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Today’s open access review paper goes back to the basics on aging and cancer, a first principles consideration of whether or not the evidence shows that we should think of cancer as a distinct process from aging. It is certainly the case that while cancer incidence increases with age, it doesn’t keep on increasing ad infinitum. In very late life, 90 and older, those who are not already dead from one cause or another actually have lower rates of cancer than younger cohorts. This may not be a only matter of those most prone to cancer having died already, but also reflect something fundamental about the way in which cellular biochemistry changes at that age.
The majority of cancer risk scales with age-related disability of the immune system, and with a growing burden of mutational damage that spreads through tissue. That growing mutational damage enables the catastrophic final change to produce runaway cancerous replication, while immune aging prevents this first cancerous cells from being caught and destroyed by immune cells. One of the primary goals of the immune system is to destroy potentially cancerous cells, but growing levels of chronic inflammation, tissue damage, and cell dysfunction prevent that from happening efficiently in later life. Cancers that predominantly occur in children are a strange exception, not the rule.
Why does cancer risk start to drop at a very old age? Plausibly because cell activity diminishes across the board; less activity means less chance of mutational damage and the creation of a cancerous cells. These are overly simplistic summaries of a much more complex reality, but they are starting points for thinking about cancer and aging.
Aging is the most important risk factor of malignant disease, the prevalence of which dramatically increases as adults age, reaching a peak around 85 or 90 years, when the incidence of new cancer diagnoses starts to decline and that of cardiovascular and other diseases ramps up. Aging is, to some degree, modulable, meaning that chronological age (measured in years) and biological age (measured by biological tests and clinical status) can be uncoupled from each other. A young biological age is linked to a reduced risk of malignant disease. For this reason, it may even be argued – in a polemic fashion – that aging is a modifiable risk factor of cancer. This speculation is apparently supported by epidemiological data indicating that lifestyle factors that slow the aging process – such as leanness, an equilibrated mostly plant-based diet, voluntary physical activity and the avoidance of environmental mutagens – also reduce the probability to develop malignant disease. This observation suggests – but does not prove – that aging and cancer share common causes that are influenced by lifestyle or, in a slightly different vision, that manifest aging precipitates the development of clinically detectable tumors that then develop as ‘age-related diseases’.
In this review, we will examine the mechanistic connections between aging and malignant disease. We will first discuss arguments in favor of the null hypothesis, namely, that aging and cancer just coincide as we become older because both are time-dependent processes but do not necessarily share a common biological basis. This null hypothesis would be in line with the existence of childhood cancers and progeroid (i.e., aging-accelerating) syndromes that do not increase the likelihood to develop cancer. We will then examine the likely more broadly applicable hypothesis that aging and cancer have common mechanistic grounds, as supported by the idea that both these processes share molecular and cellular characteristics that have been referred to as ‘meta-hallmarks’ or ‘agonistic hallmarks’. However, this hypothesis does not explain why very old age (older than 90 years) is accompanied by a reduction of the incidence of cancers, perhaps because certain ‘antagonistic hallmarks’ of aging counteract carcinogenesis.
We conclude that aging and cancer are connected by common superior causes including endogenous and lifestyle factors, as well as by a bidirectional crosstalk, that together render old age not only a risk factor of cancer but also an important parameter that must be considered for therapeutic decisions.
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