Geroncogenesis: metabolic changes during aging as a driver of tumorigenesis

Abstract

Why does cancer risk increase as we age? Frequently attributed to the multi-hit hypothesis and the time required to accumulate genomic mutations, this question is a matter of ongoing debate. Here, we propose that the normal decline in oxidative metabolism during aging constitutes an early and important "hit" that drives tumorigenesis. Central to these metabolic changes are the sirtuins, a family of NAD(+)-dependent deacylases that have evolved as coordinators of physiological responses to nutrient intake and energetic demand. Thus, the modulation of sirtuins might be a fruitful approach to reversing the age-related metabolic changes that could underlie tumorigenesis.

Figure 1. The Geroncogenesis Hypothesis: Aging-Induced Metabolic Decline as a Driver of Tumorigenesis

According to the Knudson, or “multi-hit,” hypothesis, cancer occurs more frequently as we age because time is necessary for cells to acquire genetic mutations that drive carcinogenesis (indicated by red “x”). According to this model, the shift to oxidative glycolysis, known as the Warburg effect, occurs subsequent to these early hits. An alternative possibility is that the natural decline in oxidative metabolism as we age induces a Warburg-like metabolic state in normal tissues (indicated by red mitochondria). This increases the ROS production and sets the metabolic stage for later mutations to drive tumorigenesis. Low-calorie diets, exercise, and CR mimetic compounds delay this metabolic shift, thereby reducing the chance that oncogenic mutations will occur in a cell with optimal metabolism for tumorigenesis. The model predicts that CR mimetics could be used to reverse the metabolic reprogramming of tumors and even to prevent aging tissues from undergoing this switch in the first place.

Figure 2. Sirtuins Are Central to Metabolic Reprogramming during Aging and Cancer

Sirtuins control key nodes in the regulation of glycolysis (HIF-1α, HIF-2α, and c-Myc) and oxidative phosphorylation (PGC-1α, LKB1, and TCA enzymes). A decline in the activity of the sirtuin family of enzymes in old age is hypothesized to lead to a shift toward a predominantly glycolytic, Warburg-like metabolism that could contribute to the exponential increase in cancer susceptibility during aging.