Poly(ADP-Ribosyl)ation and Aging

Abstract

In this Chapter, we review the evidence suggesting that the family of poly(ADP-ribose) polymerases (PARPs) is involved in regulation of the aging process. First, as genotoxic stress, mainly produced by reactive oxygen species, is believed to be the major driving force of cellular aging, the importance of mechanisms that counteract it or revert its consequences is quiet obvious. A pivotal pathway for eliminating oxidative DNA damage, spontaneously formed abasic sites, or DNA single strand breaks is DNA base-excision repair and its activity is facilitated by PARP-1 and PARP-2. In line with these observations, the capacity of mononuclear blood cells to synthesize poly(ADP-ribose), largely reflecting PARP-1 activity, is positively correlated with the life span of the donor species in mammalians. Second, maintenance of telomere length is very important for replicating cells to avoid cellular senescence and replicative crisis. Two important regulators are the poly(ADP-ribose) polymerases tankyrase-1 and tankyrase-2, which inhibit via modification of TRF-1 its negative influence on telomerase activity. Third, the interaction of PARP-1 with proteins important in preventing premature aging and retarding age-related disease like the Werner syndrome protein (WRN) further supports the importance of PARP-1 in this process. Forth, as several PARPs are components of the mitotic apparatus with apparent regulatory function, they counteract genomic instability also on this level of defence, i.e., beyond DNA repair. Fifth, by interacting with important cell cycle regulators such as p53, PARPs and probably their product, poly(ADP-ribose), take an active part in DNA damage surveillance and regulation of cell division. In conclusion, PARP proteins are crucial players in the cellular responses to various kinds of impaired functionality of genomic DNA, as they represent versatile tools to fight all kinds of threats to genomic integrity, thus keeping in check aging-related dysfunction and disease. In doing so, they might be importanthelpers to keep the speed of the aging process low and may also contribute to attaining “healthy aging”, i.e., a state of being old, yet free from major age-related disease or disability.