Ablation of sirtuin 1 deacetylase activity induces pulmonary emphysema by inducing cellular senescence and disrupting circadian clock in mice

Authors: WANG, XIANG-DONG - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; HU, KANG-QUAN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; LIU, CHUN - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; MCBURNEY, MICHAEL - Jean Mayer Human Nutrition Research Center On Aging At Tufts University

Submitted to: Current Developments in Nutrition
Publication Type: Abstract Only
Publication Acceptance Date: 3/1/2019
Publication Date: 6/13/2019
Citation: Wang, X., Hu, K., Liu, C., McBurney, M.W. 2019. Ablation of sirtuin 1 deacetylase activity induces pulmonary emphysema by inducing cellular senescence and disrupting circadian clock in mice [abstract]. Current Developments in Nutrition. 3(Suppl_1). Abstract No. P01-022-19. https://doi.org/10.1093/cdn/nzz028.P01-022-19.
DOI: https://doi.org/10.1093/cdn/nzz028.P01-022-19

Interpretive Summary:

Technical Abstract: Objectives: Sirtuin 1 (SIRT1), a NAD+-dependent protein/histone deacetylase has the capability to extend life span, delay aging, and prevent aging-related diseases. There are several reports showing that there is no significant decline in SIRT1 protein with age, indicating that SIRT1 protein levels alone may not reflect its deacetylase activity. We investigated the causal effect of systemic ablation of SIRT1 deacetylase activity on aging-related pulmonary disease development in mice. Methods: We used Sirt1y/y homozygous male mice carrying a point mutation (H355Y) that ablates the deacetylase activity, along with their wild type littermates (Sirt1+/+), and followed them for 6, 10 and 18 months of age. Results: Sirt1y/y homozygous mice developed severe pulmonary emphysema at the ages of 6, 10 and 18 months, with the respective incidences of 33%, 100% and 100%, while the Sirt1+/+ wild-type mice only developed emphysema (13% incidence) at 18 months of age. The development of emphysema in Sirt1y/y mice was accompanied with higher protein levels of matrix metalloproteinase (MMP)-2, MMP9, and tissue inhibitor of metalloproteinase-1, and ratio of cleaved/total anti-poly (ADP-ribose) polymerase. The ablation of SIRT1 activity significantly up-regulated mRNA expression of hypoxia-inducible factor-1alpha and retinoic acid receptor-beta, while p21 protein and phosphorylated AMPK increased and phosphorylated ribosomal S6 decreased, suggesting the association of ablation of SIRT1 activity with cellular quiescence and senescence. Additionally, the lack of SIRT1 activity down-regulated the mRNA expression of circadian clock genes (BMAL1, NPAS2, CRY1, CRY2) in the lungs of Sirt1y/y mice, as compared with that of Sirt1+/+ mice. There were no inflammatory responses in the lungs (e.g., inflammatory cell infiltrations, mRNA expressions of IL-6 and TNF-alpha) in Sirt1y/y homozygous mice compared to Sirt1+/+ mice. Conclusions: The lacking of SIRT1 enzymatic activity plays a major role in the susceptibility of organs to aging and pulmonary emphysema development by inducing cellular senescence and disrupting circadian clock genes.