Date Published: October 1, 2017
Publisher: JKL International LLC
Author(s): Adar Zinger, William C Cho, Arie Ben-Yehuda.
Aging and cancer are highly correlated biological phenomena. Various cellular processes such as DNA damage responses and cellular senescence that serve as tumor suppressing mechanisms throughout life result in degenerative changes and contribute to the aging phenotype. In turn, aging is considered a pro-tumorigenic state, and constitutes the single most important risk factor for cancer development. However, the causative relations between aging and cancer is not straight forward, as these processes carry contradictory hallmarks; While aging is characterized by tissue degeneration and organ loss of function, cancer is a state of sustained cellular proliferation and gain of new functions. Here, we review the molecular and cellular pathways that stand in the base of aging related cancer. Specifically, we deal with the inflammatory perspective that link these two processes, and suggest possible molecular targets that may be exploited to modify their courses.
Age is the single most significant risk factor for cancer development, with the majority of cancer cases being diagnosed after the age of 65 . The most common cancer types are prostate cancer in men, breast cancer in women, followed by lung and colorectal cancer in both sexes. When comparing the probability to develop invasive cancer before the age of 50 and after the age of 70, a dramatic 3.5, 36, 28 and 12 fold increase is demonstrated in breast, prostate, lung and colorectal cancer respectively . Aging is a biological process that occurs in virtually all organisms, and is characterize by a progressive organ loss of function and decline in tissue renewal capacity [3, 4]. This stands in striking contrast to the unlimited proliferation, resistance to apoptosis and gain of new, albeit aberrant, functions that are among the hallmarks of cancer [5, 6]. Advances in the research of both cancer and aging have started to decipher this inherent dichotomy, and shed some light on the common molecular and cellular pathways of these supposedly contradictory processes.
The key event that leads to cancer initiation and progression is DNA damage, which results from constant attacks by genotoxic agents throughout life. These insults might result in genome instability and mutation accumulation [23, 24]. The damaging agents may be exogenous, e.g. environmental exposure to UV light , ionizing radiation  or genotoxic chemicals . They may also be endogenous factors including reactive oxygen species (ROS), which are byproduct of multiple metabolic cellular processes , as well as a result of flaws in the cellular DNA replication machinery  or telomere dysfunction . There are various types of DNA damage, including-single strand breaks, double-strand breaks, intrastrand and interstrand crosslinking, which differ in their causative agents and in the cellular response they initiate to repair the damage .
Cellular senescence is defined as an irreversible arrest of cell proliferation. It was first described in 1961 by Hayflick and Moorhead who demonstrated that non-transformed tissue culture cells can only divide a limited number of times . Further in vitro studies showed an inverse proportion between the maximal number of cell divisions, and the age of the cell’s donor . This phenomenon, termed replicative senescence, is attributed to telomeres attrition which triggers continuous DNA damage response and cell cycle arrest . Later studies showed that not only repeated replication, but also other stressors, such as ROS accumulation , persistent oncogene activation  and chromatin modifications  can enter the cell into a senescent state. These different stressors converge into activation of two main tumor suppressor signaling pathways: p53/p21 and p16INK4a/pRB, which results in growth arrest, and in case of persistent stimuli leads to senescence .
The bacterial population of the gut microbiome outnumbers human cell by approximately 10 fold , and is sometimes referred to as the ’forgotten organ’ due to its increasingly recognized role in multiple physiological and pathological processes. Over the last decade, it was shown to have a pivotal function not only in the development of local intestinal pathologies such as inflammatory bowel disease, but also in systemic phenomena such as obesity, diabetes, cancer and various neurologic and psychiatric diseases [152-154]. The intestinal mucosa which includes epithelial cells, gut-associated lymphoid tissue (GALT) and overlying mucus layer, constitutes a mechanical, biochemical and immunological barrier between the microbiome and its host . Barrier dysfunction results in altered interaction between commensal bacteria and the host, and thus contributes to the so-called ’sterile’ inflammation that accompanies many of the above-mentioned pathologies.
MicroRNAs (miRs) are small non- coding RNAs that play a key role in the post-transcriptional regulation of many genes. It is estimated that more than 50% of human protein coding genes are regulated by miRs. Having a relatively low binding specificity, a single miR can target dozens of different genes, which place them as master regulators of multiple signaling pathways [165-167]. MiRs activity goes beyond the specific cell in which they are expressed. They can be transferred to adjacent cells via gap junction. They also reach distant cells in a non-contact dependant manner via microvesicles that are released to the microenvironment or to the blood stream. These properties make them possible candidates for being important regulators of complex systemic processes such as aging, systemic inflammatory responses, tumorigenesis and metastatatic spread. Indeed, several miRs were connected to cellular senescence, age related inflammation and cancer [168, 169].
Whereas cancer prevalence increases exponentially after the age of 65, demographic studies show it reaches a plateau at around 85, and then starts to decline [177, 178]. This deviation from the trend line may imply a unique biological behavior in this group of the very old, which help them to evade from carcinogenesis.
The dramatic increase in the average life expectancy over the last decades has brought aging related pathologies to the center of biological and medical research interest. Along with cardiovascular diseases, cancer is the leading cause of death in the western world, and its importance as a cause for morbidity and mortality is predicted to grow even further as the population continues to age.