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  • Erwan Goy

Deciphering the Impact of Aging on Cancer: Senescence and Immunoaging

Introduction

Cancer is a prevalent disease in our society. According to the Canadian Cancer Society, more than 40% of individuals will be affected by cancer. The high incidence of cancer can be attributed to numerous risk factors associated with its development, including alcohol consumption, tobacco, car pollution, dietary factors, viral and bacterial infections, among others. When considering the impact of such risk factors, one prominent factor stands out: aging. In fact, half of all cancer cases occur after the age of 70.

 

Researchers worldwide are actively working to understand the reasons behind this phenomenon. Here, we will be focusing on two main hypotheses: the accumulation of senescent cells and immune-aging.


Senescence's Secrets: Deciphering its complex relationship between disease and aging

 

Cellular senescence is a state where cells cease to proliferate due to various stressors. The first stressor discovered was telomere shortening. Telomeres are the protective ends of chromosomal DNA. As cells divide, they struggle to replicate their telomeres. Telomeres get shorter with every division, but when telomeres become too short, they trigger a cellular alarm pathway, resulting in senescence. Senescence can also be induced by other stressors, including UV exposure, smoking, and alcohol consumption, among others. Some studies suggest that senescent cells should normally be eliminated by the immune system, as they undergo significant changes, including the secretion of inflammatory molecules. The abnormal persistence or accumulation of senescent cells can pose health risks.

 

Research has shown that senescent cells accumulate in various organs as people age. The exact reasons for this accumulation remain unclear, but it is likely due to the combined effects of stressors that occur over time (e.g. telomere shortening), diminishing responses to physical stressors (such as decreased antioxidant defenses) that occur with age, and a decline in the immune system's ability to clear senescent cells [1].

 

Senescent cell accumulation with age raises an important question: is it beneficial or detrimental? Initially, the hypothesis was that senescence, as a process that prevents cells from proliferating, could prevent tumor growth. This theory was supported by the presence of senescent cells in pre-cancerous tumors taken from the pancreas and skin. For instance, in skin cancer, senescence in naevi (normal moles) prevent them from becoming full-blown melanomas even after the cells acquire cancer-causing mutations. When naevi become melanomas, there are no detectable senescence markers found within the tumor [2].

 

In contrast, some research suggests that senescent cell accumulation is a pro-tumorigenic process. Indeed, in mouse studies, researchers were able to selectively eliminate senescent cells. This elimination resulted in a reduction in cancer incidence [3]. This finding suggests that senescence accumulation is a pro-tumorigenic phenomenon. It is hypothesized that senescent cells can promote cancer development in three ways:


  1. by allowing pre-cancerous cells to remain dormant and inactive. Senescence is not a fool-proof barrier, and cells could eventually escape this state to become cancerous [4, 5].

  2. by producing molecules that cause inflammation, altering the cell’s environment, and supporting cancer formation and growth [6, 7].

  3. by participating in immune-aging and thereby preventing the clearance of cancer cells by the immune system (see the next part)


Immune-Aging: The aging immune system and cancer risk

 

Aging can have a significant impact on the anti-tumors activity of the immune system. The immune system plays a crucial role in identifying and destroying cancerous cells, in a process called immune surveillance. However, its effectiveness can decline with age in a process called immune-aging. This phenomenon is attributed to the progressive shrinking of the thymus gland that occurs normally with age, hematopoietic stem cell senescence, and chronic inflammation. Immune aging is characterized by [8-10]:

 

  • a decrease in the production of new immune cells, particularly T cells and B cells.

  • a chronic low-grade inflammation, called inflammaging, that becomes more common with age. This inflammation creates an environment that promotes the growth of cancer cells and hinders the immune system's ability to combat them effectively.

  • a decrease in T-cell Function: T cells are a critical component of the immune system's anti-tumor activity. Aging can lead to a decline in the function of T cells, reducing their ability to recognize and destroy cancer cells. This can result in a weakened adaptive immune response.

  • an increase in immunosuppressive cells in the body These cells can inhibit the immune system's ability to mount an effective anti-tumor response.

 

To summarize, aging impairs immune system function and notably its ability to detect and destroy cancerous cell. This allows cancer to develop.

 

Mitigating cancer risk in the aging population


Considering this data, various research groups propose different approaches to target cancer risk in the aging population. Recently, drugs known as senolytics have been developed to target senescent cells. However, using these drugs for healthy individuals raises ethical concerns due to their potential side effects. The deeper philosophical question is whether we should consider aging itself as a disease. If we, as a society, choose to target cancer as a consequence of aging like this, it would require the development of safe senolytic treatments with minimal side effects [3].

 

Addressing immune aging is another avenue. This approach involves using drugs to modify immune cells to restore immunosurveillance. Genetically modified immune cells, such as specialized CAR-T cells, may also be used. However, ethical issues similar to those related to senolytics must be considered [9].

 

A more practical approach would be to identify individuals at risk of developing cancer based on the levels of inflammatory molecules secreted by senescent cells in their blood and the characterization of their immune system. This would enable closer monitoring for cancer in elderly individuals with higher levels of inflammatory markers and signs of immune aging.


Conclusion

Aging, a natural process, is associated with various diseases, including osteoarthritis, Alzheimer's, Parkinson's, and cancer. Emerging data suggest that age-related cancers may be linked to the accumulation of senescent cells and immune aging. This opens possibilities for prevention, treatment, and diagnostic strategies in the future. Moreover, there are still grey zones surrounding some aspects of aging and their associations with cancer, such as how hormonal therapy for menopause effects the risk of breast and ovarian cancer.


References

1.  He, S. and N.E. Sharpless, Senescence in Health and Disease. Cell, 2017. 169(6): p. 1000-1011.

2.  Gray-Schopfer, V.C., et al., Cellular senescence in naevi and immortalisation in melanoma: a role for p16? Br J Cancer, 2006. 95(4): p. 496-505.

3.  Baker, D.J., et al., Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan. Nature, 2016. 530(7589): p. 184-9.

4.   Goy, E., et al., The out-of-field dose in radiation therapy induces delayed tumorigenesis by senescence evasion. Elife, 2022. 11.

5.  Gosselin, K., et al., Senescence-associated oxidative DNA damage promotes the generation of neoplastic cells. Cancer Res, 2009. 69(20): p. 7917-25.

6.  Faget, D.V., Q. Ren, and S.A. Stewart, Unmasking senescence: context-dependent effects of SASP in cancer. Nat Rev Cancer, 2019. 19(8): p. 439-453.

7.   Malaquin, N., et al., Senescent fibroblasts enhance early skin carcinogenic events via a paracrine MMP-PAR-1 axis. PLoS One, 2013. 8(5): p. e63607.

8.  Aiello, A., et al., Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention. Front Immunol, 2019. 10: p. 2247.

9.  Borgoni, S., et al., Targeting immune dysfunction in aging. Ageing Res Rev, 2021. 70: p. 101410.

10. Foster, A.D., A. Sivarapatna, and R.E. Gress, The aging immune system and its relationship with cancer. Aging health, 2011. 7(5): p. 707-718.

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