Cellular Aging and Cancer: The Role of Senescent Cells and Cell-Free Chromatin Particles

Introduction

Cancer incidence increases dramatically with age, with approximately 60% of all cancers diagnosed in individuals aged 65 and older. This correlation can be explained by two significant biological phenomena during aging: the accumulation of senescent cells and the buildup of cell-free chromatin particles in the extracellular environment. Understanding these mechanisms provides valuable insights into cancer development across the lifespan and offers potential targets for therapeutic intervention.

Senescent Cell Accumulation in Aging

Senescent cells are cells that have permanently stopped dividing but remain metabolically active. With advancing age, these cells accumulate in various tissues and organs throughout the body. This accumulation contributes to cancer development through several mechanisms:

1. Senescent cells develop a complex secretory phenotype known as the Senescence-Associated Secretory Phenotype (SASP), which includes pro-inflammatory cytokines, chemokines, growth factors, and matrix-remodeling enzymes. These secretions create a chronic inflammatory environment that promotes cancer initiation and progression.
2. The inflammatory factors released by senescent cells can damage DNA in neighboring cells, potentially causing mutations that lead to malignant transformation.
3. Growth factors released as part of the SASP can stimulate the proliferation of pre-malignant cells that have already acquired oncogenic mutations.
4. Senescent cells can impair immune surveillance mechanisms that would normally identify and eliminate pre-cancerous cells, allowing them to escape detection and continue proliferating.

Cell-Free Chromatin Accumulation in Aging

Cell-free chromatin (cfCh) particles consist of fragments of DNA and associated proteins released from dying cells. The age-related increase in cfCh in the extracellular environment contributes to cancer development through:

1. Direct genomic integration: These chromatin fragments can be taken up by healthy cells and integrate into their genomes, potentially causing mutations and chromosomal instability.
2. Inflammatory responses: cfCh particles activate pattern recognition receptors, such as Toll-like receptors, and stimulate inflammatory pathways, creating a tumor-promoting microenvironment.
3. Epigenetic alterations: When incorporated into recipient cells, cfCh can alter gene expression patterns, potentially activating oncogenes or silencing tumor suppressor genes.
4. DNA damage response activation: The presence of extracellular DNA fragments triggers cellular stress responses that, if chronically activated, can lead to genomic instability.

Synergistic Effects in Older Adults

The simultaneous presence of senescent cells and cfCh particles creates a particularly dangerous environment for cancer development:

1. Senescent cells release cfCh particles through various cell death mechanisms, creating a positive feedback loop that amplifies tissue damage.
2. The inflammatory environment created by senescent cells enhances the uptake of cfCh by neighboring cells, increasing the risk of genomic instability.
3. Both processes contribute to a decline in immune function with age, further reducing the body’s ability to eliminate pre-cancerous cells.
4. Together, these changes create a tissue microenvironment that facilitates the acquisition of multiple hallmarks of cancer, including sustained proliferative signaling, evasion of growth suppressors, and genomic instability.

Accelerated Cellular Aging in Young Cancer Patients

While cancer predominantly affects older adults, the same mechanisms may explain cancer development in younger individuals when cellular aging processes are accelerated. Evidence suggests that some young people, including children, may “age” cellularly faster than their peers, putting them at increased risk of cancer development despite their young chronological age.

Molecular Evidence for Accelerated Aging in Young Cancer Patients

Several biological mechanisms support this hypothesis:

1. Genetic disorders affecting DNA repair pathways can significantly accelerate cellular senescence. Conditions such as Werner syndrome, Bloom syndrome, and ataxia-telangiectasia cause defects in DNA damage response and repair mechanisms, leading to premature senescence and dramatically increased cancer risk at young ages. For example, individuals with Li-Fraumeni syndrome, caused by germline mutations in the TP53 tumor suppressor gene, have a lifetime cancer risk of nearly 100%, with many developing malignancies during childhood.
2. Epigenetic dysregulation can alter the rate of senescent cell accumulation. Studies have identified distinct “epigenetic clocks” that measure biological age based on DNA methylation patterns. Research has demonstrated that cancer tissues frequently exhibit accelerated aging according to these epigenetic markers, even in pediatric patients.
3. Environmental exposures and lifestyle factors can accelerate senescence accumulation. Children exposed to certain chemotherapeutic agents, radiation, or environmental carcinogens experience significant increases in senescent cell burden. Studies have demonstrated that childhood cancer survivors treated with certain chemotherapeutic agents showed markers of cellular senescence comparable to those normally seen in much older individuals.

Cell-Free Chromatin and Genomic Instability in Young Cancer Patients

The role of cell-free chromatin particles in pediatric and young adult cancers is equally significant:

1. Children with certain cancer predisposition syndromes show elevated levels of circulating cell-free DNA with distinct fragmentation patterns, suggesting increased genomic instability and cellular turnover. The presence of these chromatin fragments can exacerbate DNA damage in otherwise healthy cells.
2. Inflammatory conditions, common in certain pediatric populations, can increase the release of cell-free chromatin particles. Chronic inflammation has been linked to increased cellular turnover and higher levels of circulating DNA fragments, creating a tumor-promoting environment even in young individuals.

Therapeutic Implications

Understanding the role of senescent cells and cell-free chromatin in cancer development across the lifespan has important implications for treatment and prevention:

1. Senolytic drugs that selectively eliminate senescent cells have shown promise in preclinical studies for reducing cancer risk and improving outcomes.
2. Interventions that enhance the clearance of cell-free chromatin from the circulation could potentially reduce the genomic damage caused by these particles.
3. Biological age assessment may prove more valuable than chronological age in determining cancer risk and surveillance protocols. Screening for markers of cellular senescence and increased cell-free chromatin could potentially identify individuals with elevated cancer risk before disease development.
4. Targeting age-related molecular mechanisms may offer novel therapeutic approaches for adult and pediatric cancers. Early research on senolytic compounds and interventions that enhance the clearance of cell-free DNA shows promise in reducing cancer-promoting tissue environments.

Conclusion

The accumulation of senescent cells and cell-free chromatin particles with age provides a compelling explanation for the increased cancer risk observed in older adults. Moreover, accelerated accumulation of these factors can explain cancer development in younger individuals, highlighting the importance of biological rather than chronological age in determining cancer risk. These mechanisms offer potential targets for interventions to reduce cancer risk across the lifespan, from children to older adults.

References

1. Acosta JC, Banito A, Wuestefeld T, Georgilis A, Janich P, Morton JP, Athineos D, Kang TW, Lasitschka F, Andrulis M, Pascual G, Morris KJ, Khan S, Jin H, Dharmalingam G, Snijders AP, Carroll T, Capper D, Pritchard C, Inman GJ, Longerich T, Sansom OJ, Benitah SA, Zender L, Gil J. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat Cell Biol. 2013;15(8):978-990.
2. Baker DJ, Wijshake T, Tchkonia T, LeBrasseur NK, Childs BG, van de Sluis B, Kirkland JL, van Deursen JM. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature. 2011;479(7372):232-236.
3. Borghesan M, Fafián-Labora J, Eleftheriadou O, Carpintero-Fernández P, Paez-Ribes M, Vizcay-Barrena G, Swisa A, Kolodkin-Gal D, Ximénez-Embún P, Lowe R, Martín-Martín B, Peinado H, Muñoz J, Fleck RA, Dor Y, Ben-Porath I, Vossenkamper A, Muñoz-Espin D, O’Loghlen A. Small Extracellular Vesicles Are Key Regulators of Non-cell Autonomous Intercellular Communication in Senescence via the Interferon Protein IFITM3. Cell Rep. 2019;27(13):3956-3971.e6.
4. Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183-192.
5. Coppé JP, Desprez PY, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol. 2010;5:99-118.
6. Demaria M, O’Leary MN, Chang J, Shao L, Liu S, Alimirah F, Koenig K, Le C, Mitin N, Deal AM, Alston S, Academia EC, Kilmarx S, Valdovinos A, Wang B, de Bruin A, Kennedy BK, Melov S, Zhou D, Sharpless NE, Muss H, Campisi J. Cellular Senescence Promotes Adverse Effects of Chemotherapy and Cancer Relapse. Cancer Discov. 2017;7(2):165-176.
7. Dou Z, Ghosh K, Vizioli MG, Zhu J, Sen P, Wangensteen KJ, Simithy J, Lan Y, Lin Y, Zhou Z, Capell BC, Xu C, Xu M, Kieckhaefer JE, Jiang T, Shoshkes-Carmel M, Tanim KMAA, Barber GN, Seykora JT, Millar SE, Kaestner KH, Garcia BA, Adams PD, Berger SL. Cytoplasmic chromatin triggers inflammation in senescence and cancer. Nature. 2017;550(7676):402-406.
8. Faget DV, Ren Q, Stewart SA. Unmasking senescence: context-dependent effects of SASP in cancer. Nat Rev Cancer. 2019;19(8):439-453.
9. García-Olmo DC, Domínguez C, García-Arranz M, Anker P, Stroun M, García-Verdugo JM, García-Olmo D. Cell-free nucleic acids circulating in the plasma of colorectal cancer patients induce the oncogenic transformation of susceptible cultured cells. Cancer Res. 2010;70(2):560-567.
10. Hari P, Millar FR, Tarrats N, Birch J, Quintanilla A, Rink CJ, Fernández-Duran I, Muir M, Finch AJ, Brunton VG, Passos JF, Morton JP, Boulter L, Acosta JC. The innate immune sensor Toll-like receptor 2 controls the senescence-associated secretory phenotype. Sci Adv. 2019;5(6):eaaw0254.
11. He S, Sharpless NE. Senescence in Health and Disease. Cell. 2017;169(6):1000-1011.
12. Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of Cellular Senescence. Trends Cell Biol. 2018;28(6):436-453.
13. Mittra I, Khare NK, Raghuram GV, Chaubal R, Khambatti F, Gupta D, Gaikwad A, Prasannan P, Singh A, Iyer A, Singh A, Upadhyay P, Nair NK, Mishra PK, Dutt A. Circulating nucleic acids damage DNA of healthy cells by integrating into their genomes. J Biosci. 2015;40(1):91-111.
14. Paludan SR, Bowie AG. Immune sensing of DNA. Immunity. 2013;38(5):870-880.
15. Rodier F, Coppé JP, Patil CK, Hoeijmakers WA, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973-979.
16. Xu M, Pirtskhalava T, Farr JN, Weigand BM, Palmer AK, Weivoda MM, Inman CL, Ogrodnik MB, Hachfeld CM, Fraser DG, Onken JL, Johnson KO, Verzosa GC, Langhi LGP, Weigl M, Giorgadze N, LeBrasseur NK, Miller JD, Jurk D, Singh RJ, Allison DB, Ejima K, Hubbard GB, Ikeno Y, Cubro H, Garovic VD, Hou X, Weroha SJ, Robbins PD, Niedernhofer LJ, Khosla S, Tchkonia T, Kirkland JL. Senolytics improve physical function and increase lifespan in old age. Nat Med. 2018;24(8):1246-1256.
17. Zheng X, Turkowski K, Mora J, Brüne B, Seeger W, Weigert A, Savai R. Redirecting tumor-associated macrophages to become tumoricidal effectors as a novel strategy for cancer therapy. Oncotarget. 2017;8(29):48436-48452.
18. Zitvogel L, Kepp O, Kroemer G. Decoding cell death signals in inflammation and immunity. Cell. 2010;140(6):798-804.