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FEATURE
Is Aging a Risk Factor for Cancer?
Cheong Jit Kong, Ph.D
Liu Mei Hui, Ph.D

Introduction

After the defeat of small pox, measles, common flu and numerous other diseases from childhood to adulthood, cancer seems like the next obvious beast that an individual inevitably has to face. Although cancer may strike people of all ages, the relative risk of contracting this dreadful disease is higher in those aged 60 and older in Singapore (Singapore Cancer Trends, 2008-2012) and globally (AACR, 2013). Against the backdrop of an expanding aging population and estimated increase of worldwide cancer incidence to 22.2 million in the year 2030, there is a pressing need to better understand how aging of humans drives the development of cancer.

What Really Is Cancer?

As an individual grows older, a proportion of cells in his/her body may become abnormal as a result of chronic exposure to environmental or dietary insults. If left unchecked by the body, these cells propagate and form a mass of tissue known as a pre-malignant lesion that may eventually progress into a malignant cancer. Cancer often arises from one part of the body and it can damage nearby tissues/organs when it has grown to a considerable size. Cancer cells have the propensity to escape from their original establishment and colonize or metastasize to the other parts of the body. As nicely illustrated by Professor Bert Vogelstein (Johns Hopkins University) in his vogelgram of colon cancer development some thirty years ago, it takes time and multiple hits for a pre-malignant lesion to progress into cancer. Hence, early discovery and timely treatment seems to be the best way to keep cancer at bay. To date, cancer is no longer an immediate death sentence if diagnosed and treated at its earlier stages. This is, in part, due to the dedicated work of biomedical researchers who have made important scientific discoveries and translated them into innovative and improved ways to prevent, detect, diagnose, and treat cancer.

Leading Causes of Cancer in the Eldery

There are three major schools of thought to explain the link between aging and cancer. Firstly, some believe that the majority of cancer incidence occurs in the elderly because they have a prolonged exposure to extrinsic factors like cancer-inducing chemical agents (or carcinogens). Secondly, some subscribe to the thought that the age-related intrinsic changes in an aging individual may provide a progressively favorable growth environment for new or pre-existing but latent malignant cells. Lastly, by unionizing the first two hypotheses, some reason that the progression of cancer in older individuals is a result of the cumulative effects of prolonged extrinsic cellular insults and increased intrinsic cellular changes to the genome like somatic mutations, telomere or telomerase dysfunction, failure of autophagic recycling program and altered cellular energetics or metabolism.

Genomic Instability: A Common Hallmark of Aging and Cancer?

Maintaining the integrity of genome can be a routine challenge to every single cell in the body. Age-dependent increase in genomic instability has been known to exist in mammals for more than 40 years (Curtis, 1963). However, age-related accumulation of somatic mutations can vary quite extensively between different tissues of the same organism and these genetic changes may result in the stochastic variation in gene expression that is frequently observed in aging mammals (Bahar et al., 2006). For example, stem cells may accumulate damage during the course of aging and become increasingly senescent (or non-proliferative) within differentiated tissues. Incipient tumors, arising directly from stem cells or from more committed cell lineages, undergo rapid proliferation. These pre-malignant cancer cells rapidly accumulate damage, in part owing to the activation of oncogenes through mutations, leading to a larger population of cancer cells becoming senescent. Cancer cells may eventually acquire further mutations that impair the tumor suppressive senescence program to drive cancer progression to full malignancy.

Longevity Factors and Cancer

Telomeres and telomerase are known longevity factors that are critical for the maintenance of genomic stability because they prevent undesirable fusion events at the chromosome ends. Telomeres consist of tandem G-rich repeats that are expanded by telomerase (encoded by the Tert gene) de novo until the chromosome end. In most adult cells, the shortening of telomeres with aging is attributed to the declining amounts of telomerase that are insufficient to prevent telomere erosion. Although the manipulation of telomerase activity seems like a fascinating idea to delay or prevent the aging process of an organism, one has to deal with the associated "side effects" of increasing telomerase activity in the aging cell, such as increase risk of cancer development seen in two independent Tert transgenic mouse models (Gonzalez-Suarez et al., 2001; Artandi et al., 2002). Evidence of improved tissue regeneration and a slight but significant increase in life span were observed in the surviving Tert transgenic mice, despite a higher death rate as a result of tumorigenesis (Gonzalez-Suarez et al., 2005). This observation apparently holds true in many human cancers, where telomerase is activated at some point during tumorigenesis (Kim et al, 1994; Counter et al, 1994). Intriguingly, older mice with short telomeres appeared to be largely resistant to the spontaneous development of tumors (Blanco et al., 2007). Thus, it seems paradoxical that the aging process brings about the shortening of telomeres to predispose one to or help one to fight against cancer development.

Does Mismanagement of Cellular Waste-Recycling Lead to Cancer?

Cells accumulate damaged proteins and organelles, like mitochondria, during the aging process. They rely on a primitive cellular waste-recycling program (also known as autophagy) to keep them healthy. Loss of autophagy in tissues such as the brain, liver and heart is closely associated with age-related disorders, including cancer, neurodegeneration and metabolic syndromes. Interestingly, old hematopoietic stem cells (HSCs) have been recently shown to require a functional autophagy program for survival. As normal glucose uptake is impaired in old HSCs, they have to compensate for the resulting metabolic stress by using autophagy to break down intracellular components to derive nutrients for their survival. Hence, blocking autophagy in these cells can reduce their ability to form differentiated cell types (Warr et al., 2013).

The link between failure to remove cellular waste and cancer development was first observed in the cancer-prone Beclin-1 haploinsufficient mice (where one copy of the Beclin-1 gene is lost). Beclin-1, which is a key scaffolding protein critical for the initiation of autophagy, was shown to bind to anti-apoptotic proteins like Bcl-2 and Mcl-1. Since Bcl-2 and Mcl-1 are frequently overexpressed in cancer, it was thought that these anti-cell death proteins overwhelm the autophagy-dependent housekeeping activities by sequestering Beclin-1 (Yue et al., 2003; Qu et al., 2003). Failure to remove dysfunctional organelles like the mitochondria may also contribute to an increase in reactive oxygen species (ROS), which will heighten the risk of genomic instability, cellular senescence and cancer development.

Age-Related Metabolic Reprogramming: A Cancer Risk Factor?

The overall lifespan of an organism appears to be controlled by a number of sensors and effectors of cell metabolism, including AMP-activating protein kinase (AMPK), the NAD-dependent deacetylase Sirt1, the target of rapamycin (TOR) serine/threonine kinase, the Forkhead O (FoxO) transcription factors and the tumor suppressor p53. Reprogramming of energy supply can occur when an aging cell picks up genetic mutations that inactivate tumor suppressors like p53 or activate oncogenes like RAS or C-MYC. This pent-up energy supply relies on the maintenance of a healthy pool of mitochondria in the cell. Failure in housekeeping activities mediated by autophagy may predispose the aging cell to oxidative and metabolic stresses. While high level of these intracellular insults can almost certainly kill the cell, low level of cell stress may lead to vicious cycles of generating additional genetic mutations to fuel cancer progression.

Living Longer and Cancer-Free; Food For Thought

Is living to a ripe old age and yet staying cancer-free a luxurious dream? Apparently not and here is why (we are, after all, what we eat). Studies have showed that calorie restriction (CR), defined as a reduction of 10–40% in intake of a nutritious diet, increases lifespan and delays or prevents the occurrence of chronic diseases in a variety of animals. For instance, the incidence of cancer was markedly decreased in Rhesus monkeys on a long term CR regimen (Mattison et al., 2012). Besides CR, the Mediterranean and Asian diets have also been associated with decreased cancer incidence in humans (Albuquerque et al., 2014; Miller et al., 2008). Interestingly, these diets are composed largely of vegetables, fruits, fish, and soy. Similarly, putting a cap on regular alcohol consumption may bring some health benefits, as chronic intake of alcohol has been linked to increased cancer risk (Varela-Rey et al., 2013).

Although many studies suggest a relationship between nutrition, aging and cancer, their mechanistic links remain poorly defined and are likely to be controlled at multiple levels, including epigenetics. Epigenetics changes are changes to gene activity that do not involve a change in genomic sequences. Twins with identical sets of DNA can acquire different changes to their epigenetic code as they age as a result lifestyle and/or dietary preferences. Indeed, epigenetic changes may culminate in phenotypic changes and may increase one's chance of developing cancer. Hence, more research is needed to shed light on how a long-term diet of certain food may eventually protect or make us susceptible to certain cancers as we age gracefully and healthfully.

About the Authors

Jit Kong, Cheong (Ph.D) is a research fellow from the Cancer and Stem Cell Biology Program of Duke-NUS Graduate Medical School. Dr. Cheong was a Singapore Millennium Foundation Postdoctoral Fellow (2008-2010) and a recipient of the National Medical Research Council (NMRC) CBRG New Investigator Grant (2012-present). His research interests include signal transductions in cancer, autophagy and metabolism. He is also one of the coordinators of the highly rated Duke-NUS pre-medical freshmen seminar module offered at the National University of Singapore (NUS) and the Nanyang Technological University (NTU).

Mei Hui, Liu (Ph.D) is a lecturer from the Food Science and Technology Program of Department of Chemistry, National University of Singapore (NUS). Dr. Liu was a recipient of the A*STAR graduate scholarship (2004-2008, NUS) and A*STAR postdoctoral fellowship (2010-2011, Cornell University). Her research interests include molecular nutrition (with special focus on diet induced transcription regulation of Nuclear Receptors, their co-regulators and non-coding RNAs in clinically relevant pathways using genomics and molecular approaches), nutrigenetics and nutrigenomics.

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