There are many ways to slow aging to a measurable degree in short-lived species such as mice, and the work noted here is a recently discovered example. Mice have evolved to have a sizable variability of life span in response to environmental circumstances, and thus the cellular machinery relating to various stress responses has an equally sizable influence on health and longevity. Since there are many ways to adjust the operation of that machinery, by increasing or decreasing levels of specific proteins, there are also many ways to slow aging. Few of them are going to be all that useful, unfortunately, as longer-lived species such as our own have a far less plastic life span. An increased operation of stress response mechanisms does not increase human life span by anywhere near as great a proportion as is the case in mice.
Several reports indicate that caloric restriction and intermittent periods of fasting may reduce the risk of complications associated with aging. Cells use nutrient sensing to identify and respond to differences in nutrient levels; the sensing mechanisms are dysregulated during the aging process. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) pathways are nutrient sensors that have been involved in lifespan. Additionally, PASK (a serine/threonine kinase that contains PAS domains) can sense intracellular oxygen, redox state, and various metabolites.
We have previously described how PASK is a critical regulator of AMPK and mTOR pathways in the hypothalamus and liver, as well as a key regulator of oxidative stress and glucose and lipid liver metabolism. PASK-deficient mice are protected against the development of obesity and insulin resistance induced by a high-fat diet (HFD). PASK has recently been described as a target of mTORC1 during regenerative myogenesis in muscle stem cells.
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 reactive oxygen species and reactive nitrogen species 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. PASK may be a good target for reducing damage during aging.