مقالات پذیرفته شده در هشتمین کنگره بین المللی زیست پزشکی
Gene therapy as a pivotal approach in Aging
Gene therapy as a pivotal approach in Aging
Kimia Sadat Esfahani,1Mehrdad Hashemi,2,*Fatemeh Sadat Kohandani,3
1. 1- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 2. 1- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran. 2- Farhikhtegan Medical Convergence sciences Research Center, Farhikhtegan Hospital Tehran Medical sciences, Islamic Azad University, Tehran, Iran. 3. 1- Department of Genetics, Faculty of Advanced Science and Technology, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran.
Introduction: Aging is a natural process characterized by the gradual deterioration of physiological functions, and it serves as a major risk factor for conditions such as neurodegenerative disorders, cardiovascular diseases, metabolic syndromes, and malignancies. The manifestations of aging, which occur at both cellular and molecular levels, are universally observed across organisms. These include reduced genomic stability, telomere attrition, mitochondrial dysfunction, epigenetic alterations, and depletion or dysfunction of stem cells.
Numerous factors contribute to the aging process, including the activation of cellular senescence pathways and the influence of genetic variations, as well as epigenetic modifications. These elements can affect the rate at which aging occurs. While some genes are linked to extended longevity, others may heighten susceptibility to age-related diseases. Epigenetic changes, such as DNA methylation and histone modifications, play a crucial role in altering gene expression patterns, thereby contributing to aging. In contrast, gene therapy offers potential for curing age-related diseases by targeting key markers of aging. Gene therapy, originally developed to address genetic disorders, involves either the introduction of new DNA into specific cells or the correction of faulty DNA.
Promising strategies to rejuvenate the body include gene and cell therapies, often in combination with pharmacological interventions. These methods aim to rejuvenate senescent cells, eliminate dysfunctional senescent cells, and inhibit signaling pathways that contribute to cellular aging.
The aim of this review study is to introduce gene therapy as a pivotal approach in aging.
Methods: A total of twenty relevant articles exploring the role of gene therapy as a pivotal approach in aging, were identified through searches on PubMed, Google Scholar databases using predefined keywords. These articles were subsequently selected for review and analysis.
Results: Studies have shown that telomerase activators (TA) can increase TERT gene expression, offering potential therapeutic benefits. For example, in a Parkinson's disease mouse model, TA-65 improved TERT expression, motor function, and autophagy. Additionally, CRISPR technology allows precise regulation of endogenous TERT expression. In most normal somatic cells, telomerase is largely inactive, whereas it becomes active in approximately 90% of cancer cells. Consequently, therapeutic strategies focus on reactivating telomerase in normal somatic cells while suppressing its activity in cancerous cells. However, these approaches require more stringent targeting mechanisms to ensure precision in therapeutic design.
Gene therapy targeting the Klotho gene presents a promising approach in anti-aging treatments. In a study by Chen et al., the CRISPR-dCas9 complex was used to activate the Klotho promoter, leading to elevated Klotho expression at both gene and protein levels in human neuronal and kidney cell lines. These findings suggest potential therapeutic applications for improving cognitive function and treating age-related demyelinating and neurodegenerative disorders.
Macip et al. demonstrated that the systemic delivery of adeno-associated viruses encoding an inducible OSK system in 124-week-old male mice extended the median remaining lifespan by 109% compared to wild-type controls. This treatment also significantly improved health parameters, including frailty scores, indicating an enhancement in both healthspan and lifespan.
Rurik et al. developed a transient antifibrotic chimeric antigen receptor (CAR) structure encoded by modified mRNA, which was delivered via CD5-targeted lipid nanoparticles (LNPs) to generate CAR T-cells in vivo. This approach successfully reduced fibrosis and improved cardiac function in a mouse model experiencing increased cardiac afterload.
Ozes et al. demonstrated the efficacy of AAV1.NT-3 gene therapy in treating sarcopenia and age-related peripheral nerve hypomyelination in 2-year-old C57BL/6 mice, a model of natural aging. Six months post-treatment, NT-3 led to significant improvements in neuromuscular function, muscle physiology, and reduced age-related changes such as kyphosis, dermatitis, and alopecia.
Conclusion: The rise in life expectancy is a global phenomenon, primarily attributed to improved sanitation, medical advancements, enhanced nutrition, and safer living environments, which are reinforced by social interactions. The aging population presents a growing societal challenge, particularly in developed nations where the elderly demographic is increasing annually. Gene therapies, particularly those targeting aging, offer promising prospects for addressing age-related diseases. However, not all genes associated with aging are suitable targets for such therapies. With the full identification of genes related to aging and increased longevity, and the personalized application of gene therapy for each individual, we will witness the opening of new doors in the field of gene therapy and lifespan extension.