The biological basis of human aging remains one of the largest unanswered scientific questions. Aging is a complex process marked by the gradual degradation of cellular functions, influenced by biological factors, environmental factors and lifestyle. Mitochondria, as the main energy hub of cells, are highly dynamic organelles, and increasing evidence suggests that altered mitochondrial function are potential core regulators in aging, removing dysfunctional mitochondria and forming new healthy mitochondria can maintain their function and energy homeostasis, which is closely related to longevity. However, how these functions are affected during aging, and whether alternative anti-aging interventions require different mitochondrial networks, remains unclear.
PARP 1 (Poly (ADP-ribose) polymerase-1, PARP 1)), as a poly ADP ribose polymerase, plays an important role in DNA repair and the maintenance of genome integrity. On the other hand, PARP 1, as a cell death and inflammatory mediator, is also involved in the regulation of aging and longevity. PARP 1 inhibition was found to reverse mitochondrial damage and attenuate genetic defects in mitochondrial metabolism. However, whether inhibiting PARP 1 can delay the aging process, the specific mechanism that the PARP 1-related signaling network plays in aging is unknown.
On March 22,2023, Professor Liu Tiemin's team and Professor Kong Xingxing from the School of Life Science of Fudan University published a research paper entitled: Muscle PARP1 inhibition extends lifespan through AMPKα PARylation and activation in Drosophila in PNAS magazine.
This study pointed out that inhibition of PARP 1 in old flies could prolong lifespan, and found that knockdown of PARP 1 in skeletal muscle could increase AMPK α activity by downregulating ADP-ribosylation of AMPK, which accelerated mitochondrial turnover and increased muscle metabolism and function of PGC-1 α and PINK 1, explaining the molecular mechanism by which PARP 1 / AMPK participated in the precise regulation of aging process.
The team used a loss-of-function (loss of function) strategy and found that skeletal muscle-specific knockdown of Parp 1 (mPARPKD) flies increased significantly in older age, improved starvation and oxidation resistance, and no significant changes in food intake or body weight; these phenotypes were absent in young flies. Upon simultaneous knockdown of Parp 1 and Ampk α (mDKD) in skeletal muscle, longevity, crawling, starvation resistance and oxidation ability were similar to the control group and significantly inferior to the mPARPKD group.
Although previous studies have reported that PARP 1 interacts with AMPK α, the precise regulation of AMPK α by PARP 1 is not conclusive. In this study, we confirmed the interaction of PARP 1 with AMPK α by mass spectrometry, and found both binding domains. Inhibition of PARP 1 function decreases the post-translational PARylation modification of AMPK α and increases the phosphorylation of AMPK α. The posttranslational PARylation modification sites of AMPK α were identified by point mutagenesis techniques.
Mechanistic studies showed that skeletal muscle-specific knockdown of PARP 1 upregulated PGC-1 α expression with increased mitochondrial generation, and simultaneous upregulation of PINK 1 expression promoted the clearance of damaged mitochondria by mitophagy.
The study for the first time explains the DNA damage repair gene Parp 1 inhibition of energy metabolism key molecules AMPK α precise regulation, by increasing the mitochondria generation and control mitochondrial quality, complete mitochondria in skeletal muscle turnover, thus enhance skeletal muscle metabolic function, realize the extension of life, suggests that PARP 1 inhibition in addition to play a role in cancer tumor, is also beneficial to delay aging.
