Aging, Cancer, and Inflammation: The Telomerase Connection
<p>Human telomere structure and telomerase recruitment. Telomeric DNA consists of arrays of the TTAGGG telomeric repeat, forming a long region of double-stranded DNA terminating in the single-stranded G-rich overhang. Telomerase extends the length of shortened telomeres after DNA replication using TERC. TERC, telomerase RNA component; TERT, telomerase reverse transcriptase. Created with BioRender.com.</p> "> Figure 2
<p>Telomerase: The link between aging, cancer, and inflammation. This figure shows the complex interrelationships between aging, cancer, inflammation, and telomerase. It underscores the importance of telomerase in maintaining cellular integrity and its potential role in mediating both cancer risk and chronic inflammatory conditions. This visualization aids in understanding how these biological processes are interconnected and highlights the significance of telomerase as a therapeutic target in addressing age-related diseases and cancer. Created with BioRender.com.</p> ">
Abstract
:1. Introduction
2. Methodology
3. The Telomere/Telomerase Biology: Implication in Aging and Cancer
3.1. Telomerase and Aging: Insight from Age-Related Diseases and Progeroid Syndromes
3.2. Telomerase and Cancer
4. Chronic Inflammation and Telomerase Activity
The Impact of Chronic Inflammation on Telomerase Activity
- Telomerase inhibition: Proinflammatory cytokines such as IL-6 and TNF-α can inhibit telomerase activity, particularly the catalytic subunit TERT. This inhibition accelerates telomere shortening, leading to premature cellular senescence [80].
- Oxidative stress: Chronic inflammation increases oxidative stress by generating ROS. ROS directly damage telomeres, further contributing to their attrition and the aging process [33].
- Senescence and SASP: Cells with critically short telomeres often enter a state of senescence, characterized by the secretion of SASP. SASP factors perpetuate local and systemic inflammation, creating a feedback loop that exacerbates telomere dysfunction and cellular aging [81].
- Mitochondrial dysfunction: The telomere–mitochondrial axis is crucial in understanding aging processes. Telomere shortening disrupts mitochondrial function, leading to increased ROS production and further oxidative damage. Dysfunctional mitochondria exacerbate cellular aging and promote the inflammatory response [82,83].
5. Therapeutic Strategies: A Comprehensive Overview of the Key Studies and Findings
6. Conclusions and Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Modulator | Mechanism | Evidence in Animals | Evidence in Humans |
---|---|---|---|
Imetelstat (GRN163L) | Telomerase inhibitor. | Inhibited tumor growth and metastasis in mouse models of various cancers, including breast and lung cancer. | Phase II clinical trials showed partial responses and disease stabilization in patients with myelofibrosis and certain solid tumors. |
BIBR1532 | Telomerase inhibitor. | Suppressed tumor growth in xenograft models of glioblastoma and leukemia. | Preclinical studies only, no clinical trials yet. |
6-thio-2′-deoxyguanosine (6-thio-dG) | Telomerase substrate that induces telomere dysfunction. | Reduced tumor growth and improved survival in mouse models of glioblastoma and melanoma. | Preclinical studies only, showing promise for future clinical trials. |
Curcumin | Natural compound, inhibits telomerase activity. | Decreased telomerase activity and tumor growth in mouse models of prostate cancer. | Limited clinical studies suggest potential benefits, but more research is needed. |
Resveratrol | Natural compound, modulates telomerase and telomeres. | Extended lifespan and reduced tumor incidence in animal models; effects on telomerase activity are mixed. | Some clinical trials indicate potential anticancer effects, though data on telomerase modulation in humans is limited. |
RHPS4 | G-quadruplex stabilizer, inhibits telomerase. | Reduced tumor growth and telomere shortening in mouse models of melanoma and glioblastoma. | Preclinical studies only, showing potential for clinical development. |
TA-65 | Telomerase activator, derived from Astragalus membranaceus. | Improved health span and telomere length in aged mice; data on cancer effects are mixed. | Some human studies suggest telomere lengthening and improved markers of aging, but data on cancer effects is limited and controversial. |
Tert promoter mutations | Genetic modifications to increase telomerase expression. | Extended lifespan and delayed cancer onset in some transgenic mouse models; increased cancer risk in others. | Observed in various cancers; some patients show increased telomerase activity, contributing to tumor progression. |
GRNVAC1 | Telomerase-based dendritic cell vaccine. | Induced immune response and reduced tumor burden in mouse models of prostate cancer. | Phase II clinical trials showed immune activation and potential clinical benefits in patients with acute myeloid leukemia. |
Cycloastragenol | Telomerase activator, another Astragalus extract. | Improved telomere length and reduced oxidative stress in aged mice; effects on cancer are unclear. | Some small human studies indicate telomere lengthening, but more research is needed to determine cancer-related effects. |
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Boccardi, V.; Marano, L. Aging, Cancer, and Inflammation: The Telomerase Connection. Int. J. Mol. Sci. 2024, 25, 8542. https://doi.org/10.3390/ijms25158542
Boccardi V, Marano L. Aging, Cancer, and Inflammation: The Telomerase Connection. International Journal of Molecular Sciences. 2024; 25(15):8542. https://doi.org/10.3390/ijms25158542
Chicago/Turabian StyleBoccardi, Virginia, and Luigi Marano. 2024. "Aging, Cancer, and Inflammation: The Telomerase Connection" International Journal of Molecular Sciences 25, no. 15: 8542. https://doi.org/10.3390/ijms25158542