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Molecular-Cellular Basis of Ageing and Cancer

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A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Aging".

Deadline for manuscript submissions: closed (5 September 2021) | Viewed by 45765

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Prof. Dr. Ioannis Trougakos

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Guest Editor

Department of Cell Biology & Biophysics, Faculty of Biology, National & Kapodistrian University of Athens, 15784 Athens, Greece
Interests: molecular-cellular ageing; age-related diseases; carcinogenesis
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Vassilis Gorgoulis

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Guest Editor

Laboratory of Histology-Embryology, Molecular Carcinogenesis Group, Medical School, National and Kapodistrian University of Athens, 15784 Athens, Greece
Interests: cancer; cell cycle; cellular senescence; DNA damage response and repair; digital pathology; genomic instability; oncogene
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Aging is a complex phenomenon caused by the time-dependent loss of cellular homeodynamics and consequently of physiological organismal functions leading to increased morbidity (e.g. the so-called age-related diseases, including cancer) and mortality. These processes are affected by both genetic and environmental, such as diet, factors and are marked by the gradual accumulation of stressors and damaged biomolecules (including DNA and proteins) due to time-dependent decline of stress resistance. Failure to eliminate genome and/or proteome instability by the respective damage response pathways that constitute the pillars of a highly interconnected “defensive” network, eventually compromise all aspects of cellular functionality leading also to deregulated mitochondrial function which alters cell metabolism and energetics; these functional readouts are also hallmarks of tumorigenesis. In parallel, the age-related accumulation of senescent cells exerts detrimental effects fostering aging and cancer; thus, it is important to develop the rapidly expanding field of senotherapeutic agents which selectively kill senescent cells. Research or review articles addressing these topics or investigating the functional cross-talk of the different modules involved in aging and tumorigenesis in cells and/or models organisms, along with the age- and/or cancer-related deregulation of nutrients sensing and signaling pathways will be considered in this Special Issue. Novel studies on natural products or small molecules targeting aging, senescent or tumor cells will be also part of this Special Issue.

Prof. Ioannis Trougakos
Prof. Vassilis Gorgoulis
Guest Editors

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Keywords

ageing
age-related disease
cancer
DNA damage
inflammation
mitostasis
proteostasis
senescence
senotherapeutics

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Published Papers (11 papers)

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Research

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15 pages, 1875 KiB

Open AccessArticle

The Longevity-Associated Variant of BPIFB4 Reduces Senescence in Glioma Cells and in Patients’ Lymphocytes Favoring Chemotherapy Efficacy

by Annibale Alessandro Puca, Valentina Lopardo, Francesco Montella, Paola Di Pietro, Daniela Cesselli, Irene Giulia Rolle, Michela Bulfoni, Veronica Di Sarno, Giorgio Iaconetta, Pietro Campiglia, Carmine Vecchione, Antonio Paolo Beltrami and Elena Ciaglia

Cells 2022, 11(2), 294; https://doi.org/10.3390/cells11020294 - 15 Jan 2022

Cited by 7 | Viewed by 3461

Abstract

Glioblastoma (GBM) is the most common primary brain cancer with the median age at diagnosis around 64 years, thus pointing to aging as an important risk factor. Indeed, aging, by increasing the senescence burden, is configured as a negative prognostic factor for GBM stage. Furthermore, several anti-GBM therapies exist, such as temozolomide (TMZ) and etoposide (ETP), that unfortunately trigger senescence and the secretion of proinflammatory senescence-associated secretory phenotype (SASP) factors that are responsible for the improper burst of (i) tumorigenesis, (ii) cancer metastasis, (iii) immunosuppression, and (iv) tissue dysfunction. Thus, adjuvant therapies that limit senescence are urgently needed. The longevity-associated variant (LAV) of the bactericidal/permeability-increasing fold-containing family B member 4 (BPIFB4) gene previously demonstrated a modulatory activity in restoring age-related immune dysfunction and in balancing the low-grade inflammatory status of elderly people. Based on the above findings, we tested LAV-BPIFB4 senotherapeutic effects on senescent glioblastoma U87-MG cells and on T cells from GBM patients. We interrogated SA-β-gal and HLA-E senescence markers, SASP factors, and proliferation and apoptosis assays. The results highlighted a LAV-BPIFB4 remodeling of the senescent phenotype of GBM cells, enhancement of their sensitivity to temozolomide and a selective reduction of the T cells’ senescence from GBM patients. Overall, these findings candidate LAV-BPIFB4 as an adjuvant therapy for GBM. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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19 pages, 17811 KiB

Open AccessArticle

Differential Dose- and Tissue-Dependent Effects of foxo on Aging, Metabolic and Proteostatic Pathways

by Maria S. Manola, Sentiljana Gumeni and Ioannis P. Trougakos

Cells 2021, 10(12), 3577; https://doi.org/10.3390/cells10123577 - 18 Dec 2021

Cited by 7 | Viewed by 3811

Abstract

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of foxo. Interestingly, there is a defined dosage of foxo OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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19 pages, 2213 KiB

Open AccessArticle

Temporal Profiling of the Cortical Synaptic Mitochondrial Proteome Identifies Ageing Associated Regulators of Stability

by Laura C. Graham, Rachel A. Kline, Douglas J. Lamont, Thomas H. Gillingwater, Neil A. Mabbott, Paul A. Skehel and Thomas M. Wishart

Cells 2021, 10(12), 3403; https://doi.org/10.3390/cells10123403 - 2 Dec 2021

Cited by 1 | Viewed by 2532

Abstract

Synapses are particularly susceptible to the effects of advancing age, and mitochondria have long been implicated as organelles contributing to this compartmental vulnerability. Despite this, the mitochondrial molecular cascades promoting age-dependent synaptic demise remain to be elucidated. Here, we sought to examine how the synaptic mitochondrial proteome (including strongly mitochondrial associated proteins) was dynamically and temporally regulated throughout ageing to determine whether alterations in the expression of individual candidates can influence synaptic stability/morphology. Proteomic profiling of wild-type mouse cortical synaptic and non-synaptic mitochondria across the lifespan revealed significant age-dependent heterogeneity between mitochondrial subpopulations, with aged organelles exhibiting unique protein expression profiles. Recapitulation of aged synaptic mitochondrial protein expression at the Drosophila neuromuscular junction has the propensity to perturb the synaptic architecture, demonstrating that temporal regulation of the mitochondrial proteome may directly modulate the stability of the synapse in vivo. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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20 pages, 5452 KiB

Open AccessFeature PaperArticle

Single-Cell Transcriptomics Reveals the Expression of Aging- and Senescence-Associated Genes in Distinct Cancer Cell Populations

by Dominik Saul and Robyn Laura Kosinsky

Cells 2021, 10(11), 3126; https://doi.org/10.3390/cells10113126 - 11 Nov 2021

Cited by 21 | Viewed by 8219

Abstract

The human aging process is associated with molecular changes and cellular degeneration, resulting in a significant increase in cancer incidence with age. Despite their potential correlation, the relationship between cancer- and ageing-related transcriptional changes is largely unknown. In this study, we aimed to analyze aging-associated transcriptional patterns in publicly available bulk mRNA-seq and single-cell RNA-seq (scRNA-seq) datasets for chronic myelogenous leukemia (CML), colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer (LC), and pancreatic ductal adenocarcinoma (PDAC). Indeed, we detected that various aging/senescence-induced genes (ASIGs) were upregulated in malignant diseases compared to healthy control samples. To elucidate the importance of ASIGs during cell development, pseudotime analyses were performed, which revealed a late enrichment of distinct cancer-specific ASIG signatures. Notably, we were able to demonstrate that all cancer entities analyzed in this study comprised cell populations expressing ASIGs. While only minor correlations were detected between ASIGs and transcriptome-wide changes in PDAC, a high proportion of ASIGs was induced in CML, CRC, HCC, and LC samples. These unique cellular subpopulations could serve as a basis for future studies on the role of aging and senescence in human malignancies. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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12 pages, 3892 KiB

Open AccessArticle

Influence of Age and Breed on Bovine Ovarian Capillary Blood Supply, Ovarian Mitochondria and Telomere Length

by Paweł Kordowitzki, Roswitha Merle, Pascal-Kolja Hass, Johanna Plendl, Juliane Rieger and Sabine Kaessmeyer

Cells 2021, 10(10), 2661; https://doi.org/10.3390/cells10102661 - 5 Oct 2021

Cited by 2 | Viewed by 2720

Abstract

Worldwide, dairy cows of the type of high-producing cattle (HPC) suffer from health and fertility problems at a young age and therefore lose productivity after an average of only three lactations. It is still contentious whether these problems are primarily due to genetics, management, feeding or other factors. Vascularization plays a fundamental role in the cyclic processes of reproductive organs, as well as in the regeneration of tissues. In a previous study, HPC were shown to have a greater ovarian corpus luteum vascularization compared to dual-purpose breeds. We hypothesize that this activated angiogenesis could likely lead to an early exhaustion of HPC′s regenerative capacity and thus to premature reproductive senescence. The objective of this study was to investigate if a HPC breed (Holstein-Friesian, HF) exhibits higher ovarian angiogenesis than a dual-purpose breed (Polish Red cow, PR) and if this is related to early ovarian aging and finally reproductive failure. For this purpose, we assessed the degree of vascularization by means of ovarian blood vessel characterization using light microscopy. As indicators for aging, we measured ovarian mitochondrial size and telomere length in peripheral leukocytes. We report in this study that in both breeds the distance between capillaries became smaller with increasing age and that the mean telomere length decreased with increasing age. The only difference between the two breeds was that PR developed larger capillaries than HF. Neither a relationship between telomere length, nor the morphology of the mitochondrial apparatus and nor angiogenesis in HF was proven. Although the data trends indicated that the proportion of shortened telomeres in HF was higher than in the PR, no significant difference between the two breeds was detected. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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13 pages, 2175 KiB

Open AccessArticle

Amphiregulin Regulates Melanocytic Senescence

by Michaela Pommer, Silke Kuphal and Anja K. Bosserhoff

Cells 2021, 10(2), 326; https://doi.org/10.3390/cells10020326 - 5 Feb 2021

Cited by 15 | Viewed by 2539

Abstract

Oncogene-induced senescence (OIS) is a decisive process to suppress tumor development, but the molecular details of OIS are still under investigation. Using an established OIS model of primary melanocytes transduced with BRAF V600E and compared to control cells, amphiregulin (AREG) was shown to be induced. In addition, AREG expression was observed in nevi, which by definition, are senescent cell clusters, compared to melanocytes. Interestingly, treatment of melanocytes with recombinant AREG did induce senescence. This led to the assumption that extracellular AREG has an important function in this process. Inhibition of the epidermal growth factor receptor (EGFR) using Gefitinib identified AREG as one of EGFR ligands responsible for senescence. Furthermore, depletion of AREG expression in senescent BRAF V600E melanocytes resulted in a significant reduction of senescent melanocytes. This study reveals AREG as an essential molecular component of signaling pathways leading to senescence in melanocytes. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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Review

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20 pages, 689 KiB

Open AccessReview

Role of Complement in Regulating Inflammation Processes in Renal and Prostate Cancers

by Giuseppe Stefano Netti, Rossana Franzin, Alessandra Stasi, Federica Spadaccino, Andrea Dello Strologo, Barbara Infante, Loreto Gesualdo, Giuseppe Castellano, Elena Ranieri and Giovanni Stallone

Cells 2021, 10(9), 2426; https://doi.org/10.3390/cells10092426 - 15 Sep 2021

Cited by 13 | Viewed by 4149

Abstract

For decades, the complement system, the central pillar of innate immune response, was recognized as a protective mechanism against cancer cells and the manipulation of complement effector functions in cancer setting offered a great opportunity to improve monoclonal antibody-based cancer immunotherapies. Similarly, cellular senescence, the process of cell cycle arrest that allow DNA and tissue repair has been traditionally thought to be able to suppress tumor progression. However, in recent years, extensive research has identified the complement system and cellular senescence as two main inducers of tumour growth in the context of chronic, persistent inflammation named inflammaging. Here, we discuss the data describing the ambivalent role of senescence in cancer with a particular focus on tumors that are strongly dependent on complement activation and can be understood by a new, senescence-related point of view: prostate cancer and renal cell carcinoma. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

13 pages, 1098 KiB

Open AccessReview

Aging and Cancer: The Waning of Community Bonds

by Ezio Laconi, Samuele Cheri, Maura Fanti and Fabio Marongiu

Cells 2021, 10(9), 2269; https://doi.org/10.3390/cells10092269 - 31 Aug 2021

Cited by 12 | Viewed by 3400

Abstract

Cancer often arises in the context of an altered tissue landscape. We argue that a major contribution of aging towards increasing the risk of neoplastic disease is conveyed through effects on the microenvironment. It is now firmly established that aged tissues are prone to develop clones of altered cells, most of which are compatible with a normal histological appearance. Such increased clonogenic potential results in part from a generalized decrease in proliferative fitness, favoring the emergence of more competitive variant clones. However, specific cellular genotypes can emerge with reduced cooperative and integrative capacity, leading to disruption of tissue architecture and paving the way towards progression to overt neoplastic phenotypes. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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29 pages, 1511 KiB

Open AccessReview

Role of NF-κB in Ageing and Age-Related Diseases: Lessons from Genetically Modified Mouse Models

by Verónica A. García-García, Josefa P. Alameda, Angustias Page and María Llanos Casanova

Cells 2021, 10(8), 1906; https://doi.org/10.3390/cells10081906 - 27 Jul 2021

Cited by 58 | Viewed by 7343

Abstract

Ageing is a complex process, induced by multifaceted interaction of genetic, epigenetic, and environmental factors. It is manifested by a decline in the physiological functions of organisms and associated to the development of age-related chronic diseases and cancer development. It is considered that ageing follows a strictly-regulated program, in which some signaling pathways critically contribute to the establishment and maintenance of the aged state. Chronic inflammation is a major mechanism that promotes the biological ageing process and comorbidity, with the transcription factor NF-κB (nuclear factor kappa-light-chain-enhancer of activated B cells) as a crucial mediator of inflammatory responses. This, together with the finding that the activation or inhibition of NF-κB can induce or reverse respectively the main features of aged organisms, has brought it under consideration as a key transcription factor that acts as a driver of ageing. In this review, we focused on the data obtained entirely through the generation of knockout and transgenic mouse models of either protein involved in the NF-κB signaling pathway that have provided relevant information about the intricate processes or molecular mechanisms that control ageing. We have reviewed the relationship of NF-κB and premature ageing; the development of cancer associated with ageing and the implication of NF-κB activation in the development of age-related diseases, some of which greatly increase the risk of developing cancer. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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Other

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5 pages, 930 KiB

Open AccessCommentary

Nicotinamide Adenine Nucleotide—The Fountain of Youth to Prevent Oocyte Aging?

by Paweł Kordowitzki, Wing-Hong Jonathan Ho and Dave R. Listijono

Cells 2021, 10(9), 2441; https://doi.org/10.3390/cells10092441 - 16 Sep 2021

Cited by 3 | Viewed by 3192

Abstract

According to the U.S. Special Operations Command (SOCOM), new clinical trials of an anti-aging oral treatment using nicotinamide adenine nucleotide are planned for 2022. All over the globe, the discovery of the fountain of youth is still a great goal to reach, not only among aging researchers, since people desire to stay longer healthy and feel young when reaching old age. Since the 1960s, women delaying pregnancy to pursue higher educational levels and a career path has contributed to drastically diminished overall female fertility rates (e.g., number of born offspring/woman). Consequently, a growing number of advanced-aged women depend on assisted reproductive technologies (ART) to become pregnant. In 2019, the Society for Assisted Reproductive Technology reported 293,672 cycles for oocyte retrieval. This change of demographics influenced women’s age of having their first child, which has increased significantly. However, their reproductive tract shows hallmarks of aging very early in life without an effective preventive treatment. Therefore, we will present whether NAD+ could help to prevent oocyte aging. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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6 pages, 1274 KiB

Open AccessCommentary

Oxidative Stress Induces Telomere Dysfunction and Shortening in Human Oocytes of Advanced Age Donors

by Paweł Kordowitzki

Cells 2021, 10(8), 1866; https://doi.org/10.3390/cells10081866 - 23 Jul 2021

Cited by 18 | Viewed by 3021

Abstract

Research from the past decades provided strong evidence that in humans the pool of oocytes starts to decline already before the birth of a female individual, and from menarche to menopause the oocyte is exposed to different environmental stimuli. Since more and more women of the 21st century in developed countries wish to postpone the first pregnancy to their thirties, higher rates of miscarriage and chromosomal non-disjunction might occur. In oocytes of advanced maternal age, meaning above 35 years of age, characteristics such as chromosomal instabilities/abnormalities, spindle defects, decreased mitochondrial function and telomere shortening become more prevalent than in younger counterparts. Telomere attrition belongs to the so-called “hallmarks of aging” which are also relevant for the female germ-line cells. In oocytes, telomeres shorten with advancing maternal age due to the effects of reactive oxygen species and not upon replicative senescence, similar to how it is common in dividing cells. Full article

(This article belongs to the Special Issue Molecular-Cellular Basis of Ageing and Cancer)

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