Cancer and Aging: Two Tightly Interconnected Biological Processes

Abstract

Age is one of the main risk factors of cancer; several biological changes linked with the aging process can explain this. As our population is progressively aging, the proportion of older patients with cancer is increasing significantly. Due to the heterogeneity of general health and functional status amongst older persons, treatment of cancer is a major challenge in this vulnerable population. Older patients often experience more side effects of anticancer treatments. Over-treatment should be avoided to ensure an optimal quality of life. On the other hand, under-treatment due to fear of toxicity is a frequent problem and can lead to an increased risk of relapse and worse survival. There is a delicate balance between benefits of therapy and risk of toxicity. Robust biomarkers that reflect the body's biological age may aid in outlining optimal individual treatment regimens for older patients with cancer. In particular, the impact of age on systemic immunity and the tumor immune infiltrate should be considered, given the expanding role of immunotherapy in cancer treatment. In this review, we summarize current knowledge concerning the mechanistic connections between aging and cancer, as well as aging biomarkers that could be helpful in the field of geriatric oncology.

Keywords: aging; biomarkers; cancer.

Figure 1

Simple overview of the DNA damage response after oxidative DNA damage. Double strand breaks recruit ataxia-telangictasia-mutated (ATM), whereas single strand breaks induce ataxia-telangictasia-Rad3-related (ATR). DNA damage response mediators and downstream kinase can be activated whereby either DNA repair, apoptosis or cell cycle arrest will occur.

Figure 2

Pathways of cellular senescence. Due to cellular stressors like telomere shortening, DNA damage, oxidative stress and the expression of oncogenes, senescence genes are induced. The TP53 gene encodes for P53, which induces P21, a cyclin dependent kinase inhibitor (CDK) blocking CDK4/6. As a result, phosphorylation of the retinoblastoma protein (pRB) is hindered. Consequently, the cell cannot enter the S-phase and the cell cycle is arrested in the G1 phase. The INK4a/ARF locus encodes for P14^ARF and P16^INK4a protein. P14^ARF is a regulator of P53 activity: by binding mouse double minute 2 homolog (MDM2), degradation of p53 is avoided. Like P53, P16^INK4a represses CDK4/6 by which pRB is not phosphorylated and cell cycle progression is prohibited. Figure adapted from [32].

Figure 3

Schematic overview of antitumor protection by cellular senescence. Damaged cells can become apoptotic, enter the state of senescence (antiproliferative responses) or continue to replicate (expansion). When the latter occurs, a lesion may form where cells, again, can become apoptotic or enter the state of senescence. If suitable defense mechanisms are absent or fail, the lesion can further expand and by gaining additional mutations, a cancerous lesion (tumor) may be formed. Moreover, senescent cells still can escape this state and become cancerous as well. Normal cells are indicated in green, damaged cells in yellow, cancer cells in red, senescent cells in blue, and apoptotic cells in grey. Reprinted with permission from ref. [33]. Copyright 2021 American Pharmaceutical Association.

Figure 4

Overview of the important SASP functions. SASP components induce wound healing, tissue remodeling and recruit immune cells. Protumor effects of the SASP are tumor cell invasion and/or migration, stimulation of vessel formation, induction of cell proliferation, and the development of an inflammatory environment. Different SASP factors establish autocrine and paracrine senescence. Figure adapted from [32].

Figure 5

Overview of the age-related changes in the innate immune system, including neutrophils, monocytes, NK-cells, dendritic cells, and adaptive immune system with the cytotoxic CD8⁺ T-cells (most affected by aging), CD4⁺ T-helper cells, Tregs, and B-cells.

Figure 6

Schematic overview of strong interconnection between aging and cancer. The discussed biomarkers of aging are summarized as well as the clinical symptoms of frailty. The aging process and cancer share several biological processes impacting oncological decision making. However, treatment choices, toxicity and tolerability and treatment efficacy are highly influenced by age and more importantly frailty status. Taking all this together, age and frailty have an immense impact on the risk of developing cancer, cancer biology, prognosis, and therapy choices and thus the outcome for older patients with cancer.