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

Oxidative stress is one of the major causes of the age-related functional decline in cells and tissues. The KEAP1-NRF2 system plays a central role in the regulation of redox balance, and NRF2 activation exerts antiageing effects by controlling oxidative stress in aged tissues. alpha-Klotho was identified as an ageing suppressor protein based on the premature ageing phenotypes of its mutant mice, and its expression is known to gradually decrease during ageing. Because alpha-klotho has been shown to possess antioxidant function, ageing-related phenotypes of alpha-klotho mutant mice seem to be attributable to increased oxidative stress at least in part. To examine whether NRF2 activation antagonizes ageing-related phenotypes caused by alpha-klotho deficiency, we crossed alpha-klotho-deficient (Kl(-/-)) mice with a Keap1-knockdown background, in which the NRF2 pathway is constitutively activated in the whole body. NRF2 pathway activation in Kl(-/-) mice extended the lifespan and dramatically improved ageing-related renal phenotypes. With elevated expression of antioxidant genes accompanied by an oxidative stress decrease, the antioxidant effects of NRF2 seem to make a major contribution to the attenuation of ageing-related renal phenotypes of Kl(-/-) mice. Thus, NRF2 is expected to exert an antiageing function by partly compensating for the functional decline of alpha-Klotho during physiological ageing.

Automated summary

Oxidative stress is a major cause of age-related decline in cells and tissues, and the KEAP1-NRF2 system plays a key role in regulating redox balance. Alpha-Klotho, a protein associated with aging suppression, has been found to have antioxidant function. NRF2 activation can counteract aging-related phenotypes caused by alpha-Klotho deficiency by reducing oxidative stress.