aging might be a major cause for organismal aging. Using the examples of hematopoietic stem cell aging and human pluripotent stem cell models, we propose that stem cell models of aging are valuable for studying tissue-specific causes and mechanisms of aging and can provide unique insights into the mammalian aging process that may be inaccessible in simple model organisms.

Mammalian Target of Rapamycin: A Target for (Lung) Diseases and Aging.

The mammalian target of rapamycin (mTOR) signaling pathway has been studied in the context of an impressive number of biological processes and disease states, including major diseases of the lung such as idiopathic pulmonary fibrosis and chronic obstructive pulmonary disease, as well as the rare condition lymphangioleiomyomatosis. The involvement of mTOR in so many disease states (in and out of the lung) raises the question how one signaling pathway can have overlapping but diverse roles seemingly everywhere. Findings in the last decade have placed the mTOR pathway in a new context as an important, conserved mediator of the aging process. This offers one explanation for the pleiotropic effects of mTOR: -that many chronic diseases are also diseases of aging and that pathways modulating aging will have widespread effects on associated disease. However, this may not be the entire story, because mTOR is also implicated in a large number of diseases not linked to aging. In this article, we discuss the current state of knowledge regarding mTOR, especially in the context of lung pathologies, and offer a potential explanation for its widespread involvement in human disease.

SIRT6, oxidative stress, and aging.

The role of oxidative stress in the aging process has been highly debated for decades and remains equivocal. A new study published in Cell Research reports a novel role for the aging-associated SIRT6 deacetylase in the control of oxidative homeostasis in human mesenchymal stem cells.

A Periodic Diet that Mimics Fasting Promotes Multi-System Regeneration, Enhanced Cognitive Performance, and Healthspan.

Prolonged fasting (PF) promotes stress resistance, but its effects on longevity are poorly understood. We show that alternating PF and nutrient-rich medium extended yeast lifespan independently of established pro-longevity genes. In mice, 4 days of a diet that mimics fasting (FMD), developed to minimize the burden of PF, decreased the size of multiple organs/systems, an effect followed upon re-feeding by an elevated number of progenitor and stem cells and regeneration. Bi-monthly FMD cycles started at middle age extended longevity, lowered visceral fat, reduced cancer incidence and skin lesions, rejuvenated the immune system, and retarded bone mineral density loss. In old mice, FMD cycles promoted hippocampal neurogenesis, lowered IGF-1 levels and PKA activity, elevated NeuroD1, and improved cognitive performance. In a pilot clinical trial, three FMD cycles decreased risk factors/biomarkers for aging, diabetes, cardiovascular disease, and cancer without major adverse effects, providing support for the use of FMDs to promote healthspan.