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The Na/K-ATPase Oxidant Amplification Loop Regulates Aging
Komal Sodhi1, Alexandra Nichols1, Amrita Mallick1
1Departments of Medicine, Surgery, and Biomedical sciences, Joan C. Edwards School of Medicine, Marshall University, Huntington, USA.
Abstract:
As aging involves oxidant injury, we examined the role of the recently described Na/K-ATPase oxidant amplification loop (NKAL). First, C57Bl6 old mice were given a western diet to stimulate oxidant injury or pNaKtide to antagonize the NKAL. The western diet accelerated functional and morphological evidence for aging whereas pNaKtide attenuated these changes. Next, human dermal fibroblasts (HDFs) were exposed to different types of oxidant stress in vitro each of which increased expression of senescence markers, cell-injury, and apoptosis as well as stimulated the NKAL. Further stimulation of the NKAL with ouabain augmented cellular senescence whereas treatment with pNaKtide attenuated it. Although N-Acetyl Cysteine and Vitamin E also ameliorated overall oxidant stress to a similar degree as pNaKtide, the pNaKtide produced protection against senescence that was substantially greater than that seen with either antioxidant. In particular, pNaKtide appeared to specifically ameliorate nuclear oxidant stress to a greater degree. These data demonstrate that the NKAL is intimately involved in the aging process and may serve as a target for anti-aging interventions.
Insights
The Na/K-ATPase oxidant amplification loop (NKAL) drives aging. Targeting NKAL with pNaKtide may offer a novel anti-aging strategy by reducing cellular damage and senescence.
Area of Science:
- Gerontology
- Cellular Biology
- Biochemistry
Background:
- Aging is characterized by increasing oxidant injury.
- The Na/K-ATPase oxidant amplification loop (NKAL) is a newly identified pathway potentially involved in aging.
- Understanding NKAL's role is crucial for developing anti-aging interventions.
Purpose of the Study:
- To investigate the involvement of NKAL in the aging process.
- To evaluate the potential of antagonizing NKAL as an anti-aging strategy.
Main Methods:
- Utilized aged C57Bl6 mice fed a western diet or treated with pNaKtide.
- Exposed human dermal fibroblasts (HDFs) to various oxidant stressors in vitro.
- Assessed senescence markers, cell injury, apoptosis, and NKAL activity.
- Compared the effects of pNaKtide with antioxidants N-Acetyl Cysteine and Vitamin E.
Main Results:
- A western diet accelerated aging phenotypes in mice, while pNaKtide attenuated these effects.
- Oxidant stress in HDFs stimulated NKAL, increased senescence, injury, and apoptosis.
- Ouabain augmented senescence, whereas pNaKtide treatment attenuated it.
- pNaKtide provided superior protection against senescence compared to N-Acetyl Cysteine and Vitamin E, particularly by reducing nuclear oxidant stress.
Conclusions:
- The Na/K-ATPase oxidant amplification loop (NKAL) plays a significant role in aging.
- Targeting NKAL with agents like pNaKtide shows promise as an effective anti-aging intervention.
- pNaKtide demonstrates specific efficacy in mitigating nuclear oxidant stress and cellular senescence.
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