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Calorie restriction enhances cell adaptation to hypoxia through Sirt1-dependent mitochondrial autophagy in mouse aged

Shinji Kume1, Takashi Uzu, Kihachiro Horiike

  • 1Department of Medicine, Shiga University of Medical Science, Japan.

The Journal of Clinical Investigation
|March 26, 2010
PubMed

Insights

Calorie restriction (CR) protects aged kidneys from hypoxia by boosting mitochondrial autophagy via the Sirt1-Foxo3 pathway. This mechanism enhances cell survival and offers potential for new anti-aging therapies.

Area of Science:

  • Gerontology
  • Mitochondrial Biology
  • Molecular Medicine

Background:

  • Mitochondrial oxidative damage is a key aging mechanism.
  • Calorie restriction (CR) is known to attenuate aging processes.
  • The precise molecular mechanisms of CR's protective effects on mitochondrial dysfunction remain unclear.

Purpose of the Study:

  • To investigate the molecular mechanisms of CR-mediated protection against hypoxia in aged mouse kidneys.
  • To elucidate the role of sirtuin 1 (Sirt1) in CR-induced mitochondrial autophagy.
  • To explore the Sirt1-Foxo3 axis in cellular adaptation to hypoxia.

Main Methods:

  • Adult-onset, long-term CR was implemented in mice.
  • Sirt1 expression and its role in autophagy were assessed in aged kidneys.
  • Primary renal proximal tubular cells (PTCs) were cultured using serum from CR mice.
  • Hypoxia and Sirt1 deficiency models were utilized to evaluate renal damage and mitochondrial accumulation.

Main Results:

  • CR increased Sirt1 expression in aged kidneys, reducing hypoxia-associated damage.
  • CR enhanced BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy.
  • Sirt1-mediated forkhead box O3 (Foxo3) deacetylation in PTCs was crucial for Bnip3 and p27Kip1 expression, promoting autophagy and cell survival under hypoxia.
  • Aged Sirt1+/- mice showed resistance to CR's benefits on mitochondrial damage accumulation under hypoxia.

Conclusions:

  • The Sirt1-Foxo3 axis is vital for cellular adaptation to hypoxia.
  • CR's anti-aging effects involve enhancing mitochondrial autophagy through the Sirt1-Foxo3 pathway.
  • These findings may guide the development of therapies for age- and hypoxia-related tissue damage.

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