Researchers at the Wistar Institute sought to understand how senescence is regulated, and its significant role in promoting healthy aging and treating age-associated illnesses. A protein involved in RNA editing is also involved in senescence, and its implications in tissue aging.
The authors' findings have been published in the journal Nature Cell Biology, which is titled, ADAR1 downregulation by autophagy increases p16INK4a levels independent of RNA editing. Dr. Rugang Zhang, PhD, is deputy director of the Ellen and Ronald Caplan Cancer Center, the Christopher M. Davis endowed professor, and program leader of the Wistar Institute's Immunology, Microenvironment, and Metastasis Program.
Zhang believes that studying the senescence mechanism that drives tissue aging is challenging. Senescence offers an insight into the complex biology that drives tissue aging. These mechanistic findings gained by studying senescence regulation during tissue aging may in turn be utilized to promote healthy aging and combat age-related diseases.
Previous studies have shown that depletion of p16INK4a-expressing cells is sufficient to defy age-associated illnesses. Thus, strategies that prevent age-associated p16INK4a expression might have important implications in strategies to maintain healthy aging.
ADAR1 is a specialized enzyme involved in RNA editing that is now revealed in senescence, according to a postdoctoral researcher at the Zhang lab and the first author of the paper Xue Hao, PhD, who explained that previous independent research in model organisms such as fruit flies and worms demonstrated that age-dependent changes such as neurodegeneration are reduced.
The first question we set out to inquire about was whether ADAR1 is related to cellular senescence, and secondly, how does it regulate senescence, and what is its potential impact on tissue aging, according to Hao.
The researchers first examined ADAR1's expression in human fibroblasts and in vivo in young and elderly mice. Then, they modified ADAR1's expression in petri dishes and mouse tissues to establish ADAR1 as a critical regulator of p16INK4a expression. SIRT1, another protein known to regulate both senescence and tissue aging
According to Hao, ADAR1's downregulation by an autophagy process (degradation and recycling of damaged or unneeded cell components) during senescence decreased the stability of SIRT1 mRNA, which in turn increased the translation of p16INK4a to induce senescence, and this newly defined function of ADAR1 is independent of its RNA editing function.
The researchers believe their research may uncover the missing link between ADAR1 and tissue aging through p16INK4a expression during senescence.
According to Hao, one possible approach to restore ADAR1 expression as a mechanism to suppress p16INK4a and senescence during tissue aging is by inhibiting autophagy. In addition, our research may shed light on whether or not interventions that have been linked to p16INK4a expression have been effective in treating age-related illnesses.