Cellular aging, otherwise referred to as cell senescence, occurs when cells remain in a constant and terminal state of growth arrest that prevents their proliferation despite optimal growth conditions.1
Aging results from the gradual loss of cellular information, primarily in the form of epigenetic information, leading to the erosion of cellular identity.”
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Understanding Cellular Aging
Existing research suggests that cellular aging protects tissues against damage and tumorgenesis, which extends the viability of these cells through several possible biological mechanisms.
One possible stressor that may induce cell senescence is nuclear DNA damage, primarily in the form of DNA double-strand breaks (DSBs) that activate the DNA damage response (DDR) pathway. Persistent DNA damage can lead to prolonged DDR signaling that ultimately results in cellular senescence.1
Telomeres are present at the end of chromosomal DNA and protect this genetic material from nucleolytic degradation and unnecessary recombination. However, in the absence of these protective mechanisms, telomeres shorten with each subsequent round of DNA replication.
Telomere shortening leads to the loss of telomere-capping factors and other protective structures, which induces a DDR that closely resembles this response to DNA DSBs.
Senescence-associated secretory phenotype (SASP) is activated by transcriptional processes that induce the release of cytokines, chemokines, growth factors, and extracellular matrix (ECM) proteases like matrix metalloproteinases (MMPS), serine/cysteine proteinase inhibitors (SERPINs), and tissue inhibitors of metalloproteinases (TIMPs). SASP activity can further contribute to senescence, with almost all SASPs comprising interleukin-6 (IL-6), IL8, and monocyte chemoattractant protein 1 (MCP1).1
Increased oxidative stress can lead to the accumulation of dysfunctional mitochondria, which leads to increased mitochondrial mass, changes in mitochondrial membrane potential, and altered mitochondrial morphology.
In fact, several studies have described the mitochondrial dysfunction-associated senescence (MiDAS) phenotype, which has been implicated in altered cellular metabolism observed in cell aging.
Cellular senescence can lead to significant epigenome changes, including reduced global heterochromatin and DNA hypomethylation, site-specific DNA hypermethylation, altered histone modification, and the dysregulation of non-coding ribonucleic acid (ncRNA) expression3.
In addition to cell aging, these epigenetic modifications can lead to genomic instability, telomere shortening, loss of proteostasis, and mitochondrial dysfunction.
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Current Strategies for Reversing Cellular Aging
Several studies have investigated how different genetic interventions can be used to maintain telomere length and/or modulate telomerase activity to delay the effects of cellular aging.
Likewise, numerous therapeutic strategies, including telomerase activators like TA-65 and cycloastragenol (CAG), may restore telomerase activity to combat the impact of cell senescence.2
Senolytic agents target senescent cells for their elimination. To date, several drugs have demonstrated their senolytic activity, some of which include ABT-737 and ABT-263, both of which inhibit the activity of the anti-apoptotic protein BCL-2 to induce apoptosis of senescent cells.1
Tyrosine kinase (TK) inhibitors like dasatinib, as well as histone deactylases (HDAC) inhibitors, also exhibit senolytic activity by initiating the death of certain senescent cell types.
Both complete and partial epigenetic reprogramming have also been proposed as an approach to mitigate the effects of anti-aging. Complete reprogramming refers to processes that convert somatic cells into pluripotent stem cells (iPSCs) with self-renewal capabilities and the ability to differentiate into different cell types; however, this approach appears better suited for regenerative medicine applications rather than anti-aging strategies.3
Comparatively, partial reprogramming allows cells to retain their original phenotype while simultaneously reversing the effects of aging. For example, cells can be rejuvenated by increasing the expression of Yamanaka factors, which consist of Oct4, Sox2, Klf4, and cMyc3.
What is Cell Biology?
Challenges and Ethical Considerations
As the age of the elderly population throughout the world continues to increase, the prevalence of age-related diseases like neurodegenerative, cardiovascular, and metabolic conditions also rises. Thus, there is precedent to investigate potential therapeutic approaches that can slow down the rate of cellular aging, thereby increasing the lifespan of people.
In addition to providing these individuals with more years in which to live healthy and fulfilling lives, there are also numerous economic advantages associated with a healthy aging population. For example, current estimates suggest that slowing down aging by one year is equivalent to $38 trillion USD, with an additional 10 healthy years valued at over $367 trillion USD.3
Despite these advantages, anti-aging therapies raise several ethical and social concerns. Thus, it is crucial to devise appropriate regulations that consider cultural, social, and moral factors to prior to conducting any research on potential longevity interventions.
If aging is an integral part of the human experience, intervening in this process may be viewed as altering the fundamental nature of what it means to be human.”
Currently, the growing global population is increasing stress on the environment by depleting resources and straining modern infrastructure systems.
Thus, a dichotomy exists between ensuring equitable access to these interventions while also avoiding overpopulation, and this should be carefully deliberated prior to the development of anti-aging therapeutics.
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Future Prospects and Conclusions
Cellular aging is the result of highly complex processes that likely vary based on the cell type, as well as the type and duration of exposure to stimuli that induce senescence.
The likelihood of identifying a universal marker of senescence is not promising; however, the identification of specific biomarkers that may differentiate between different senescent phenotypes may support the development of targeted therapeutics that can mitigate the effects of cellular aging.
Single-cell transcriptomics and proteomic studies, for example, have the potential to distinguish between different subtypes of senescent cells.
References
- Di Micco, R., Krizhanovksy, V., Baker, D., & d’Adda di Fagagna, F. (2021). Cellular senescence in ageing: from mechanisms to therapeutic opportunities. Nature Reviews Molecular Cell Biology 22; 75-95. doi:10.1038/s41580-020-00314-w.
- Schellnegger, M., Hofmann, E., Carnieletto, M., & Kamolz, L. (2024). Unlocking longevity: the role of telomeres and its targeting interventions. Frontiers in Aging 5. doi:10.3389/fragi.2024.1339317.
- Pereira, B., Correia, F. P., Alves, I. A., et al. (2024). Epigenetic reprogramming as a key to reverse ageing and increase longevity. Ageing Research Reviews 95. doi:10.1016/j.arr.2024.102204.
Further Reading