Age-Related Hyperglycemia as a Cause of Increased Cancer Incidence

Why is cancer an age-related condition? One can propose a range of mechanisms: the spread of stochastic DNA damage through cell populations; rising levels of chronic inflammation; ever more senescent cells turning out disruptive, pro-growth signals; the growing inability of the immune system to promptly destroy errant cells. The authors of this open access paper argue that the metabolic dysfunction of later life that leads to raised blood sugar, hyperglycemia, is also an important contributing factor to cancer risk. Most hyperglycemia is self-inflicted via obesity, but it can manifest in other ways as damage and systems failure accumulates in late life.

Aging can increase cancer incidence because of accumulated mutations that initiate cancer and via compromised body control of premalignant lesions development into cancer. Relative contributions of these two factors are debated. Recent evidence suggests that the latter is rate limiting. In particular, hyperglycemia caused by compromised body control of blood glucose may be a factor of selection of somatic mutation-bearing cells for the ability to use glucose for proliferation. High glucose utilization in aerobic glycolysis is a long known characteristic of cancer.

The new evidence adds to the concepts that have been being developed starting from mid-1970s to suggest that age-related shifts in glucose metabolism and lipid metabolism increase the risk of cancer and compromise prognoses for cancer patients and to propose antidiabetic biguanides, including metformin, for cancer prevention and as an adjuvant means of cancer treatment aimed at the metabolic rehabilitation of patients.

The new evidence is consistent with several effects of glucose contributing to aging and acting synergistically to enhance carcinogenesis. Glucose can affect (i) separate cells (via promoting somatic mutagenesis and epigenetic instability), (ii) cell populations (via being a factor of selection of phenotypic variants in cell populations for higher glucose consumption and, ultimately, for high aerobic glycolysis); (iii) cell microenvironment (via modification of extracellular matrix proteins), and (iv) the systemic levels (via shifting the endocrine regulation of metabolism toward increasing blood lipids and body fat, which compromise immunological surveillance and promote inflammation). Thus, maintenance of youthful metabolic characteristics must be important for cancer prevention and treatment.

Link: https://doi.org/10.18632/oncotarget.27344

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