The Interrelated Multifactorial Actions of Cortisol and Klotho: Potential Implications in the Pathogenesis of Parkinson’s Disease

Abstract

The pathogenesis of Parkinson’s disease (PD) is complex, multilayered, and not fully understood, resulting in a lack of effective disease-modifying treatments for this prevalent neurodegenerative condition. Symptoms of PD are heterogenous, including motor impairment as well as non-motor symptoms such as depression, cognitive impairment, and circadian disruption. Aging and stress are important risk factors for PD, leading us to explore pathways that may either accelerate or protect against cellular aging and the detrimental effects of stress. Cortisol is a much-studied hormone that can disrupt mitochondrial function and increase oxidative stress and neuroinflammation, which are recognized as key underlying disease mechanisms in PD. The more recently discovered klotho protein, considered a general aging-suppressor, has a similarly wide range of actions but in the opposite direction to cortisol: promoting mitochondrial function while reducing oxidative stress and inflammation. Both hormones also converge on pathways of vitamin D metabolism and insulin resistance, also implicated to play a role in PD. Interestingly, aging, stress and PD associate with an increase in cortisol and decrease in klotho, while physical exercise and certain genetic variations lead to a decrease in cortisol response and increased klotho. Here, we review the interrelated opposite actions of cortisol and klotho in the pathogenesis of PD. Together they impact powerful and divergent mechanisms that may go on to influence PD-related symptoms. Better understanding of these hormones in PD would facilitate the design of effective interventions that can simultaneously impact the multiple systems involved in the pathogenesis of PD.

Salivary Biomarkers for Parkinson’s Disease: A Systematic Review with Meta-Analysis

“…Cortisol is a hormone, which may alter mitochondrial function and contribute to oxidative stress or neuroinflammation, characteristic of PD [102]. One of the studies concentrated on cortisol levels in the saliva of PD patients.…”

New Pieces for an Old Puzzle: Approaching Parkinson’s Disease from Translatable Animal Models, Gut Microbiota Modulation, and Lipidomics

“…Other environmental factors that may contribute to the pathogenesis of PD are those related to lifestyle [ 40 ], somewhat more disputed but probably also relevant to the current increasing rate of appearance of the disease. For example, chronic stress and vitamin D deficiency, associated with increased levels of cortisol and decreased levels of klotho (findings also encountered in PD), are thought to play a role in the pathogenesis of PD, favoring mitochondrial dysfunction, oxidative stress, insulin resistance, and neuroinflammation [ 41 , 42 ]. In contrast, physical exercise, which reduces psychological stress and helps to achieve healthy aging, might exert neuroprotective actions, through improvements of cortisol and klotho levels, as well as promoting metabolic and mitochondrial remodeling, improving the endocrine profile derived from the muscle and adipose tissue, with potential beneficial effects in PD [ 42 ].…”

“…For example, chronic stress and vitamin D deficiency, associated with increased levels of cortisol and decreased levels of klotho (findings also encountered in PD), are thought to play a role in the pathogenesis of PD, favoring mitochondrial dysfunction, oxidative stress, insulin resistance, and neuroinflammation [ 41 , 42 ]. In contrast, physical exercise, which reduces psychological stress and helps to achieve healthy aging, might exert neuroprotective actions, through improvements of cortisol and klotho levels, as well as promoting metabolic and mitochondrial remodeling, improving the endocrine profile derived from the muscle and adipose tissue, with potential beneficial effects in PD [ 42 ]. Sleep disturbance and circadian disruption might be not only a chronic symptom of PD, but an additional risk factor for its development [ 43 ].…”

Identification of metabolites reproducibly associated with Parkinson’s Disease via meta-analysis and computational modelling

“…Stress-sensitive cortisol, produced by the adrenal cortex, may affect motor and non-motor symptoms of PD [142]. Increased stress in the neurodegenerative process may induce the dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and further influence cortisol levels; the increased cortisol levels may relate to mitochondrial dysfunction and the vulnerability of nigral neurons [143,144]. Besides, the dysfunction of sphingolipid metabolism may affect steroidogenesis metabolism [48].…”

“…Sphingolipids are strongly connected with sterol metabolism through the physical association of the planar ring of sterols with the acyl chains of sphingolipids; they may interact through the cross-talk on metabolic pathways, resulting in increased steroid levels [145]. Therefore, cortisol and its related metabolites could have the potential to be the biomarkers to reflect dysfunctional lipid metabolism and the stress in the brain leading to the disruption of mitochondrial function and neuroinflammation [144].…”