Aging and Cancer | The Scientist Magazine®

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Is Cancer Age Related?

It is now widely established that cancer and aging are intrinsically linked;1 age is one of the most significant risk factors for most chronic diseases, including cancer.2 Aging cells and tissues exhibit low-grade, chronic inflammation profiles, a phenomenon sometimes referred to by scientists as inflammaging.3 The majority of age-related diseases are inflammatory in origin.4

People over the age of 65 make up 60 percent of new cancer diagnoses and 70 percent of cancer deaths.5 As advances in medicine and healthcare maximize human life expectancy and the elderly population continues to grow, cancer rates are predicted to increase accordingly.5

How Does Aging Increase Cancer Risk?

There are several key factors that underpin both aging and cancer, including but not limited to cellular damage, cellular senescence, and reduced immune function.

Table 1: Age-related factors and how they contribute to cancer

Age-related factor or pathway

Effects contributing to cancer onset

Accumulation of cellular damage and oxidative stress

  •       DNA damage
  •       Genomic instability
  •       Compromised DNA repair
  •       DNA misrepair 

Cellular senescence

Senescence-associated secretory phenotype (SASP) leads to the production of

  •      Inflammatory cytokines
  •      Chemokines
  •      Growth factors
  •      Proteases 

Decline in immune function (immunosenescence)

  •       Impaired production of new immune cells
  •       Decrease in circulating B cells
  •       Decrease in naïve T cell numbers
  •       Transition of naïve T cells to memory T cells
  •       Accumulation of terminally differentiated CD8+ effector T cells
  •       Remodeling of natural killer cell populations
a DNA double helix with damaged sections

As people age, cells accumulate DNA damage that can trigger the onset of cancer.

RASI BHADRAMANI

Cellular damage 

As people age, cells accumulate significant damage, which is a major contributor to aging and disease. Much of this damage is caused by a lifetime of exposure to reactive oxygen species (ROS) and other free radicals, ultraviolet radiation, and chemicals, which results in oxidative stress.1 This causes genomic instability and DNA damage, including single-stranded and double-stranded breaks in the double helix, point mutations, translocations, and large-scale chromosomal rearrangements, known as chromothripsis.6

When this type of damage occurs, the DNA damage response (DDR) is activated so that cells can attempt to repair the broken DNA and prevent carcinogenesis.7 However, if the mutations occur in genes involved in the DDR pathway, a cell’s ability to repair the damage will be compromised.8 Mutations in DDR genes are common in cancer and cause further genomic instability that support tumor growth and metastasis.8 DNA misrepair can also trigger the onset of cancer.7

Cellular senescence

If the cell cannot repair DNA damage, one of two possible pathways will be activated: apoptosis or senescence, the latter of which has been established as a key contributor to the process of aging.1 Cellular senescence permanently arrests the cell cycle, preventing cells with DNA damage from proliferating, and aging tissues exhibit an accumulation of senescent cells.6 However, some cells are able to evade or bypass senescence and can go on to initiate tumorigenesis.1

Despite being unable to proliferate, senescent cells remain metabolically active, secreting substances that promote cancer onset.9 This is termed the senescence-associated secretory phenotype (SASP), and involves proinflammatory cytokines and chemokines, proteases, and growth factors.9 SASP impairs tissue homeostasis and is thought to contribute significantly to aging.10 Scientists are currently studying cellular senescence and SASP in an effort to create regenerative therapies.10 

Reduced immune function

Aging leads to a reduction in the renewal of hematopoietic stem cells (HSCs) from bone marrow; because HSCs give rise to immune cells, this prevents new immune cells from forming.11 As such, aging is accompanied by a progressive decline in immune function called immunosenescence,12 which is highly interconnected with inflammaging.1 Immunosenescence impairs the ability of the immune system to mount an effective response against tumors.12

Immunosenescence has a range of consequences for both adaptive and innate immune cells that are involved in tumor recognition and killing.11 This includes a decrease in naïve T cell numbers and associated T cell dysfunction, the phenotypic transition of naïve T cells to memory T cells, and the accumulation of terminally differentiated CD8+ effector T cells,12 as well as a decrease in the number of circulating memory B cells11 and remodeling of natural killer cell populations.13 

 Infographic depicting age-related factors that can lead to cancer. The example centers around a cell experiencing oxidative stress that undergoes DNA damage. If the DNA is misrepaired, the cell can undergo apoptosis, become cancerous, or become senescent. Senescent cells can express the senescence-associated phenotype (SASP), where they secrete substance such as pro-inflammatory cytokines, proteases, and growth factors that can turn cells cancerous.

Cellular damage, senescence, and reduced immune function can contribute to cancer formation as people age.

The Scientist

What Are the Most Common Types of Age-Related Cancers?

While aging increases the risk of almost all cancers, some types are more common in the elderly. In a global 2018 study of the oldest adults, defined as individuals aged 80 years and over, scientists estimated global cancer incidence rates.14 In female participants of this age range, breast, lung, and colon cancers were the most common, while in male participants prostate, lung, and colon cancers were the most common.14 

Age-Related Cancer Screening

Despite the aging population making up a significant portion of cancer diagnoses, guidelines for different types of cancer frequently recommend that screening should cease at a particular age. For example, cervical cancer screening guidelines suggest individuals should stop testing themselves at age 65, yet individuals in this age group make up 20 percent of new cervical cancer diagnoses.15 Clinicians suggest that current guidelines do not adequately reflect the continual increase of elderly people in the population, and they are recommending a more conservative approach to cancer prevention in the elderly.15

Cancer Treatment in the Elderly and Biomarkers of Aging

Elderly cancer patients are more likely to have preexisting medical conditions or comorbidities at the time of diagnosis, which creates a variety of treatment challenges.16 Immunosenescence in the elderly also means that they are likely to respond differently to certain treatments, like immunotherapies, than younger patients, and they also experience more frequent cancer treatment side effects, often leading to under-treatment.1 These considerations are complicated by the fact that the aging population is currently underrepresented in clinical trials for cancer therapies.1

Scientists suggest that the identification and validation of more robust biomarkers that accurately reflect a person’s biological age would allow clinicians to design more optimal and individualized treatment regimens for cancer, rather than relying on chronological age to decide treatment options.1

These potential biomarkers include many factors that are also associated with inflammaging, immunosenescence, and cancer, such as1

  • Gene expression changes
  • Mutations, such as single nucleotide polymorphisms
  • DNA methylation changes
  • Telomere attrition
  • Oxidative stress
  • MicroRNA expression
  • Abnormal proteostasis
  • Inflammation markers
  • Immune cell subpopulation changes
  • Aberrant insulin signaling
  • Microbiome changes
  • Cellular senescence markers
  • Altered circadian rhythms 

Studying cancer in the elderly population is crucial for its adequate prevention and treatment, particularly as human populations continue to age.17 As scientists continue to unravel the complex relationship between aging and cancer, they will gain a better understanding of the molecular mechanisms underpinning these conditions, enabling more adequate preventative screening and enhanced therapeutic outcomes.

References

  1. Berben L, et al. Cancer and aging: two tightly interconnected biological processes. Cancers (Basel). 2021;13(6).

  2. Rae MJ, et al. The demographic and biomedical case for late-life interventions in aging. Sci Transl Med. 2010;2(40):40cm21-40cm21. 

  3. Franceschi C, et al. Inflamm-aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci. 2000;908(1):244-254. 

  4. Franceschi C, Campisi J. Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases. Journals Gerontol Ser A. 2014;69(Suppl_1):S4-S9. 

  5. Berger NA, et al. Cancer in the elderly. Trans Am Clin Climatol Assoc. 2006;117:146-147.

  6. López-Otín C, et al. The hallmarks of aging. Cell. 2013;153(6):1194-1217. 

  7. Valko M, et al. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem. 2004;266(1):37-56. 

  8. Groelly FJ, et al. Targeting DNA damage response pathways in cancer. Nat Rev Cancer. 2023;23(2):78-94. 

  9. Campisi J. Aging, cellular senescence, and cancer. Annu Rev Physiol. 2013;75:685-705. 

  10. Baar MP, et al. Targeted apoptosis of senescent cells restores tissue homeostasis in response to chemotoxicity and aging. Cell. 2017;169(1):132-147.e16. 

  11. Hakim FT, et al. Aging, immunity and cancer. Curr Opin Immunol. 2004;16(2):151-156. 

  12. Foster AD, et al. The aging immune system and its relationship with cancer. Aging health. 2011;7(5):707-718. 

  13. Gayoso I, et al. Immunosenescence of human natural killer cells. J Innate Immun. 2011;3(4):337-343. 

  14. Pilleron S, et al. Estimated global cancer incidence in the oldest adults in 2018 and projections to 2050. Int J Cancer. 2021;148(3):601-608. 

  15. Dilley S, et al. It’s time to re-evaluate cervical Cancer screening after age 65. Gynecol Oncol. 2021;162(1):200-202. 

  16. Yancik R. Cancer burden in the aged. Cancer. 1997;80(7):1273-1283.

  17. The importance of aging in cancer research. Nat Aging. 2022;2(5):365-366. 

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