The staples of cancer treatment remain chemotherapy and radiotherapy, even today. Despite tremendous progress in the laboratory and in trials, the medical community has not yet passed the point at which immunotherapy and other targeted approaches take over the mainstream. Thus cancer treatment programs are still very much a balancing act between harming the cancer and harming the patient, while metastasis is still largely the beginning of the end, in which cancer slips out of reach of the dosage of poisons a patient can survive. Neither chemotherapy nor radiation therapies are treatments that anyone would voluntarily undergo if there were any other viable options on the table, as they are simply not selective enough. The whole point of the next generation of targeted therapies is to retain the ability to harm cancer while removing near all of the harm done to the patient. That can even be achieved with present day chemotherapy drugs, if they can be delivered in minuscule doses and only to cancerous cells. It is easy to kill cells; the hard part has always been to kill only the cells that you want killed.
Thus most cancer therapy today is the carefully calibrated application of damage. Toxins and radiation cause inflammation, make cells become senescent, and create range of other effects, some temporary, some lasting. We can say the same for a smoking habit, a terrible thing to maintain unless your goal is to cut short your life and health. A useful distinction to make here is between primary aging and secondary aging. Primary aging is what your body does to you even under the best of circumstances: cell and tissue damage that accumulates as a form of biological wear and tear, created as a result of the normal, healthy operation of metabolism. Secondary aging is additional damage heaped upon you by your choices and by the environment: the effects of infectious disease, obesity, a sedentary lifestyle, smoking, and, of course, chemotherapy or radiotherapy. The line between primary and secondary aging is fuzzy at best. Senescent cells accumulate to cause harm and age-related disease even in the bodies of individuals with the best and most fortunate of lives. Their presence is one of the root causes of aging. If chemotherapy piles on an additional lingering population of these cells, secreting signals that disrupt metabolism and degrade tissue function, then do we call that accelerated aging? This paper answers that question in the affirmative:
Cancer Treatment as an Accelerated Aging Process: Assessment, Biomarkers, and Interventions
Presently, there are 8 million cancer survivors age 65 or older in the United States, and this number is anticipated to continue to grow to 11 million by 2020. A key survivorship issue facing these older adults is the short- and long-term impact of cancer therapy on the aging process. It has been suggested that cancer and/or its treatment may contribute to an accelerated aging phenotype. The majority of these data come from the pediatric literature, but a smaller yet growing body of literature points toward similar findings in the geriatric population.
The aging process is unique to the individual, and chronological age is a poor descriptor of an older adult. For example, two individuals who are chronologically age 75 can have very different functional ages. A geriatric assessment identifies factors other than chronological age that can predict the risk of morbidity and mortality in older adults. These include functional status, cognition, comorbidity, psychological state, social support, and nutritional status. Geriatric assessment is the cornerstone for assessing function in patients with cancer prior to treatment. It can be helpful in predicting survival, treatment-related toxicity, and other outcomes. However, geriatric assessment can be time consuming, and many clinicians do not have the resources to perform a geriatric assessment in daily practice. Biomarkers of aging may help fill this gap. Potential biomarkers include chronic inflammatory markers, markers of cellular senescence, and sarcopenia.
Inflammatory markers have been extensively studied, and increased levels have been shown to correlate with frailty, functional decline, and survival. These markers now are receiving wide attention, as there is good evidence that chronically elevated levels may accelerate or exacerbate the aging process. These markers, which include interleukins, tumor necrosis factors, and others, have been studied extensively in frail patients in whom they independently correlate with other measures of physical function. Interleukin-6 (IL-6) has probably been the most extensively studied cytokine and has been shown to predict functional decline, including a diminution in the ability to perform activities of daily living, poor ambulation, and decreased mobility. There also appears to be a major relationship between inflammatory markers and cell senescence. Senescent cells are viable and capable of secreting proinflammatory markers that have led to the definition of a senescence-associated secretory phenotype. To date, however, none of these markers has assumed a major role in clinical care or further studies designed to see if any single marker or combination might have an independent role in the management of the older patient with cancer. These studies would test whether such markers could be independent predictors of treatment tolerance, including acute and chronic toxicities, functional loss, and cognitive decline.
There is little doubt that the treatment of cancer, especially radiation therapy and chemotherapy, greatly accelerates aging. A recent overview of survivors of childhood cancer showed that these individuals were at greatly increased risk for substantial comorbidity and premature death. Data from one of the large cohorts described in this review demonstrated the cumulative prevalence for a serious or life-threatening chronic condition of 81% by age 45; in addition, there was an extremely high incidence of second neoplasms that was directly related to the radiation dose. In another study of survivors of childhood cancer, the prevalence of prefrailty and frailty were 31.5 and 13.1% among women and 12.9 and 2.7% among men, respectively. This prevalence of frailty among young adult survivors of cancer with a mean age of 34 years was similar to that of adults age 65 or older.
p16ink4a has major promise as a biomarker of chemotherapy toxicity. p16ink4a expression increases approximately 10-fold between ages 20 and 80, and this dynamic range provides for a more robust marker as a predictor of molecular aging. In one study of women receiving adjuvant chemotherapy for early-stage breast cancer, p16ink4a expression measured in peripheral blood T cells increased by almost one log2 order of magnitude immediately after treatment and remained elevated 12 months after treatment. This change corresponds to almost a 15-year increase in chronologic age. In this study, the cytokines VEGFA and monocyte chemotactic protein-1 also significantly increased and remained elevated at 12 months, but telomere length was not affected. In a cross-sectional cohort of patients in the same study, prior chemotherapy exposure was independently associated with increased p16ink4a expression comparable to 10 years of chronologic aging.
"Don't get cancer" is great advice. It is a pity that it is so very hard to follow in practice. For my money the most important work in the cancer research community is that focused on building technology platforms that can be applied to either all or many cancers with comparatively little additional work. Victory in the sense of control over cancer will only come by crushing down the time and cost required to defeat each new variety of cancerous cell. The present morass of slow and painstaking progress exists because it has historically required an entire lengthy research initiative to be focused on each one of the thousands of noteworthy individual types of cancer, and that is still largely how business is conducted in this industry. This must change, and thankfully the signs of that change are beginning to emerge.
One of the most promising fields of early stage cancer research, still only undertaken by a few scientific groups, is focused on interfering in telomere lengthening. Telomeres shorten with each cell division, and thus all cancers must continually lengthen their telomeres in order to survive. This is the one useful universal commonality shared by all cancers. There are a limited set of mechanism by which this telomere lengthening can take place: either telomerase or one of the less well mapped alternative lengthening of telomeres (ALT) processes. If that short list can all be blocked in a tissue-selective manner - or even blocked globally for a while - then that will be the end of cancer as a serious threat.
View the full article at FightAging
