Deficiency in Poly(ADP-ribose) Polymerase-1 (PARP-1) Accelerates Aging and Spontaneous Carcinogenesis in Mice.
Genetic and biochemical studies have shown that PARP-1 and poly(ADP-ribosyl)ation play an important role in DNA repair, genomic stability, cell death, inflammation, telomere maintenance, and suppressing tumorigenesis, suggesting that the homeostasis of poly(ADP-ribosyl)ation and PARP-1 may also play an important role in aging. Here we show that PARP-1(-/-) mice exhibit a reduction of life span and a significant increase of population aging rate. Analysis of noninvasive parameters, including body weight gain, body temperature, estrous function, behavior, and a number of biochemical indices suggests the acceleration of biological aging in PARP-1(-/-) mice. The incidence of spontaneous tumors in both PARP-1(-/-) and PARP-1(+/+) groups is similar; however, malignant tumors including uterine tumors, lung adenocarcinomas and hepatocellular carcinomas, develop at a significantly higher frequency in PARP-1(-/-) mice than PARP-1(+/+) mice (72% and 49%, resp.; P < .05). In addition, spontaneous tumors appear earlier in PARP-1(-/-) mice compared to the wild type group. Histopathological studies revealed a wide spectrum of tumors in uterus, ovaries, liver, lungs, mammary gland, soft tissues, and lymphoid organs in both groups of the mice. These results demonstrate that inactivation of DNA repair gene PARP-1 in mice leads to acceleration of aging, shortened life span, and increased spontaneous carcinogenesis.
Piskunova
Tatiana S
TS
Department of Carcinogenesis and Oncogerontology, N.N. Petrov Research Institute of Oncology, Pesochny-2, St. Petersburg 197758, Russia.
Yurova
Maria N
MN
Ovsyannikov
Anton I
AI
Semenchenko
Anna V
AV
Zabezhinski
Mark A
MA
Popovich
Irina G
IG
Wang
Zhao-Qi
ZQ
Anisimov
Vladimir N
VN