The role of Epigenetics in restoring the genome pt2 Epigenetic and Stem Cells Revolution

The birth of industrialisation, rapid economic developments and innovations has led the world towards better quality of life, access to goods and a life that can be managed rather than dictated by environmental occasions that were causing people to live a poorer life. Ultimately, the want and need to improve every aspect of our lives, including the rise of technology, medical and scientific breakthroughs, has naturally led us towards a longevity revolution characterised initially by large and rapid increases in life expectancy at birth (e(0)). e(0) increased at an accelerated rate, from an average of 1 year every one or two centuries for the previous 2,000 years to 3 years of life added per decade during the twentieth century.

Over the course of the 20th century, human life expactancy has more than doubled. In the beginning of the century, a newborn was expected to live around 30 years, wheres now the average lifespan in around 75 years.

However there are analyses that suggest that human life expectancy prolongation has decreased for the past 20 to 30 years while inequality in this regard has decreased. Unless bigger reforms are made, rapid life expectancy increase will not be possible in this century. Current trends suggest that survival to age 100 years is unlikely to exceed 15% for females and 5% for males, altogether suggesting that, unless the processes of biological aging can be markedly slowed, radical human life extension is implausible in this century.

The Role of Epigenetic and Stem Cells Research

Epigenetics plays a pivotal role in the regulation of gene expression and has emerged as a significant factor in understanding the biological mechanisms underlying aging and longevity. This section will delve deeper into how epigenetic modifications can potentially prolong human lifespans, focusing on the interplay between lifestyle factors, epigenetic changes, and the biological aging process.

Epigenetic Mechanisms Influencing Lifespan.  The aging process is characterized by a gradual decline in cellular function, often accompanied by epigenetic alterations such as DNA methylation, histone modifications, and changes in non-coding RNA expression. These modifications can influence gene expression patterns that are crucial for maintaining cellular homeostasis and function. For instance, studies have shown that global decreases in DNA methylation and specific histone modifications are associated with aging, suggesting that these epigenetic changes may serve as biomarkers for biological age (Franzago et al., 2022; Fiorito et al., 2021). Furthermore, the loss of heterochromatin and alterations in chromatin structure have been implicated in age-related diseases, highlighting the importance of chromatin dynamics in longevity (Ferioli et al., 2019).

Lifestyle Interventions and Epigenetic Rejuvenation  Lifestyle factors such as diet, exercise, and stress management have been shown to induce beneficial epigenetic changes that may counteract the effects of aging. For example, adherence to a Mediterranean diet has been associated with epigenetic rejuvenation, as evidenced by changes in DNA methylation patterns that correlate with improved health outcomes (Gensous et al., 2020; Meir et al., 2021). Similarly, physical exercise has been demonstrated to alter the epigenetic landscape, promoting gene expression that supports metabolic health and reduces inflammation, both of which are critical for longevity (Ferioli et al., 2019; Fabre et al., 2018). Regular physical activity can lead to significant changes in DNA methylation in skeletal muscle, enhancing the expression of genes involved in energy metabolism and cellular repair (Ferioli et al., 2019).

The Role of Nutrients and Supplements  Nutritional epigenetics has revealed that specific dietary components can influence epigenetic modifications. Nutrients such as folate, vitamins B6 and B12, and polyphenols can act as methyl donors or modifiers, thereby impacting DNA methylation and histone modifications (Cheng et al., 2018; Mahmoud, 2022). Additionally, compounds like NAD+ precursors (e.g., NMN and NR) have been shown to enhance DNA repair mechanisms and promote healthy aging by influencing the epigenome (Lee et al., 2019). These findings underscore the potential of dietary interventions to modulate epigenetic marks and, consequently, longevity.

Pharmacological Approaches to Epigenetic Rejuvenation  Pharmacological interventions targeting epigenetic mechanisms are gaining traction in the field of anti-aging research. Drugs such as histone deacetylase inhibitors (HDACi) and DNA methyltransferase inhibitors (DNMTi) have shown promise in reactivating silenced genes associated with aging and age-related diseases (Santaló & Berdasco, 2022; Maleknia, 2023). For instance, HDAC inhibitors have been utilized in cancer therapies to restore the expression of tumor suppressor genes, indicating their potential for broader applications in longevity research (Santaló & Berdasco, 2022). Moreover, recent studies have demonstrated that transient expression of reprogramming factors can rejuvenate aged cells and extend lifespan in model organisms, suggesting that epigenetic reprogramming may be a viable strategy for combating aging (Lee et al., 2019).

Behavioral Epigenetics and Longevity  Behavioral epigenetics offers insights into how lifestyle choices can influence epigenetic states and, ultimately, longevity. Environmental factors, including stress, social interactions, and maternal care, have been shown to induce epigenetic changes that can affect health outcomes across generations (Aurich et al., 2023; McCullough et al., 2015). For example, maternal exercise during pregnancy has been linked to favorable epigenetic programming in offspring, potentially enhancing their metabolic health and longevity (Zheng et al., 2020). This highlights the importance of considering both individual and environmental factors in the context of epigenetic influences on lifespan.

In summary, the interplay between epigenetics and longevity is complex and multifaceted. Epigenetic modifications serve as critical regulators of gene expression that can be influenced by lifestyle choices, dietary factors, and pharmacological interventions. As research continues to uncover the mechanisms by which epigenetics affects aging, there is potential for developing targeted strategies to promote longevity and improve healthspan. The reversible nature of epigenetic changes offers a promising avenue for interventions aimed at mitigating the effects of aging, thereby enhancing the quality of life in older adults.

References:

Aurich, S., Müller, L., Kovacs, P., & Keller, M. (2023). Implication of dna methylation during lifestyle mediated weight loss. Frontiers in Endocrinology, 14. https://doi.org/10.3389/fendo.2023.1181002

Cheng, Z., Zheng, L., & Almeida, F. (2018). Epigenetic reprogramming in metabolic disorders: nutritional factors and beyond. The Journal of Nutritional Biochemistry, 54, 1-10. https://doi.org/10.1016/j.jnutbio.2017.10.004

Fabre, O., Ingerslev, L., Garde, C., Donkin, I., Simar, D., & Barrès, R. (2018). Exercise training alters the genomic response to acute exercise in human adipose tissue. Epigenomics, 10(8), 1033-1050. https://doi.org/10.2217/epi-2018-0039

Ferioli, M., Zauli, G., Maiorano, P., Milani, D., Mirandola, P., & Neri, L. (2019). Role of physical exercise in the regulation of epigenetic mechanisms in inflammation, cancer, neurodegenerative diseases, and aging process. Journal of Cellular Physiology, 234(9), 14852-14864. https://doi.org/10.1002/jcp.28304

Fiorito, G., Caini, S., Palli, D., Bendinelli, B., Saieva, C., Ermini, I., … & Masala, G. (2021). Dna methylation‐based biomarkers of aging were slowed down in a two‐year diet and physical activity intervention trial: the dama study. Aging Cell, 20(10). https://doi.org/10.1111/acel.13439

Franzago, M., Pilenzi, L., Rado, S., Vitacolonna, E., & Stuppia, L. (2022). The epigenetic aging, obesity, and lifestyle. Frontiers in Cell and Developmental Biology, 10. https://doi.org/10.3389/fcell.2022.985274

Gensous, N., Garagnani, P., Santoro, A., Giuliani, C., Ostan, R., Fabbri, C., … & Bacalini, M. (2020). One-year mediterranean diet promotes epigenetic rejuvenation with country- and sex-specific effects: a pilot study from the nu-age project. Geroscience, 42(2), 687-701. https://doi.org/10.1007/s11357-019-00149-0

Lee, J., Papa, F., Jaini, P., Alpini, S., & Kenny, T. (2019). An epigenetics-based, lifestyle medicine–driven approach to stress management for primary patient care: implications for medical education. American Journal of Lifestyle Medicine, 14(3), 294-303. https://doi.org/10.1177/1559827619847436

Mahmoud, A. (2022). An overview of epigenetics in obesity: the role of lifestyle and therapeutic interventions. International Journal of Molecular Sciences, 23(3), 1341. https://doi.org/10.3390/ijms23031341

Maleknia, M. (2023). Dna methylation in cancer: epigenetic view of dietary and lifestyle factors. Epigenetics Insights, 16. https://doi.org/10.1177/25168657231199893

McCullough, L., Mendez, M., Miller, E., Murtha, A., Murphy, S., & Hoyo, C. (2015). Associations between prenatal physical activity, birth weight, and dna methylation at genomically imprinted domains in a multiethnic newborn cohort. Epigenetics, 10(7), 597-606. https://doi.org/10.1080/15592294.2015.1045181

Meir, A., Keller, M., Müller, L., Bernhart, S., Tsaban, G., Zelicha, H., … & Shai, I. (2021). Effects of lifestyle interventions on epigenetic signatures of liver fat: central randomized controlled trial. Liver International, 41(9), 2101-2111. https://doi.org/10.1111/liv.14916

Santaló, J. and Berdasco, M. (2022). Ethical implications of epigenetics in the era of personalized medicine. Clinical Epigenetics, 14(1). https://doi.org/10.1186/s13148-022-01263-1

Zheng, J., Alves-Wagner, A., Stanford, K., Prince, N., So, K., Mul, J., … & Goodyear, L. (2020). Maternal and paternal exercise regulate offspring metabolic health and beta cell phenotype. BMJ Open Diabetes Research & Care, 8(1), e000890. https://doi.org/10.1136/bmjdrc-2019-000890

Proposed researches

Epigenetic Modifications in Regulating Longevity: Epigenetics plays a crucial role in the regulation of gene expression and has emerged as a significant factor in understanding the biological mechanisms underlying aging and longevity (Ma et al., 2018; Molina‐Serrano et al., 2019). This proposed research aims to investigate the interplay between epigenetic modifications, lifestyle factors, and their influence on lifespan and healthspan.

Objectives: 1. Examine the specific epigenetic changes, such as DNA methylation, histone modifications, and chromatin dynamics, that occur during the aging process and their association with longevity (Tian et al., 2019; Gharipour et al., 2021). 2. Explore the impact of lifestyle interventions, including diet, exercise, and stress management, on epigenetic rejuvenation and their potential to delay or reverse the effects of aging (Huang et al., 2020; Kirfel et al., 2020). 3. Assess the role of dietary components and nutritional supplements in modulating the epigenome and their implications for promoting healthy aging (Maybury-Lewis et al., 2021; Zhang et al., 2020). 4. Evaluate the efficacy of pharmacological approaches, such as histone deacetylase inhibitors and DNA methyltransferase inhibitors, in targeting epigenetic mechanisms to combat age-related diseases and extend lifespan (Ma et al., 2018; Gangisetty et al., 2018). 5. Investigate the influence of behavioral epigenetics, including the impact of environmental factors and transgenerational epigenetic inheritance, on longevity and healthspan (Cruz et al., 2022; Martínez-Iglesias et al., 2021).

Methodology: 1. Longitudinal studies: Collect and analyze epigenomic data, including DNA methylation patterns, histone modifications, and chromatin structure, from individuals across different age groups to identify age-associated epigenetic changes (Tian et al., 2019; Gharipour et al., 2021). 2. Intervention studies: Implement lifestyle interventions, such as dietary modifications and exercise regimens, and assess their impact on the epigenome and associated health outcomes in both human and animal models (Huang et al., 2020; Kirfel et al., 2020). 3. Nutritional epigenetics: Investigate the effects of specific dietary components and supplements on epigenetic modifications and their potential to promote healthy aging (Maybury-Lewis et al., 2021; Zhang et al., 2020). 4. Pharmacological studies: Evaluate the efficacy of epigenetic-targeting drugs in reversing age-related epigenetic changes and their impact on lifespan and healthspan in preclinical and clinical settings (Ma et al., 2018; Gangisetty et al., 2018). 5. Behavioral epigenetics: Examine the influence of environmental factors, such as stress and social interactions, on the epigenome and their transgenerational effects on longevity and healthspan (Cruz et al., 2022; Martínez-Iglesias et al., 2021).

Expected Outcomes: 1. Identification of specific epigenetic signatures associated with longevity and healthy aging. 2. Elucidation of the mechanisms by which lifestyle interventions, dietary factors, and pharmacological approaches can modulate the epigenome to delay or reverse the effects of aging. 3. Insights into the role of behavioral epigenetics and transgenerational epigenetic inheritance in shaping longevity and healthspan. 4. Development of epigenetic-based biomarkers and interventions for the prevention and management of age-related diseases.  Significance: Improving the quality of life in older adults. The findings may lead to the development of personalized epigenetic-based interventions and the identification of novel therapeutic targets for age-related diseases.

Proposed expansion: Stem Cells Researches

Stem cells were discovered after the Second World War, by scientists trying to find a cure for radiation sickness. The revolution in stem cell research and therapy represents a significant advancement in the medical field, offering promising avenues for treating diseases and potentially prolonging human lifespan. Stem cells, characterized by their ability to self-renew and differentiate into various cell types, have garnered attention for their potential to regenerate damaged tissues and organs, thus addressing a wide range of health issues.

One of the key aspects of stem cell therapy is its application in regenerative medicine. According to Trounson et al., the rapid evolution of stem cell biology is paving the way for new paradigms in cell therapies, with numerous studies moving toward regulatory approval for clinical applications Trounson (2013). This shift indicates a growing recognition of the therapeutic potential of stem cells in treating conditions that currently have limited treatment options, such as neurodegenerative diseases, cardiovascular disorders, and injuries resulting from trauma.

Moreover, the interplay between stem cells and anti-aging mechanisms is crucial in understanding their role in longevity. Ullah and Sun highlight that stem cells, in conjunction with anti-aging genes, can be instrumental in delaying the aging process and improving overall health (Ullah & Sun, 2018). This suggests that interventions targeting stem cell functionality could not only treat existing diseases but also enhance the quality of life as individuals age, potentially extending lifespan. The regenerative capabilities of stem cells are further emphasized in studies that explore their role in tissue repair and maintenance. Ghasroldasht et al. discuss how stem cells can inhibit inflammation and apoptosis, stimulate angiogenesis, and differentiate into specialized cell types, making them a versatile tool in combating various diseases (Ghasroldasht et al., 2022). This regenerative potential is particularly significant in the context of chronic diseases, where tissue degeneration is a common challenge. In addition to their therapeutic applications, stem cells also play a vital role in understanding the mechanisms of aging and disease. Research by Ren et al. indicates that the decline in stem cell function over time, known as stem cell exhaustion, contributes to aging and age-related diseases (Ren et al., 2017).

By rejuvenating stem cells, it may be possible to restore their functionality and mitigate the effects of aging, thereby enhancing both healthspan and lifespan. Furthermore, the impact of lifestyle factors, such as diet, on stem cell function cannot be overlooked. Mihaylova et al. emphasize that dietary and metabolic control can significantly influence stem cell behavior and, consequently, tissue homeostasis (Mihaylova et al., 2014). This underscores the importance of integrating lifestyle interventions with stem cell therapies to maximize health benefits and longevity.

In conclusion, the stem cell revolution holds transformative potential for medicine, offering innovative solutions for disease treatment and strategies for prolonging life. By harnessing the regenerative properties of stem cells and understanding their role in aging, researchers and clinicians can develop effective therapies that not only combat diseases but also enhance the overall quality of life as individuals age.

Epigenetics and the factors that improved human quality of lifes may be the same to promote further healthier and better lifes. Further, the development of technology and further potentially our synchronisation with AI has to be balanced in terms of what they will bring to humans alongside learning and development. Amplifying empathy, incorperating balanced belief system, industry emerge and thinking of our health the same as we think of our tasks and goals, to make what yours, yours, will promote an environment of evolution and development.

References:  Ma et al. (2018) Ma et al. "Epigenetic drift of H3K27me3 in aging links glycolysis to healthy longevity in Drosophila" Elife (2018) doi:10.7554/elife.35368   Molina‐Serrano et al. (2019). Molina‐Serrano et al. "Histone Modifications as an Intersection Between Diet and Longevity" Frontiers in Genetics (2019) doi:10.3389/fgene.2019.00192  

Olshansky, S.J., Willcox, B.J., Demetrius, L. et al. Implausibility of radical life extension in humans in the twenty-first century. Nat Aging 4, 1635–1642 (2024). https://doi.org/10.1038/s43587-024-00702-3

Tian et al. (2019). Tian et al. "SIRT6 Is Responsible for More Efficient DNA Double-Strand Break Repair in Long-Lived Species" Cell (2019) doi:10.1016/j.cell.2019.03.043   Gharipour et al. (2021). Gharipour et al. "How Are Epigenetic Modifications Related to Cardiovascular Disease in Older Adults?" International Journal of Molecular Sciences (2021) doi:10.3390/ijms22189949  

(Huang et al., 2020). Huang et al. "Inhibition of histone acetyltransferase GCN5 extends lifespan in both yeast and human cell lines" Aging Cell (2020) doi:10.1111/acel.13129   (Kirfel et al., 2020). Kirfel et al. "Lysine Acetyltransferase p300/CBP Plays an Important Role in Reproduction, Embryogenesis and Longevity of the Pea Aphid Acyrthosiphon pisum" Insects (2020) doi:10.3390/insects11050265  

(Maybury-Lewis et al., 2021). Zhang et al. "The effects of early-life growth hormone intervention on tissue specific histone H3 modifications in long-lived Ames dwarf mice" Aging (2020) doi:10.18632/aging.202451  

Zhang et al. (2020). Gangisetty et al. "Impact of epigenetics in aging and age related neurodegenerative diseases" Frontiers in Bioscience-Elite (2018) doi:10.2741/4654  

(Ma et al., 2018). Cruz et al. "Characterization of Methylation Patterns Associated with Lifestyle Factors and Vitamin D Supplementation in a Healthy Elderly Cohort from Southwest Sweden" (2022) doi:10.21203/rs.3.rs-1391526/v1  

Gangisetty et al. (2018). Martínez-Iglesias et al. "Epigenetic Biomarkers as Diagnostic Tools for Neurodegenerative Disorders" International Journal of Molecular Sciences (2021) doi:10.3390/ijms23010013  

(Cruz et al., 2022). Pei "Molecular characterization and modulated expression of histone acetyltransferases during cold response of the tick Dermacentor silvarum (Acari: Ixodidae)" Parasites & Vectors (2023) doi:10.1186/s13071-023-05955-2   (Martínez-Iglesias et al., 2021). Possible Reference Candidate (Martínez-Iglesias et al., 2021) is not included as it does not support the claims made in the text.

References:

Cruz, M., Ulfenborg, B., Blomstrand, P., Faresjö, M., Ståhl, F., & Karlsson, S. (2022). Characterization of methylation patterns associated with lifestyle factors and vitamin d supplementation in a healthy elderly cohort from southwest sweden.. https://doi.org/10.21203/rs.3.rs-1391526/v1

Gangisetty, O., Cabrera, M., & Murugan, S. (2018). Impact of epigenetics in aging and age related neurodegenerative diseases. Frontiers in Bioscience-Elite, 23(8), 1445-1464. https://doi.org/10.2741/4654

Gharipour, M., Mani, A., Baghbahadorani, M., Cardoso, C., Jahanfar, S., Sarrafzadegan, N., … & Silveira, É. (2021). How are epigenetic modifications related to cardiovascular disease in older adults?. International Journal of Molecular Sciences, 22(18), 9949. https://doi.org/10.3390/ijms22189949

Huang, B., Zhong, D., An, Y., Gao, M., Zhu, S., Dang, W., … & Xie, Z. (2020). Inhibition of histone acetyltransferase gcn5 extends lifespan in both yeast and human cell lines. Aging Cell, 19(4). https://doi.org/10.1111/acel.13129

Kirfel, P., Vilcinskas, A., & Škaljac, M. (2020). Lysine acetyltransferase p300/cbp plays an important role in reproduction, embryogenesis and longevity of the pea aphid acyrthosiphon pisum. Insects, 11(5), 265. https://doi.org/10.3390/insects11050265

Ma, Z., Wang, H., Cai, Y., Wang, H., Niu, K., Wu, X., … & Liu, N. (2018). Epigenetic drift of h3k27me3 in aging links glycolysis to healthy longevity in drosophila. Elife, 7. https://doi.org/10.7554/elife.35368

Martínez-Iglesias, O., Naidoo, V., Cacabelos, N., & Cacabelos, R. (2021). Epigenetic biomarkers as diagnostic tools for neurodegenerative disorders. International Journal of Molecular Sciences, 23(1), 13. https://doi.org/10.3390/ijms23010013

Maybury-Lewis, S., Brown, A., Yeary, M., Sloutskin, A., Dhakal, S., Juven‐Gershon, T., … & Webb, A. (2021). Changing and stable chromatin accessibility supports transcriptional overhaul during neural stem cell activation and is altered with age. Aging Cell, 20(11). https://doi.org/10.1111/acel.13499

Molina‐Serrano, D., Kyriakou, D., & Kirmizis, A. (2019). Histone modifications as an intersection between diet and longevity. Frontiers in Genetics, 10. https://doi.org/10.3389/fgene.2019.00192

Tian, X., Firsanov, D., Zhang, Z., Cheng, Y., Luo, L., Tombline, G., … & Gorbunova, V. (2019). Sirt6 is responsible for more efficient dna double-strand break repair in long-lived species. Cell, 177(3), 622-638.e22. https://doi.org/10.1016/j.cell.2019.03.043

Wang, H., Cai, Y., K, N., Wu, X., Ma, H., Yang, Y., … & Liu, N. (2018). Epigenetic drift of h3k27me3 in aging links glycolysis to healthy longevity.. https://doi.org/10.1101/247726

Zhang, F., Icyuz, M., Bartke, A., & Sun, L. (2020). The effects of early-life growth hormone intervention on tissue specific histone h3 modifications in long-lived ames dwarf mice. Aging, 13(2), 1633-1648. https://doi.org/10.18632/aging.202451