Abstract
Aging is the greatest challenge to humankind worldwide. Aging is associated with a progressive loss of physiological integrity due to a decline in cellular metabolism and functions. Such metabolic changes lead to age-related diseases, thereby compromising human health for the remaining life. Thus, there is an urgent need to identify geroprotectors that regulate metabolic functions to target the aging biological processes. Nutrients are the major regulator of metabolic activities to coordinate cell growth and development. Iron is an important nutrient involved in several biological functions, including metabolism. In this study using yeast as an aging model organism, we show that iron supplementation delays aging and increases the cellular lifespan. To determine how iron supplementation increases lifespan, we performed a gene expression analysis of mitochondria, the main cellular hub of iron utilization. Quantitative analysis of gene expression data reveals that iron supplementation upregulates the expression of the mitochondrial tricarboxylic acid (TCA) cycle and electron transport chain (ETC) genes. Furthermore, in agreement with the expression profiles of mitochondrial genes, ATP level is elevated by iron supplementation, which is required for increasing the cellular lifespan. To confirm, we tested the role of iron supplementation in the AMPK knockout mutant. AMPK is a highly conserved controller of mitochondrial metabolism and energy homeostasis. Remarkably, iron supplementation rescued the short lifespan of the AMPK knockout mutant and confirmed its anti-aging role through the enhancement of mitochondrial functions. Thus, our results suggest a potential therapeutic use of iron supplementation to delay aging and prolong healthspan.
Highlights
The aging population is growing dramatically worldwide [1–3]
Since cellular metabolism is the major determinant of aging and iron is crucial for several diverse metabolic functions, we investigated the effect of iron supplementation on aging
We investigated the effect of Iron(II) sulfate (FeSO4) supplementation on the chronological lifespan (CLS) of yeast in a 96-well plate
Summary
The aging population is growing dramatically worldwide [1–3]. Aging is the biggest risk factor for several chronic diseases including cancer, neurodegeneration, heart disease, diabetes, cognitive impairment, and immune system decline [4–8]. Recent research in different organisms, from single-celled yeast to animal model systems, has shown that aging mechanisms are conserved and controlled by a highly interconnected and functionally redundant gene and protein interaction network of cellular metabolism [9–11]. The budding yeast Saccharomyces cerevisiae is a powerful model organism for studying the biology of aging as many of its cellular processes are conserved in humans. Yeast has been extensively used to study human replicative and chronological aging by analyzing its replicative lifespan (RLS) and chronological lifespan (CLS) [13–15]. The RLS analyzes the number of times a mother cell divides to form daughter cells, a replicative human aging model for mitotic cells such as stem cells. The CLS is the duration of time that a non-dividing cell is viable in the stationary phase, a chronological human aging model for post-mitotic cells such as neurons
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