Transient p53 inhibition sensitizes aged white adipose tissue for beige adipocyte recruitment by blocking mitophagy

Area of Science:

• Cellular and Molecular Biology
• Metabolic Health
• Aging Research

Background:

• Aging white adipose tissue (WAT) is linked to reduced insulin sensitivity and impaired glucose tolerance.
• Age-related WAT dysfunction includes diminished cold-induced beige adipocyte recruitment (beiging), potentially due to adipose progenitor cell senescence.
• The role of tumor suppressor p53 in mature white adipocyte aging and its impact on WAT beiging remains unclear.

Purpose of the Study:

• To investigate if p53-related cellular aging in mature white adipocytes causes impaired WAT beiging.
• To determine if transient p53 inhibition can rescue age-impaired WAT beiging and improve metabolic function.

Main Methods:

• Analysis of p53 levels in young and aged mice WAT before and after cold exposure.
• Inducible p53 ablation in differentiated adipocytes of aged mice.
• Assessment of WAT beiging, whole-body energy expenditure, and insulin sensitivity.
• Investigation of autophagy and mitophagy (microtubule-associated protein light chain 3-mediated mitochondria clearance) pathways.

Main Results:

• p53 levels were elevated in aged mice with impaired WAT beiging.
• Cold exposure failed to decrease p53 in aged WAT, unlike in young mice.
• Inducible p53 ablation or transient pharmacological inhibition in aged mice restored WAT beiging, increased energy expenditure, and improved insulin sensitivity.
• p53-ablation reduced mitophagy, facilitating mitochondrial increase during beiging.

Conclusions:

• p53 accumulation in aged white adipocytes impedes cold-induced beiging.
• p53-induced mitophagy in aged WAT contributes to impaired beiging and reduced insulin sensitivity.
• Transient p53 inhibition is a potential therapeutic strategy to rejuvenate aged WAT and improve metabolic health.