Poly(ADP-ribose) polymerase 1 at the crossroad of metabolic stress and inflammation in aging

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is a chromatin-associated nuclear protein, which functions as molecular stress sensor. Reactive oxygen species, responsible for the most plausible and currently acceptable global mechanism to explain the aging process, strongly activate the enzymatic activity of PARP1 and the formation of poly(ADP-ribose) (PAR) from NAD(+). Consumption of NAD(+) links PARP1 to energy metabolism and to a large number of NAD(+)-dependent enzymes, such as the sirtuins. As transcriptional cofactor for NF-kappaB-dependent gene expression, PARP1 is also connected to the immune response, which is implicated in almost all age-related or associated diseases. Accordingly, numerous experimental studies have demonstrated the beneficial effects of PARP inhibition for several age-related diseases. This review summarizes recent findings on PARP1 and puts them in the context of metabolic stress and inflammation in aging.

Keywords: NAD+; NF-κB; PARP-1; ROS; aging; inflammation.

Figure 1.. PARP1 at the crossroad of metabolic stress and inflammation in aging.

PARP1 is activated by cellular stress, e.g. by oxidative damage due to increased levels of reactive oxygen species (ROS). As NAD⁺-dependent enzyme, PARP1 senses energy levels and crosstalks with other NAD⁺-consuming enzymes. Over-activation of PARP1 leads to energy depletion and cell death. On the other hand, PARP1 functions as cofactor for NF-κB-dependent transcription and is therefore implicated in many inflammatory processes. Both, PARP1-mediated metabolic stress and PARP1-regulated inflammation can lead to tissue degeneration underlying many age-related pathologies. See text for further details.