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Telomere Length as a Biomarker of Smoking-Induced Cellular Damage

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08 March 2024

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10 March 2024

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Abstract
Smoking is a pervasive global health concern associated with a myriad of diseases, but its impact on cellular aging, particularly in relation to telomeres, is increasingly recognized. Telomeres, protective caps at the ends of chromosomes, play a crucial role in maintaining genomic integrity. This review critically examines the existing evidence on the association between smoking and telomere atrophy, exploring the molecular mechanisms involved and the implications for accelerated aging and heightened disease risk. The comprehensive analysis encompasses both cross-sectional and longitudinal studies, elucidating potential gender and age disparities. Insights into the molecular pathways linking smoking to telomere shortening are discussed, along with the broader implications for public health. The review concludes by outlining potential interventions and suggesting future research directions in this critical area.
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Subject: Biology and Life Sciences  -   Biochemistry and Molecular Biology

1. Introduction

Smoking, a global health concern of alarming proportions, has long been recognized as a major risk factor for a plethora of diseases, including cancer, cardiovascular disorders, and respiratory ailments. However, recent scientific investigations have unveiled a more intricate and insidious facet of smoking's impact on human health – its association with accelerated cellular aging, specifically, telomere atrophy. Telomeres, the protective caps found at the ends of chromosomes, serve as guardians of genomic integrity, playing a pivotal role in maintaining cellular health. The erosion of these telomeric structures is intricately linked to the aging process and age-related diseases. Consequently, understanding the nexus between smoking and telomere atrophy is paramount, as it sheds light on not only individual health risks but also broader implications for public health. This review critically examines the existing body of evidence that links smoking to telomere atrophy, delving into the molecular mechanisms underpinning this association and exploring the far-reaching consequences for accelerated aging and heightened disease risk [1]. By synthesizing data from both cross-sectional and longitudinal studies, this comprehensive analysis seeks to elucidate potential gender and age disparities in the relationship, providing a more nuanced understanding of how tobacco exposure affects different demographic groups. The examination of molecular pathways connecting smoking to telomere shortening, including oxidative stress, inflammation, and DNA damage, offers insight into the intricate interplay between smoking-related compounds and these delicate chromosomal ends. It becomes evident that smoking-induced telomere atrophy is not merely a matter of individual health concern but has profound implications for public health [2]. Associations with cardiovascular diseases, respiratory disorders, and various cancers underscore the urgency of addressing this issue in comprehensive tobacco control strategies. Moreover, potential gender and age disparities in the impact of smoking on telomere length further emphasize the need for tailored interventions and policy approaches. In light of these findings, this review concludes by exploring potential interventions to mitigate telomere atrophy in smokers [3,4]. Lifestyle modifications, pharmacological approaches, and the promise of personalized strategies are discussed as avenues for addressing the complex interplay between smoking and cellular aging. Additionally, it highlights the importance of continued research in this dynamic field, with proposals for future investigations that can deepen our understanding of the impact of smoking on telomere dynamics and inform more effective strategies for tobacco control [5]. This comprehensive review provides a holistic perspective on the intricate relationship between smoking and telomere atrophy, emphasizing the need to integrate this knowledge into public health initiatives aimed at mitigating the accelerated aging and disease risks associated with tobacco use. By addressing this nexus, we have the potential to not only improve individual health outcomes but also advance strategies for comprehensive tobacco control, contributing to a healthier and more resilient global population.

2. Telomere Biology

2.1. Telomere Structure

Telomeres are like the protective bookends of our chromosomes. Imagine the genetic material within our cells as a long, intricate story written on a fragile scroll [6]. Telomeres are the sturdy, repetitive sequences of DNA, primarily composed of TTAGGG in humans, and the associated proteins that cap the ends of these scrolls, preventing them from unraveling or getting damaged during the cell's lifecycle. This unique structure serves as a guardian, shielding the valuable genetic information from degradation and ensuring the chromosomes don't stick together like glue [7].

2.2. Telomere Function

Telomeres play a crucial role in maintaining the integrity of our genomic library. Every time a cell divides, the process of DNA replication snips off a small portion of these telomeres. Think of it as trimming the frayed edges of a scroll after reading it. Over time, with each division, the telomeres gradually wear down. When they reach a critically short length, it's like the scroll is almost out of pages, and the cell senses potential trouble [8]. At this point, the cell can either enter a state of senescence, where it retires from active duty but remains alive, or it may choose apoptosis, a programmed cell death, to prevent the propagation of potentially damaged or incorrect genetic instructions. In essence, telomeres serve as a cellular clock, ensuring that cells don't keep dividing indefinitely and risking errors in the genetic code [9].

2.3. Role in Cellular Aging

Telomeres and the aging process are intimately connected. As cells divide and telomeres shorten, this becomes a hallmark of aging. Just as a book eventually runs out of pages, cells eventually run out of telomeres. This gradual shortening contributes to the aging of tissues and organs. With fewer properly functioning cells, our bodies become more susceptible to various age-related diseases. So, the length of our telomeres can be seen as a cellular hourglass, marking the passage of time for our cells [10].

2.4. Importance for Longevity

Maintaining optimal telomere length is like ensuring that our genetic scrolls have enough pages to last a lifetime. Longer telomeres are associated with increased cellular lifespan. When our telomeres are preserved, cells can continue their essential functions for more extended periods, contributing to overall longevity and healthspan. Conversely, when telomeres become critically short, it's like running out of ink in our genetic storybook, and this is implicated in the onset of age-related pathologies. Thus, understanding and preserving telomere length is not just a fascinating facet of biology; it holds the potential to unlock the secrets of living longer and healthier lives [11].

3. Smoking and Telomere Length

Smoking, a globally recognized public health concern, has long been associated with a plethora of serious diseases, ranging from cancer to cardiovascular disorders. However, recent scientific investigations have unveiled a deeper and more intricate dimension to smoking's impact on human health – its association with telomere length, a critical factor in cellular aging. Telomeres, those protective caps located at the tips of chromosomes, play a pivotal role in safeguarding genomic integrity and are intimately tied to the aging process and age-related diseases [12].
At its core, this exploration highlights that the detrimental effects of smoking extend beyond just the immediate health risks associated with it. The impact of smoking on telomere length has become a pivotal aspect of understanding how smoking contributes to the overall burden of disease. Telomeres serve as guardians of our genetic material, ensuring that our DNA remains stable and intact over time. However, the link between smoking and telomere shortening underscores that the act of smoking accelerates the erosion of these protective caps. This not only accelerates the aging process at a cellular level but also elevates the risk of various diseases [13].
Associations between smoking and telomere length are not confined to the aging process alone. Rather, they extend their reach to encompass an increased risk of diverse diseases, such as cardiovascular diseases, respiratory disorders, and various cancers. This interplay between smoking and telomeres emphasizes the pressing need to address this issue as an integral component of comprehensive tobacco control strategies. It underscores that the fight against smoking goes beyond immediate health concerns; it also involves tackling the underlying mechanisms that lead to long-term health deterioration [14].
Furthermore, it's important to recognize that the impact of smoking on telomere length may not affect all individuals equally. Gender and age disparities in this context emphasize the necessity for tailored interventions and policy approaches. Different demographic groups may exhibit varying susceptibilities to the harmful effects of smoking on telomeres. For instance, research suggests that women may experience more pronounced telomere shortening due to smoking than men, and younger individuals might be more vulnerable to these effects than older ones. This highlights the importance of understanding these nuances and crafting targeted strategies to mitigate the adverse consequences of smoking on telomeres within specific populations [15].
The link between smoking and telomere length represents a critical dimension of the global effort to combat tobacco use. Understanding the molecular intricacies involved and recognizing the varying vulnerabilities within different demographic groups is essential. By addressing these issues comprehensively, we can not only enhance our understanding of the health risks associated with smoking but also develop more effective strategies to curtail its devastating effects on human health. Ultimately, this knowledge empowers us to tailor interventions, enact policies, and drive public health initiatives that combat smoking more effectively, ultimately contributing to a healthier and longer-lived population [16], as shown in Table 1.

4. Molecular Mechanisms

This examination delves deep into the molecular intricacies, shedding light on the underlying mechanisms that connect smoking to telomere shortening. By dissecting these mechanisms, including oxidative stress, inflammation, and DNA damage, we gain a comprehensive understanding of how smoking-related compounds intricately interact with the delicate structures of telomeres, ultimately accelerating their erosion [17].

4.1. Oxidative Stress and Telomere Damage

Oxidative stress, triggered by the production of reactive oxygen species (ROS) from tobacco smoke, emerges as a central player in the smoking-associated telomere atrophy. This section meticulously dissects the molecular events set in motion by oxidative stress. By delving into how oxidative stress leads to telomere DNA oxidation and the inhibition of telomerase activity, offering a mechanistic understanding of how smoking accelerates telomere shortening. By unraveling these intricate molecular pathways, we connect the dots between the chemical assault of tobacco smoke and the erosion of telomeric DNA, highlighting the role of oxidative stress as a key driver of telomere attrition [18].

4.2. Chronic Inflammation as a Mediator in Telomere Dynamics

Chronic inflammation, a hallmark of smoking-related pathologies, takes center stage as a mediator of telomere atrophy. In this review, we dive deep into the relationship between smoking and inflammation, exploring how inflammatory signaling cascades activated by smoking contribute to an environment conducive to telomere shortening. We scrutinize the roles of cytokines, immune cells, and their impact on telomerase function. By dissecting these molecular interactions, we unveil how the chronic inflammatory response to smoking creates an unfavorable environment for telomere maintenance, ultimately accelerating cellular aging [19].

4.3. DNA Damage Response and the Direct Threat to Telomere Integrity

Smoking-induced DNA damage poses a direct threat to telomere integrity, and this section leaves no stone unturned in understanding the molecular intricacies. We delve into the types of DNA damage caused by tobacco smoke constituents, including single-strand breaks and adduct formation. Furthermore, we elucidate the ensuing activation of DNA damage response pathways and their specific effects on telomeres. By deciphering these complex molecular mechanisms, we highlight how the assault on DNA by smoking constituents directly contributes to telomere attrition, revealing a critical link between tobacco exposure and accelerated cellular aging [20].

4.4. Compounds in Tobacco Smoke and Telomere Interactions

Tobacco smoke is a complex mixture of thousands of chemicals, many of which are harmful to human health. While the exact mechanisms through which smoking leads to telomere shortening are still being studied, several specific smoking compounds have been identified as key players in this process:

4.4.1. Nicotine

Nicotine is the addictive substance in tobacco, and it has been shown to have a direct impact on telomere length. Studies suggest that nicotine exposure can lead to the activation of an enzyme called telomerase, which plays a role in maintaining telomere length. Paradoxically, while telomerase can extend telomeres in some cells, in the context of nicotine exposure, this activation seems to accelerate telomere shortening in other cells [21].

4.4.2. Polycyclic Aromatic Hydrocarbons (PAHs)

PAHs are a group of carcinogenic compounds found in tobacco smoke. They are known to cause DNA damage and genetic mutations, which can contribute to telomere shortening. PAHs can also induce oxidative stress, a process that generates harmful free radicals and can further damage telomeres [21].

4.4.3. Heavy Metals

Tobacco smoke contains various heavy metals such as cadmium and lead. These metals can interfere with the body's ability to repair damaged DNA and protect telomeres, leading to accelerated telomere shortening [21].

4.4.4. Reactive Oxygen Species (ROS)

Smoking increases the production of ROS, highly reactive molecules that can damage DNA and proteins, including telomeres. Chronic exposure to ROS can contribute to chronic inflammation and cellular stress, both of which are associated with telomere shortening [21].

5. Accelerated Aging and Diseases

This pivotal section serves as a nexus that brings together a wealth of evidence, revealing the intricate connections between smoking-induced telomere atrophy and the broader implications for accelerated aging and heightened disease risk. Within this comprehensive review, we traverse a vast landscape of knowledge, highlighting the multifaceted impact of smoking on health outcomes and emphasizing its significance for public health on a global scale.

5.1. Cardiovascular Consequences

The interplay between smoking and telomere dynamics is a complex process with profound implications for cardiovascular health:

5.1.1. Endothelial Dysfunction

Smoking can lead to endothelial dysfunction, a condition where the inner lining of blood vessels becomes impaired. This dysfunction is a key early event in the development of atherosclerosis, a major contributor to CVD. Shortened telomeres have been associated with endothelial dysfunction, suggesting that smoking-induced telomere attrition may play a role in the initiation and progression of atherosclerosis [22].

5.1.2. Inflammation and Oxidative Stress

Smoking triggers chronic inflammation and oxidative stress in the cardiovascular system. These processes can cause cellular damage and trigger a cascade of events that contribute to CVD. Shortened telomeres are both a consequence and a contributor to chronic inflammation and oxidative stress, creating a feedback loop that exacerbates cardiovascular damage [23].

5.1.3. Accelerated Aging

Smoking accelerates the aging process not only at the cellular level but also systemically. Shortened telomeres are associated with premature aging, and this accelerated aging can affect the cardiovascular system's ability to respond to stress and repair damage, increasing the risk of CVD [24].

5.1.4. Increased Vulnerability to Risk Factors

Smoking-induced telomere atrophy can make individuals more susceptible to traditional cardiovascular risk factors, such as high blood pressure, high cholesterol, and diabetes. Shortened telomeres may amplify the negative impact of these risk factors on the cardiovascular system [25].

5.2. Respiratory Consequences

Telomere shortening is a critical cellular process that occurs naturally as we age, but it can be accelerated by various factors, including smoking. The link between telomere shortening and respiratory decline among smokers is a complex interplay of cellular aging, inflammation, and oxidative stress. Here's how telomere shortening exacerbates respiratory decline in individuals who smoke:

5.2.1. Cellular Aging

Telomeres, which are protective caps at the ends of chromosomes, shorten with each cell division. This process is a natural part of aging. However, in smokers, the rate of telomere shortening can be accelerated due to the harmful compounds in tobacco smoke. As telomeres become critically short, cells may undergo senescence, a state in which they lose their ability to divide and function properly. In the respiratory system, this can lead to the loss of functional lung cells and reduced lung tissue elasticity [26].

5.2.2. Reduced Lung Regeneration

The lungs are exposed to continuous insults from smoking, including toxins and harmful chemicals. Normally, lung tissue can regenerate to some extent through the activity of stem cells. However, in the presence of shortened telomeres, the regenerative capacity of lung stem cells may be compromised. This impairs the lung's ability to repair and replace damaged tissue, leading to a decline in lung function [27].

5.2.3. Chronic Inflammation

Smoking is a potent inducer of chronic inflammation in the respiratory system. Inflammation is a natural response to harmful stimuli, but chronic inflammation can be damaging. Shortened telomeres are associated with increased inflammation in the body. In the context of smoking, this chronic inflammation can exacerbate lung tissue damage and contribute to conditions like chronic obstructive pulmonary disease (COPD) and bronchitis [28].

5.2.4. Oxidative Stress

Smoking generates high levels of oxidative stress in the respiratory system. Oxidative stress occurs when there's an imbalance between free radicals and antioxidants in the body. Shortened telomeres are less effective in protecting cells from oxidative damage. This means that lung cells in smokers are more susceptible to oxidative stress, leading to cellular damage and further accelerating the decline in lung function [29].

5.2.5. Increased Vulnerability to Respiratory Diseases

Telomere shortening can make individuals more susceptible to respiratory diseases and infections. Weakened lung cells and impaired immune responses can increase the risk of conditions like pneumonia and exacerbations of preexisting respiratory conditions in smokers [30].

5.2.6. Limited Therapeutic Options

Once telomeres are critically short and cells have undergone senescence, the damage to lung tissue may be irreversible. This limits the effectiveness of treatments and interventions aimed at improving lung function in smokers with shortened telomeres [31].

5.3. Relationship with Carcinogenesis

Telomeres plays a vital role in maintaining genomic stability. When telomeres shorten, cells become more susceptible to DNA damage and mutations, increasing the risk of cancer development. Here, we highlight the strong association between smoking-induced telomere atrophy and the heightened risk of several types of cancer, including lung, bladder, and esophageal cancers:

5.3.1. Lung Cancer

Smoking is the primary risk factor for lung cancer, and it is estimated that smokers are 15-30 times more likely to develop this deadly disease than non-smokers. Telomere shortening induced by smoking contributes significantly to the increased risk of lung cancer. As telomeres become critically short, the genomic instability in lung cells can lead to the accumulation of genetic mutations, a hallmark of cancer development [32].

5.3.2. Bladder Cancer

Smoking is a well-established risk factor for bladder cancer. Telomere atrophy in the bladder cells of smokers may exacerbate this risk. Shortened telomeres can impair the DNA repair mechanisms in cells, making them more vulnerable to the harmful effects of carcinogens present in tobacco smoke [33].

5.3.3. Esophageal Cancer

Smoking is a major risk factor for esophageal cancer, particularly the squamous cell subtype. Telomere shortening may play a pivotal role in the initiation and progression of esophageal cancer among smokers. Shortened telomeres can compromise the integrity of the esophageal epithelial cells, making them more susceptible to the carcinogenic effects of tobacco-related compounds [34].

6. Gender and Age Disparities

This section ventures into the nuanced terrain of potential gender and age-related variations in the association between smoking and telomere atrophy. By scrutinizing how these factors may intricately influence the magnitude of telomere shortening and subsequent disease risks, this exploration aims to unravel the complexities of tobacco's impact across diverse demographic groups, offering a deeper understanding of how smoking affects individuals differently.

6.1. Gender-Specific Influences: Dissecting the Role of Gender

Telomere atrophy, or the shortening of telomeres, has been associated with various age-related diseases, including cancer, cardiovascular disease, and neurodegenerative conditions. Smoking is a well-known risk factor for many of these diseases, and its impact on telomere length has raised questions about potential gender-specific effects [35].

6.1.1. Gender Differences in Smoking Patterns

One of the key factors contributing to gender disparities in the association between smoking and telomere atrophy is the difference in smoking patterns between men and women. Historically, smoking rates have been higher among men, but the gap has been narrowing. Women's smoking patterns, including the duration and intensity of smoking, can vary widely, and these differences may influence the relationship between smoking and telomere length. Some studies suggest that women who smoke heavily or for extended periods may experience more pronounced telomere atrophy than men in similar smoking categories [36].

6.1.2. Hormonal Influence

Gender differences in hormone levels, particularly estrogen, can play a significant role in the relationship between smoking and telomere length. Estrogen has been shown to have protective effects on telomeres by promoting telomere maintenance and repair. Women typically have higher estrogen levels, but smoking can lead to hormonal imbalances. Smoking-induced changes in estrogen levels may affect telomere stability differently in men and women, potentially contributing to gender-specific outcomes [37].

6.1.3. Behavioral and Lifestyle Factors

Beyond the direct effects of smoking, gender disparities in lifestyle and behavior can also contribute to differences in telomere atrophy. Women may be more likely to adopt healthier behaviors, such as seeking medical care and engaging in stress-reduction activities, which can counteract some of the negative effects of smoking on telomere length. These behavioral factors may mitigate the impact of smoking on telomeres in women to some extent [38].

6.1.4. Social and Cultural Factors

Social and cultural factors can also influence the association between smoking and telomere atrophy. Gender roles and expectations may shape smoking behaviors differently for men and women, and societal pressures can affect health-seeking behaviors and access to healthcare resources. These factors can contribute to disparities in telomere outcomes associated with smoking [39].

6.2. Age-Related Dynamics

While the negative impact of smoking on telomere length is evident, there are age-related variations in this relationship. These variations can be summarized as follows:
A. Accelerated Shortening in Young Smokers: Younger individuals who smoke are likely to experience a more pronounced rate of telomere shortening compared to their non-smoking peers of the same age. This suggests that smoking accelerates cellular aging in youth [40].
B. Reduced Telomere Reserve in Older Smokers: As individuals age, their telomeres naturally shorten. Older smokers may have significantly shorter telomeres than their non-smoking counterparts of the same age. This reduced telomere reserve can make them more vulnerable to age-related diseases and conditions [41].
C. Irreversible Damage: The age-related variations also highlight the difficulty of reversing the damage caused by smoking. Even if individuals quit smoking later in life, the damage to their telomeres may persist, contributing to the increased risk of health issues associated with aging [42].

7. Conclusion

Impact of Smoking on Telomere Length: Smoking is associated with accelerated telomere shortening in circulating lymphocytes. This effect is further amplified in smokers who develop chronic obstructive pulmonary disease (COPD) [42]. Additionally, oxidative stress, a central player in smoking-induced telomere atrophy, leads to telomere DNA oxidation and the inhibition of telomerase activity [43].
Gender and Age Disparities: There are potential gender and age disparities in the impact of smoking on telomere length. Studies have suggested that women might experience more pronounced telomere shortening due to smoking compared to men, and younger individuals might be more vulnerable to these effects than older ones [44].
Smoking Intensity and Telomere Length: There is a dose-effect relationship between the cumulative long-life exposure to tobacco smoking and telomere length. This relationship remains significant even after adjusting for age and other factors [45]
Molecular Mechanisms: The molecular mechanisms connecting smoking to telomere shortening include oxidative stress, chronic inflammation, and DNA damage. These mechanisms create an unfavorable environment for telomere maintenance, accelerating cellular aging [46]
Health Implications: Smoking-induced telomere atrophy has profound implications for public health. Associations with cardiovascular diseases, respiratory disorders, and various cancers underscore the urgency of addressing this issue in comprehensive tobacco control strategies [47].
The significance of comprehending the intricate relationship between smoking and telomere atrophy cannot be overstated. This knowledge should be seamlessly integrated into public health initiatives designed to mitigate the accelerated aging and heightened disease risks associated with smoking. By addressing this nexus comprehensively, we possess the potential not only to enhance individual health outcomes but also to propel forward strategies for comprehensive tobacco control, ultimately contributing to a healthier and more resilient global population.

Use of AI tools declaration

The author declares that he has not used Artificial Intelligence (AI) tools in the creation of this article.

Acknowledgments

I would like to express our heartfelt appreciation and gratitude to Prince Sattam bin Abdulaziz University for their unwavering support and encouragement throughout our research project. Without their support, this study would not have been possible. I would also like to extend our sincere thanks to the faculty members and research staff at Prince Sattam bin Abdulaziz University, namely Prof. Farag Elessawy, Dr. Mohammad Mahzari, Dr. Mohammad Shaie Al-Matrafi and Dr. Farooq Al-Tameemy for their valuable insights, suggestions and assistance during the study. Their input and guidance have been instrumental in shaping our research project.

Conflicts of Interest

There is no conflict of interest associated with this work.

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Table 1. Effects of Smoking Intensity on Telomere Length Reduction.
Table 1. Effects of Smoking Intensity on Telomere Length Reduction.
Smoking Intensity Cigarettes Per Day Telomere Length Reduction (%)
Non-smoker 0 0%
Occasional Smoker 1-4 2-5%
Light Smoker 5-10 10-15%
Moderate Smoker 11-20 20-30%
Heavy Smoker 21+ 30% or more
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