Aging and Cancer

ABSTRACT Background Lung cancer is the leading cause of cancer death in the world. While cigarette smoking is the major preventable factor for cancers in general and lung cancer in particular, old age is also a major risk factor. Aging‐related chronic, low‐level inflammation, termed inflammaging, has been widely documented; however, it remains unclear how inflammaging contributes to increased lung cancer incidence. Aim The aim of this study was to establish connections between aging‐associated changes in the lungs and cancer risk. Methods We analyzed public databases of gene expression for normal and cancerous human lungs and used mouse models to understand which changes were dependent on inflammation, as well as to assess the impact on oncogenesis. Results Analyses of GTEx and TCGA databases comparing gene expression profiles from normal lungs, lung adenocarcinoma, and lung squamous cell carcinoma of subjects across age groups revealed upregulated pathways such as inflammatory response, TNFA signaling via NFκB, and interferon‐gamma response. Similar pathways were identified comparing the gene expression profiles of young and old mouse lungs. Transgenic expression of alpha 1 antitrypsin (AAT) partially reverses increases in markers of aging‐associated inflammation and immune deregulation. Using an orthotopic model of lung cancer using cells derived from EML4‐ALK fusion‐induced adenomas, we demonstrated an increased tumor outgrowth in lungs of old mice while NLRP3 knockout in old mice decreased tumor volumes, suggesting that inflammation contributes to increased lung cancer development in aging organisms. Conclusions These studies reveal how expression of an anti‐inflammatory mediator (AAT) can reduce some but not all aging‐associated changes in mRNA and protein expression in the lungs. We further show that aging is associated with increased tumor outgrowth in the lungs, which may relate to an increased inflammatory microenvironment.

Catherine Pham‐Danis

Shi B. Chia

Hannah A. Scarborough

Etienne Danis

Travis Nemkov

Vadym Zaberezhnyy

Jessica L. Christenson

Emily K. Kleczko

Andre Navarro

Andrew Goodspeed

Elizabeth A. Bonney

Charles A. Dinarello

Carlo Marchetti

Raphael A. Nemenoff

Kirk C. Hansen

James DeGregori

Inflammation Promotes Aging‐Associated Oncogenesis in the Lung

炎症促进肺部衰老相关性肿瘤发生

Dr. Samuel Waxman has dedicated his career to the treatment of cancer patients and to cancer research. While he led an extraordinarily successful medical practice for 45 years, he understood very early that knowledge is power and that without research, cancer treatment would remain highly toxic. His passion for research is best illustrated by the creation of the Samuel Waxman Cancer Research Foundation (SWCRF) in 1976. The SWCRF currently funds a network of 30 researchers across the world and raised over $100 million for cancer research. To this day, the passion of this remarkable physician-scientist has only become stronger. His most recent goal is to understand the link between cancer and aging. While cancer is known to be an age-related disease, surprisingly, little research focuses on how and why cancer is more frequent in older individuals. Dr. Waxman has, therefore, not only established collaboration between his foundation and the National Institute of Aging to specifically fund research projects aimed at understanding the link between aging and cancer but also teamed up with Wiley Publishing to launch this new journal in 2020. In this third edition of Aging and Cancer, three articles from SWCRF investigators were selected to illustrate the range of questions and approaches needed to cover the complexity of the link between aging and cancer. The first article by our group (Jenkins et al. Are the estrogen receptor and SIRT3 axes of the mitochondrial UPR key regulators of breast cancer sub-type determination according to age? Aging and Cancer, 2021. https://doi.org/10.1002/aac2.12035) focuses on the counterintuitive observation that breast cancer in post-menopausal women, which have much lower levels of circulating estrogen due to the cessation of ovarian function at menopause, tends to develop cancers that show elevated expression of the estrogen receptor. The second article by Edward Evans and SWCRF investigator James DeGregori (Evans et al. Cells with Cancer-associated Mutations Overtake Our Tissues as We Age. Aging and Cancer, 2021) uses an unbiased approach of a meta-analysis of published sequencing data on normal tissues to determine how many cancer-associated mutations are present in cancer-free individuals with age. They present evidence that these mutations are actually found at high frequency across tissues. This finding immediately raises the question as to why some individuals go on to develop cancer, while others do not. In direct line with the Evans study, the third article by SWCRF-associated investigator Paolo Boffetta and colleagues (Franchi et al. Developing a multimorbidity prognostic score in elderly patients with solid cancer using administrative databases from Italy. Aging and Cancer, 2021) takes an epidemiological approach to interrogate multiple conditions and their association with Cancer Multimorbidity Score (CMS). Their study suggests that the CMS may be used clinically to identify cancer patients at higher risk of mortality within 5 years. Finally, a fourth article by SWCRF investigator Ruibao Ren and colleagues (Li et al. The potential of cord blood to replenish young immune cells against cancer. Aging and Cancer. 2021;2:36â€“44. https://doi.org/10.1002/aac2.12032) was published in the second issue of Aging and Cancer and focused on whether interventions aimed at improving healthy aging can reduce the risk of cancer with age. In this review, the authors summarized the most recent findings regarding the potential therapies leveraging cord blood to replenish young immune cells in elderly cancer patients. Collectively, these perspective, review, and research articles provide a brief overview of some of the research perform by scientists funded by the SWCRF in the emerging field of Aging and Cancer. SWCRF funding recipient since 2002.

Doris Germain

Introduction to the third issue of <i>Aging and Cancer</i>

《<i>衰老与癌症</i>第三期导言》

Abstract Background Glioblastoma (GBM) is an aggressive, age‐associated malignant glioma that contains populations of cancer stem cells. These glioma stem cells (GSCs) evade therapeutic interventions and repopulate tumors due to their existence in a slowly cycling quiescent state. Although aging is well known to increase cancer initiation, the extent to which the mechanisms supporting GSC tumorigenicity are related to physiological aging remains unknown. Aims Here, we investigate the transcriptional mechanisms by which Forkhead Box O3 (FOXO3), a transcriptional regulator that promotes healthy aging, affects GSC function and the extent to which FOXO3 transcriptional networks are dysregulated in aging and GBM. Methods and results We performed transcriptome analysis of clinical GBM tumors and observed that high FOXO3 activity is associated with gene expression signatures of stem cell quiescence, reduced oxidative metabolism, and improved patient outcomes. Consistent with these findings, we show that elevated FOXO3 activity significantly reduces the proliferation of GBM‐derived GSCs. Using RNA‐seq, we find that functional ablation of FOXO3 in GSCs rewires the transcriptional circuitry associated with metabolism, epigenetic stability, quiescence, and differentiation. Since FOXO3 has been implicated in healthy aging, we then investigated the extent to which it regulates common transcriptional programs in aging neural stem cells (NSCs) and GSCs. We uncover a shared transcriptional program and, most strikingly, find that FOXO3‐regulated pathways are associated with altered mitochondrial functions in both aging and GBM. Conclusions This work identifies a FOXO‐associated transcriptional program that correlates between GSCs and aging NSCs and is enriched for metabolic and stemness pathways connected with GBM and aging.

Amanda J. Audesse

Galina Karashchuk

Zachary A. Gardell

Nelli S. Lakis

Sun Y. Maybury‐Lewis

Abigail K. Brown

Dena S. Leeman

Yee Voan Teo

Nicola Neretti

Douglas C. Anthony

Alexander S. Brodsky

Ashley E. Webb

FOXO3 regulates a common genomic program in aging and glioblastoma stem cells

FOXO3调控衰老和胶质母细胞瘤干细胞中的共同基因组程序

Abstract Aims In patients with breast cancer, skin assessment is useful for the treatment and prevention of postoperative adverse effects of radiotherapy. This study was designed to clarify the long‐term changes in the irradiated skin of patients after breast‐conserving surgery using visual inspection and noninvasive imaging. Methods We compared changes in the irradiated skin over time between evaluations, based on visual inspection and noninvasive imaging in 31 patients receiving postmastectomy radiation therapy. The condition of the skin was evaluated by visual inspection of the thermogram, and analysis of skin surface temperature, intensity of erythema, intensity of melanin, and hydration level. Results Skin surface temperature remained higher at the irradiation site after 11 months, despite the absence of erythema per visual inspection. The intensity of erythema was higher at the irradiated site until 17–19 months after completion of irradiation. Similarly, the intensity of melanin tended to be higher at the irradiated site compared with the nonirradiated site until 17–19 months. The hydration level at the irradiated site was lower at 6 months but recovered to match the nonirradiated site at 11–13 months. Impaired skin conditions assessed by noninvasive objective procedures persist longer than the assessment made by visual inspection. Conclusions Adverse effects should be treated or prevented in the long term in patients receiving postmastectomy radiation therapy.

Kasumi Mikami

Maiko Kitajima

Yuka Noto

Chieko Itaki

Yasuyo Fukushi

Yoshiko Hirota

Yasushi Mariya

Megumi Tsushima

Keiichi Kattou

Tomohiro Osanai

Long‐term analysis of irradiated skin after breast‐conserving surgery in breast cancer patients using noninvasive imaging

使用无创成像对接受保乳手术的乳腺癌患者术后照射皮肤的长期分析

Estimates indicate that nearly eight percent of the over 500,000 survivors of childhood cancer living in the United States are frail in their fourth and fifth decades of life, a phenotype typically seen in geriatric populations. Participation in regular physical activity to improve physical fitness in healthy and diseased populations reduces risk for frail health by increasing physiologic reserve. However, physical activity may not have the same effects on fitness in childhood cancer survivors as it does among their peers with no cancer history.This scoping review seeks to describe associations between physical activity, physical fitness, chronic disease, and mortality in childhood cancer survivors.Relevant literature was identified through a comprehensive search in the PubMed, Web of Science, CINAHL, and Cochrane databases. A narrative synthesis was performed on observational studies that had physical activity or physical fitness clearly defined and compared with chronic disease outcomes.A total of 595 studies were screened, and results from 11 studies are presented. Childhood cancer survivors who participate in regular physical activity have improved markers of cardiovascular health, decreased risk of overt cardiovascular disease, and decreased risk of all-cause mortality compared to survivors who are not physically active. Childhood cancer survivors who are physically fit have increased neurocognition, and decreased risk of all-cause mortality compared to survivor's who are not fit. The differential effects of physical activity on fitness and health among childhood cancer survivors when compared to peers is potentially related to treatment exposures that damage cardiovascular tissue and impact regenerative potential.Research is needed to determine the optimal timing, frequency, intensity, and duration of physical activity necessary to optimize fitness in childhood cancer survivors.

Matthew D. Wogksch

Chelsea G. Goodenough

Emily R. Finch

Robyn E. Partin

Kirsten K. Ness

Physical activity and fitness in childhood cancer survivors: A scoping review

儿童癌症幸存者的身体活动与体能：范围综述

ABSTRACT Background From the perspective of biology, the characteristics of life can be categorized as cellular organizations, homeostasis, metabolism, growth, reproduction and heredity, response to stimuli and adaptation to the environment. From the perspective of physics, living organisms are highly ordered, complex, thermodynamically open systems; they are in non‐equilibrium phase. According to the second law of thermodynamics, every system in the universe is going to the disorder spontaneously. Maximum entropy signifies a thermodynamic equilibrium which means the death. Today, cancer is a major global health problem and despite the explosive development of our knowledge about the carcinogenesis the “war on cancer” has not yet been won. Aims To examine life and cancer together based on current biophysical approach and to shed light on new paradigms. Materials &amp; Methods A systematic literature search for publications on a thermodynamic approach to understand life and cancer was conducted in PubMed without language restrictions. The reference lists of identified studies were also used as additional knowledge. Results Living organisms exchange entropy and they gain information from the external environment. Information can be stored as memory. Life is a category of emergence like art composed from correct modules. On the contrary, cancer is the emergence of a disease formed by incorrect modules. Cancer is a chaotic disease at least for a limited period and cannot arise from healthy functional tissue units. Chaos of the lower level may be associated with the entropy increase of upper level. Conclusions Biologic chaos control is possible.

Nuri Faruk Aykan

Biophysical Approach to Understand Life and Cancer

理解生命与癌症的生物物理方法

ABSTRACT Background DNA double‐strand breaks are known to be the most lethal kind of DNA damage as they cause genomic instability. Visualization and quantification of these breaks are possible via staining of the phosphorylated histone H2A variant H2AX at serine 139 with the anti‐phospho‐histone H2AX (γ‐H2AX) antibody. Methods The literature was searched with the following keywords: DNA damage, double‐strand break, PBMC, DNA repair, H2AX, γ‐H2AX. Discussion This review discusses various methods for the quantification of γ‐H2AX and the use of γ‐H2AX in cell culture, tissue biopsies, and peripheral blood mononuclear cells. The current research into basal DNA damage as quantified by γ‐H2AX is discussed in relation to cancer. Conclusions This review suggests that γ‐H2AX has the potential for use in the prediction of cancer risk when applied to healthy tissue and peripheral blood mononuclear cells.

Holly Hosking

Wayne Pederick

Paul Neilsen

Andrew Fenning

Considerations for the Use of the DNA Damage Marker γ‐H2AX in Disease Modeling, Detection, Diagnosis, and Prognosis

疾病模型、检测、诊断和预后中使用DNA损伤标志物γ‐H2AX的考量

ABSTRACT Background Type 2 diabetes (T2D) is a complex metabolic disorder characterized by insulin resistance, hyperglycemia, and hyperinsulinemia. A significant portion of individuals with T2D are unaware of their condition until it has reached advanced stages. T2D is also associated with an increased risk and worse prognosis of cardiovascular disease, cognitive decline, and cancer. Understanding the mechanisms underlying the emergence of insulin resistance is critical for improving early detection and therapeutic interventions. Methods An updated framework is proposed to describe the emergence of insulin resistance that precedes the development of T2D. The model focuses on the impact of diminishing capacity to store excess glucose, which can occur due to a multitude of factors, including age‐related muscle loss. The model is used to simulate responses to oral glucose tolerance tests (OGTTs) to capture the transition from a normal to a diabetic phenotype, as defined by the Kraft criteria. Additionally, the model is used to explore how the metabolic environment influences tumor progression, drawing on experimental data regarding the impact of transient diabetic phenotypes and hyperinsulinemia on cancer therapy efficacy. Results The model successfully demonstrates that reduced glucose storage capacity can qualitatively reproduce the progression from normal to diabetic phenotypes observed in OGTT responses. Furthermore, it shows that tumor progression or regression is highly dependent on the host's metabolic environment, particularly hyperinsulinemia. This aligns with experimental results that connect drug‐induced hyperinsulinemia to a loss of therapeutic efficacy against tumors, whereas the reversal of the diabetic phenotype could restore drug sensitivity and treatment response. Conclusions This study highlights the critical role of hyperinsulinemia, even in normoglycemic individuals, in both the progression of T2D and the modulation of cancer therapy outcomes. Addressing hyperinsulinemia emerges as a promising strategy to enhance cancer treatment efficacy and improve overall health outcomes in patients with or at risk for T2D.

Irina Kareva

From Hyperinsulinemia to Cancer Progression: How Diminishing Glucose Storage Capacity Fuels Insulin Resistance

从高胰岛素血症到癌症进展：葡萄糖储存能力下降如何加剧胰岛素抵抗

The gut microbiome changes with age and affects regions beyond the gut, including the ovarian cancer tumor microenvironment. In this review summarizing the literature on the gut microbiome in ovarian cancer and in aging, we note trends in the microbiota composition common to both phenomena and trends that are distinctly opposite. Both ovarian cancer and aging are characterized by an increase in proinflammatory bacterial species, particularly those belonging to phylum Proteobacteria and genus

涉及主题	cancergeriatric oncologyepigeneticsageing
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Inflammation Promotes Aging‐Associated Oncogenesis in the Lung

Introduction to the third issue of Aging and Cancer

FOXO3 regulates a common genomic program in aging and glioblastoma stem cells

Long‐term analysis of irradiated skin after breast‐conserving surgery in breast cancer patients using noninvasive imaging

Physical activity and fitness in childhood cancer survivors: A scoping review

Inflammation Promotes Aging‐Associated Oncogenesis in the Lung

Biophysical Approach to Understand Life and Cancer

Considerations for the Use of the DNA Damage Marker γ‐H2AX in Disease Modeling, Detection, Diagnosis, and Prognosis

From Hyperinsulinemia to Cancer Progression: How Diminishing Glucose Storage Capacity Fuels Insulin Resistance

The Gut Microbiome in Aging and Ovarian Cancer