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NRF2 pathway activation attenuates ageing-related renal phenotypes due to α-klotho deficiency

Mingyue Zhao1, Shohei Murakami1, Daisuke Matsumaru1

  • 1Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan.

Journal of Biochemistry
|February 9, 2022
PubMed

Insights

Activating the KEAP1-NRF2 pathway combats aging by reducing oxidative stress. This approach improved lifespan and kidney function in mice lacking the aging suppressor protein alpha-Klotho.

Area of Science:

  • Gerontology and cellular aging research.
  • Molecular mechanisms of oxidative stress regulation.

Background:

  • Oxidative stress contributes significantly to age-related cellular and tissue dysfunction.
  • The KEAP1-NRF2 system regulates redox balance, with NRF2 activation showing anti-aging potential.
  • Alpha-Klotho (a key aging suppressor) deficiency leads to premature aging phenotypes, partly due to increased oxidative stress.

Purpose of the Study:

  • To investigate if NRF2 pathway activation can counteract the aging phenotypes associated with alpha-Klotho deficiency.
  • To determine the role of NRF2 in mitigating oxidative stress in the context of alpha-Klotho deficiency.

Main Methods:

  • Generation of alpha-Klotho-deficient (Kl-/-) mice with a constitutively activated NRF2 pathway (Keap1-knockdown).
  • Assessment of lifespan and age-related phenotypes, particularly in the kidneys.
  • Analysis of antioxidant gene expression and oxidative stress markers.

Main Results:

  • NRF2 pathway activation in Kl-/- mice significantly extended lifespan.
  • Marked improvement in age-related renal phenotypes was observed in these mice.
  • Elevated antioxidant gene expression and decreased oxidative stress correlated with the observed phenotypic improvements.

Conclusions:

  • NRF2 activation effectively antagonizes aging-related phenotypes caused by alpha-Klotho deficiency.
  • The antioxidant effects of NRF2 play a crucial role in attenuating age-related kidney dysfunction.
  • NRF2 is a potential therapeutic target for anti-aging strategies, partly by compensating for declining alpha-Klotho function.
Keywords:
KEAP1–NRF2 systemageingkidneyoxidative stressα-klotho

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