Impact of Mlkl or Ripk3 deletion on age-associated liver inflammation, metabolic health, and lifespan.

Sabira Mohammed, Phoebe Ohene-Marfo, Chao Jiang, Zongkai Peng, Nidheesh Thadathil, Albert Tran, Evan Nicklas, Shylesh Bhaskaran, Dawei Wang, Ramasamy Selvarani, Amit Singh, Zhibo Yang, Nagib Ahsan, Sathyaseelan S Deepa

Stephenson Cancer Center, Department of Biochemistry and Physiology, Oklahoma Center for Geroscience & Brain Aging, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA.Stephenson Cancer Center, Department of Biochemistry and Physiology, Oklahoma Center for Geroscience & Brain Aging, University of Oklahoma Health Sciences Center, 975 NE 10th Street, Oklahoma City, OK, 73104, USA. · pubmed

Paper

Abstract

Chronic, low-grade inflammation is a hallmark of aging and various age-related diseases, including metabolic dysfunction-associated steatotic liver disease (MASLD). The prevalence of metabolic dysfunction-associated steatohepatitis (MASH), an advanced form of MASLD, increases with age and contributes to morbidity and mortality among the elderly. This study investigates the role of necroptosis, a programmed cell death pathway that promotes inflammation, in liver inflammaging and age-associated MASLD by utilizing genetic ablation models of two key necroptosis proteins, Mlkl or Ripk3. The absence of Mlkl or Ripk3 significantly reduced liver inflammation, steatosis, and fibrosis in aged male mice, supporting the role of necroptosis in age-associated MASLD. Additionally, Mlkl or Ripk3 deletion impacted other non-necroptotic cellular processes that drive inflammation and MASLD, such as cellular senescence, apoptosis, and autophagy in aged liver. Levels of plasma TNFα and IL6, key proinflammatory cytokines associated with inflammaging, are reduced in Mlkl

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Research summary

The paper claims that the deletion of Mlkl or Ripk3 reduces liver inflammation and metabolic dysfunction associated with aging. This research addresses the mechanisms of inflammation and necroptosis in the context of aging and age-related diseases, which are critical for understanding and potentially mitigating the root causes of aging.

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