Abstract
Several signaling pathways may be affected during aging. All are regulated by nutrient levels leading to a decline in mitochondrial function and autophagy and to an increase in oxidative stress. PAS Domain Kinase (PASK) is a nutrient and bioenergetic sensor. We have previously found that PASK plays a role in the control of hepatic metabolic balance and mitochondrial homeostasis. To investigate PASK’s role in hepatic oxidative stress during aging, we analyzed the mitochondrial function, glucose tolerance, insulin resistance, and lipid-related parameters in aged PASK-deficient mice. Hepatic Pask mRNA decreased in step with aging, being undetectable in aged wild-type (WT) mice. Aged PASK-deficient mice recorded lower levels of ROS/RNS compared to aged WT. The regulators of mitochondrial biogenesis, PGC1a, SIRT1 and NRF2, decreased in aged WT, while aged PASK-deficient mice recorded a higher expression of NRF2, GCLm and HO1 proteins and CS activity under fasted conditions. Additionally, aged PASK-deficient mice recorded an overexpression of the longevity gene FoxO3a, and maintained elevated PCNA protein, suggesting that hepatic cell repair mechanisms might be functional. PASK-deficient mice have better insulin sensitivity and no glucose intolerance, as confirmed by a normal HOMA-IR index. PASK may be a good target for reducing damage during aging.
Highlights
Aging can be defined as a multifactorial process characterized by a progressive decrease in physiological functions resulting from the lifelong accumulation of damage
We have previously described how PAS Domain Kinase (PASK) is a critical regulator of AMP-activated protein kinase (AMPK) and mammalian target of rapamycin (mTOR) pathways in the hypothalamus, neuroblastoma N2A cells and liver [19, 20], as well as a key regulator of oxidative stress and glucose and lipid liver metabolism [21, 22]
The mRNA levels coding to PASK were measured by real-time polymerase chain reaction (PCR) to analyze the effects of aging on Pask expression
Summary
Aging can be defined as a multifactorial process characterized by a progressive decrease in physiological functions resulting from the lifelong accumulation of damage. Such damage could be mediated by, among others, oxidative stress, an impaired mitochondrial function, the deregulation of autophagy, and the shortening of telomeres [1]. ROS, such as radical superoxide, non-radical hydrogen peroxide, and hydroxyl radicals, are highly reactive molecules that play contrasting roles They can act as signal transducers in cell proliferation [4], and in cellular senescence [5] or cell death [6]. Their excess causes oxidative stress, damaging essential cellular components such as DNA, proteins, and lipids [7, 8]
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