Frontiers | Unlocking longevity: the role of telomeres and its ...

Frontiers | Unlocking longevity: the role of telomeres and its targeting interventions REVIEW article Front. Aging , 25 January 2024 Sec. Healthy Longevity Volume 5 - 2024 | https://doi.org/10.3389/fragi.2024.1339317 Published in Frontiers in Aging Healthy Longevity 4.3 impact factor 5.1 citescore Part of a Research Topic Insights in Healthy Longevity 2023/2024 117k views 6 articles Editor & Reviewers Edited by R C Richard C Siow School of Cardiovascular Medicine & Sciences, Faculty of Life Sciences & Medicine, King's College London, United Kingdom Reviewed by P C Paolina Crocco University of Calabria, Italy J S Jorge Sanz-Ros Stanford University, United States Outline Figures and Tables FIGURE 1 View in article REVIEW article Front. Aging , 25 January 2024 Sec. Healthy Longevity Volume 5 - 2024 | https://doi.org/10.3389/fragi.2024.1339317 Unlocking longevity: the role of telomeres and its targeting interventions M S Marlies Schellnegger 1,2 * E H Elisabeth Hofmann 1,2,3 M C Martina Carnieletto 1,2 L K Lars-Peter Kamolz 1,2 1. Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria 2. COREMED–Centre for Regenerative and Precision Medicine, JOANNEUM RESEARCH Forschungsgesellschaft mbH, Graz, Austria 3. Research Unit for Tissue Regeneration, Repair and Reconstruction, Division of Plastic, Aesthetic and Reconstructive Surgery, Department of Surgery, Medical University of Graz, Graz, Austria See more Article metrics View details Abstract Average life expectancy has been steadily increasing in developed countries worldwide. These demographic changes are associated with an ever-growing social and economic strain to healthcare systems as well as society. The aging process typically manifests as a decline in physiological and cognitive functions, accompanied by a rise in chronic diseases. Consequently, strategies that both mitigate age-related diseases and promote healthy aging are urgently needed. Telomere attrition, characterized by the shortening of telomeres with each cell division, paradoxically serves as both a protective mechanism and a contributor to tissue degeneration and age-related ailments. Based on the essential role of telomere biology in aging, research efforts aim to develop approaches designed to counteract telomere attrition, aiming to delay or reduce age-related diseases. In this review, telomere biology and its role in aging and age-related diseases is summarized along with recent approaches to interfere with telomere shortening aiming at well- and healthy-aging as well as longevity. As aging research enters a new era, this review emphasizes telomere-targeting therapeutics, including telomerase activators and tankyrase inhibitors, while also exploring the effects of antioxidative and anti-inflammatory agents, along with indirectly related approaches like statins. 1 Introduction In the past century, the average life expectancy has roughly doubled basically in all developed countries worldwide. Demographic data estimate that by the year 2050, the global population of individuals aged 60 and above is expected to reach 2.1 billion, effectively doubling the figure reported in 2020. Additionally, the number of adults over 80 years old will triple and reach 426 million ( United Nations Department of Economic and Social Affairs, 2022 ). This demographic shift is clearly associated with an escalating social and economic burden, challenging not only for our healthcare system but also the social security systems, workforce dynamics, housing infrastructure, and intergenerational relationships ( Partridge et al., 2018 ). Primarily, the aging process involves a functional decline, which in turn leads to a steady increase in chronic diseases, including cancer, neurodegenerative diseases, diabetes melitus, and cardiovascular diseases ( Hou et al., 2019 ; Bellary et al., 2021 ; Liberale et al., 2022 ). These age-associated diseases predictively double in incidence every 5 years after the age of sixty. Furthermore, the WHO designates advanced age as an independent risk factor for major life-threatening disorders. For instance, when considering coronary heart disease, advanced age is rated as an equally significant risk factor as smoking ( Melzer et al., 2020 ). Therefore, it seems to be of utmost importance to develop strategies and interventions that interfere with the aging process, prevent or at least mitigate age-associated diseases, and support healthy aging patterns, not only to elongate the lifespan but also to increase the healthspan - the phase of life spent in health, active, and in absent of chronic diseases ( Seals et al., 2016 ). Over the past decades, the healthspan has not increased at the same pace as the lifespan and lags far behind; this observed disparity raises significant concerns. The quality of life and wellbeing during aging is to prioritize; otherwise, the challenges posed by an excessively growing aging population will become unmanageable ( Gonzalez-Freire et al., 2020 ). Not surprisingly, the potential to positively intervene and modulate the aging process has been a longstanding area of interest. Specifically, the defined hallmarks of aging are frequently targeted in intervention strategies aiming to mitigate or decelerate the mechanisms of the aging process ( Shetty et al., 2018 ; Campisi et al., 2019 ). The hallmarks of aging comprise twelve identified variables as crucial contributors to the aging process ( López-Otín et al., 2013 ; López-Otín et al., 2023 ). These hallmarks encompass genomic instability, the shortening of telomeres, deregulated nutrient sensing, mitochondrial dysfunction, changes in epigenetic regulation, loss of proteostasis, cellular senescence, stem cell exhaustion, and altered intercellular communication ( Campisi et al., 2019 ). Telomere attrition belongs to the cardinal hallmarks of aging and has garnered significant attention in gerontological research over the past years. Telomeres, the protective ends of chromosomes, progressively diminish with each cell division. Once a critical length is reached, cells may undergo senescence or apoptosis, serving as a safeguard against genetic irregularities ( Blackburn et al., 2006 ). While this mechanism has actually protective origins, in the context of aging, it counterintuitively accelerates tissue degradation and ushers in age-related disorders. The central role of telomere biology in aging has led research into therapies designed to counteract telomere attrition, aiming to delay or mitigate age-linked diseases ( Aubert and Lansdorp, 2008 ; Shay and Wright, 2019 ; Alder and Armanios, 2022 ). Targeting telomere dynamics presents a promising avenue in gerontology, well-aging, and the development of therapies for age-associated ailments, underlining the importance of understanding telomere dynamics ( Blackburn et al., 2015a ). Despite telomeres’ established role in aging, the field of telomere biology faces a significant challenge: the lack of effective, clinically proven therapies that directly target telomeres. This gap underscores the complexity of translating fundamental telomere research into therapeutic applications and the challenges in addressing the multifaceted nature of telomere dynamics and their systemic impact on aging and age-related diseases. Therefore, continued exploration and innovative strategies in telomere research are essential to develop tangible, effective treatments for age-related pathologies. 2 Telomere biology: the basics and beyond A comprehensive understanding of the underlying mechanisms of aging and their impact on long-term health provides valuable insights into resilience mechanisms, their influence on stress responses, and the ensuing effects on health ( Ferrucci et al., 2020 ). The defined hallmarks of aging are a fundamental part of current research in aging; each one fulfills three premises: an age-associated manifestation, an experimentally amplification accelerates the aging process, and interventions targeting these hallmarks offer potential to decelerate, maintain, or even reverse aging ( López-Otín et al., 2023 ). Although the individual hallmarks are intricately interwoven, specific ones are selectively targeted to develop intervention strategies and therapeutic approaches. 2.1 Telomere shortening: at the nexus of cellular aging In 2013, telomere attrition was described as a primary hallmark of aging ( López-Otín et al., 2013 ), and its research has increasingly garnered attention in recent years. However, the notion of telomeres emerged already in the 1930s when Creighton and McClintock studied Zea mays and hypothesized the presence of a distinctive structure at chromosome ends, critical for preventing chromosome end fusion ( Creighton and McClintock, 1931 ). Since then, extensive research in this field has been has continually revealed new insights, recognizing its role in the aging process and various diseases ( Cawthon et al., 2003 ; Rizvi et al., 2014 ; Wang et al., 2018 ; Yuan et al., 2018 ). Telomeres are described as consecutive repeats of the six-nucleotide sequence (TTAGGG) in the form of a cap structure ( Blackburn and Gall, 1978 ), serving to protect chromosome ends from initiating a DNA damage response. Due to the inherent constraints of DNA polymerases in replication, telomeric DNA cannot be completely replicated. This leads to the gradual shortening of telomeres with each cycle of cell division ( Allsopp et al., 1992 ; Rhodes et al., 2002 ). When telomeres shorten to a critical point, they cause genomic instability, which hinders further replication, leading to senescence and eventually cell death ( Blackburn, 2001 ). At note, DNA polymerase requires a transient primer to commence the unidirectional synthesis from the 5′to the 3′end, but it cannot fully replicate the 3′ ends of the chromosome, which is described as the “end-replication problem” ( Levy et al., 1992 ). Certain mechanisms are req