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Could α-Klotho Unlock the Key Between Depression and Dementia in the Elderly: from Animal to Human Studies

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α-Klotho is known for its aging-related functions and is associated with neurodegenerative diseases, accelerated aging, premature morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been proposed as the preclinical stage of dementia such as Alzheimer’s disease (AD). To see whether and how α-Klotho can be a key biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link between depression and dementia through the regulation of oxidative stress and inflammation.
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Could α-Klotho Unlock the Key Between Depression and Dementia
in the Elderly: from Animal to Human Studies
Xiang Gao
1
&Yuhong Li
1
&Zuoli Sun
2
&Hong Xu
2
&Guangwei Ma
1
&Qi Deng
1
&Claire X. Zhang
1
&Rena Li
1,2
Received: 12 June 2020 / Accepted: 25 January 2021
#The Author(s), under exclusive licence to Springer Science+Business Media, LLC part of Springer Nature 2021
Abstract
α-Klotho is known for its aging-related functions and isassociatedwith neurodegenerative diseases, accelerated aging, premature
morbidity, and mortality. Recent literature suggests that α-Klotho is also involved in the regulation of mental functions, such as
cognition and psychosis. While most of studies of α-Klotho are focusing on its anti-aging functions and protective role in
dementia, increasing evidence showed many shared symptoms between depression and dementia, while depression has been
proposed as the preclinical stage of dementia such as Alzheimers disease (AD). To see whether and how α-Klotho can be a key
biological link between depression and dementia, in this review, we first gathered the evidence on biological distribution and
function of α-Klotho in psychiatric functions from animal studies to human clinical investigations with a focus on the regulation
of cognition and mood. Then, we discussed and highlighted the potential common underlying mechanisms of α-Klotho between
psychiatric diseases and cognitive impairment. Finally, we hypothesized that α-Klotho might serve as a neurobiological link
between depression and dementia through the regulation of oxidative stress and inflammation.
Keywords α-Klotho .Aging .Dementia .Depression
Introduction
The α-Klotho gene is located on human chromosome 13 and
contains five exons [1,2] and encodes a single-pass type I
transmembrane protein with three domains: a short intracellu-
lar domain (~60 amino acids), a transmembrane domain, and a
large extracellular domain (~950 amino acids). As an anti-
aging protein, α-Klotho is widely expressed throughout the
human tissues, and the brain is one of the organs with highest
expression [3]. A full-length α-Klotho protein (~140 kD) can
be substrates for several enzymes [4,5], and the cleaved ex-
tracellular domain (~130 kD) gets into the blood, urine, and
cerebrospinal fluid as a soluble α-Klotho protein [6,7]. While
the full-length membrane-bound α-Klotho is known as a co-
receptor for fibroblast growth factor-23 (FGF23) and plays a
role in regulating the excretion of phosphate and synthesis of
active vitamin D [810], the soluble α-Klotho acts as a hor-
monal factor as well as an enzyme in regulating growth factor
signaling [1113], oxidative stress [14], and ion channels and
transporters [1518].
α-Klotho plays a well-recognized anti-aging function in
both animal models and human studies. Mice with lower ex-
pression of α-Klotho gene show shortened life span and pre-
mature onset of age-related phenotypes [1], while overexpres-
sion of α-Klotho gene prolongs the life span [19].
Furthermore, human studies reveal that allelic variations in
α-Klotho gene are closely associated with longevity, as well
as the risk of aging-related health conditions, such as cardio-
vascular disease [20], glucose metabolism [21], bone mineral
density [22], renal stones [23], breast cancer [24], and cogni-
tive impairment [2527]. α-Klotho is also well studied in
Alzheimers disease (AD), the most common dementia in
the elderly [28], while few studies also proposed the potential
role of α-Klotho in the mood disorders [2931].
With strong clinical evidence showing that depression and
dementia often share common symptoms, depression might
be a preclinical stage of dementia. For example, 511% of
AD patients also suffer from depression [32], and individuals
with depression had higher risk of dementia [3336]. Studies
also reported a reduction of hippocampal volume in both
*Rena Li
renali@ccmu.edu.cn
1
Beijing Institute of Brain Disorders, Laboratory of Brain Disorders,
Ministry of Science and Technology, Collaborative Innovation
Center for Brain Disorders, Capital Medical University,
Beijing 100069, China
2
Beijing Key Laboratory of Mental Disorders, Beijing Anding
Hospital, Beijing 100088, China
https://doi.org/10.1007/s12035-021-02313-0
/ Published online: 1 February 2021
Molecular Neurobiology (2021) 58:2874–2885
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Because considerable evidence has confirmed the importance of Klotho in both depression and cognitive impairments, which often coexist, it is suggested that Klotho may be a molecular factor linking these disorders [21]. ...
... A better understanding of the mechanism underlying how Klotho-Nrf2-NF-κB induces antioxidant and anti-inflammatory effects may lead to the development of new pharmacological strategies for depression. Gao et al., 2021 suggest that peripheral changes in Klotho protein concentration are more important for elderly MDD patients. While young MDD patients (also older patients with recurrent depressive episodes) showed no changes in plasma α-Klotho levels, a significant decrease was observed in elderly MDD patients, associated with increased disease severity and the number of T rs9315202 alleles. ...
... Increased Klotho expression was associated with BDNF and c-fos levels, as indicated using a Klotho inhibitor [123]. Gao et al. (2021) proposed an interesting concept: Klotho may represent a neurobiological link between depression and dementia. According to this, depression may be a risk factor for AD. ...
Article
Full-text available
Depression is a serious neuropsychiatric disease affecting an increasing number of people worldwide. Cognitive deficits (including inattention, poor memory, and decision-making difficulties) are common in the clinical picture of depression. Cognitive impairment has been hypothesized to be one of the most important components of major depressive disorder (MDD; referred to as clinical depression), although typical cognitive symptoms are less frequent in people with depression than in people with schizophrenia or bipolar disorder (BD; sometimes referred to as manic-depressive disorder). The importance of α-Klotho in the aging process has been well-documented. Growing evidence points to the role of α-Klotho in regulating other biological functions, including responses to oxidative stress and the modulation of synaptic plasticity. It has been proven that a Klotho deficit may contribute to the development of various nervous system pathologies, such as behavioral disorders or neurodegeneration. Given the growing evidence of the role of α-Klotho in depression and cognitive impairment, it is assumed that this protein may be a molecular link between them. Here, we provide a research review of the role of α-Klotho in depression and cognitive impairment. Furthermore, we propose potential mechanisms (related to oxidative stress and glutamatergic transmission) that may be important in α-Klotho-mediated regulation of mental and cognitive function.
... It was observed that a lack of klotho may result in cardiovascular events, but maintaining elevated levels of serum klotho can decrease cardiovascular mortality [7]. In fact, α-klotho is not only implicated in the aging process, but also has a role in regulating psychological functioning in cognitive and mental disorders [10]. A new study discovered a relationship between middle-aged and older people's serum αklotho and depression, especially in women [11]. ...
Article
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This study examines α-klotho levels in depressed American adults and their association with cardiovascular disease and all-cause mortality, utilizing data from the National Health and Nutrition Examination Survey (2007–2016) and mortality details from the National Death Index up to December 31, 2019. Including 3329 participants with depression, findings revealed 485 all-cause and 113 cardiovascular deaths. To investigate the nonlinear association between α-klotho and mortality, the Cox proportional hazards regression model, restricted cubic splines, and two-piecewise Cox proportional hazards model were developed. Analyzes indicated an “L-shaped” relationship between ln-transformed α-klotho levels and all-cause mortality, with a significant threshold effect at 6.53 ln(pg/ml). Below this threshold, ln-transformed α-klotho levels were inversely related to all-cause mortality (adjusted HR 0.33, 95%CI = 0.19–0.56), with no significant association above it (adjusted HR 1.41, 95%CI = 0.84–2.36). Cardiovascular mortality showed no link to α-klotho levels. Subgroup analysis shown that, the association between ln-transformed α-klotho concentration and all-cause mortality was consistent in subgroups according to gender, age, BMI, race, and depression(adjusted P > 0.05). The study uncovers a non-linear “L-shaped” association between ln-transformed α-klotho levels and all-cause mortality in depressed individuals, suggesting α-klotho assessment as a tool for identifying high-risk patients and guiding preventive strategies to enhance survival.
... Research data suggested a strong association between klotho and depression, which may be attributed to oxidative stress (Gold et al., 2013). Additionally, literature also suggested a relationship between klotho, cognitive function, and stress response (Gao et al., 2021). In the "double-hit" hypothesis of NAFLD, inflammation mediated by oxidative stress is considered as the "second hit" (Chitturi and Farrell, 2001). ...
Article
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Introduction This study investigated the potential link between serum klotho levels and cognitive function in patients with non-alcoholic fatty liver disease (NAFLD). Materials and Methods Utilizing NHANES data from 2011 to 2014, the research included 356 eligible participants. NAFLD was identified with the United States Fatty Liver Index (US-FLI), and cognition was measured by various tests including the Animal Fluency Test (AFT), Digit Symbol Substitution Test (DSST), Immediate Recall Test (IRT), and Delayed Recall Test (DRT). Weighted logistic regression and restricted cubic splines were employed to analyze the relationship between klotho levels and cognitive scores. Results A significant nonlinear association was observed between klotho levels and the performance in DSST and Delayed Recall Test (DRT). After controlling for confounding factors, the study found a positive association between higher serum klotho levels and improved cognitive performance in both AFT and DSST. However, there was no significant relationship between klotho levels and the IRT or DRT, regardless of whether the natural logarithm or quartile was considered. Discussion The findings suggest that a higher serum klotho level may be positively correlated with better cognitive performance in NAFLD patients.
... Alpha-Klotho is associated with renal function decline, along with a potential role in the pathogenesis of CoI and depression. It could establish a neurobiological connection between CKD, depression, and dementia by regulating oxidative stress and inflammation [73]. Studies have indicated a correlation between decreased serum α-Klotho and cognitive decline in older adults [74,75]. ...
Article
Full-text available
Background Cognitive impairment (CoI), chronic kidney disease (CKD), and depression are prevalent among older adults and are interrelated, imposing a significant disease burden. This study evaluates the association of CKD and depression with CoI and explores their potential interactions. Method Data for this study were sourced from the 2011–2014 National Health and Nutritional Examination Survey (NHANES). Multiple binary logistic regression models assessed the relationship between CKD, depression, and CoI while controlling for confounders. The interactions were measured using the relative excess risk of interaction (RERI), the attributable proportion of interaction (AP), and the synergy index (S). Results A total of 2,666 participants (weighted n = 49,251,515) were included in the study, of which 700 (16.00%) had CoI. After adjusting for confounding factors, the risk of CoI was higher in patients with CKD compared to non-CKD participants (odds ratio [OR] = 1.49, 95% confidence interval [CI]:1.12–1.99). The risk of CoI was significantly increased in patients with depression compared to those without (OR = 2.29, 95% CI: 1.73–3.03). Furthermore, there was a significant additive interaction between CKD and depression in terms of the increased risk of CoI (adjusted RERI = 2.01, [95% CI: 0.31–3.71], adjusted AP = 0.50 [95% CI: 0.25–0.75], adjusted S = 2.97 [95% CI: 1.27–6.92]). Conclusion CKD and depression synergistically affect CoI, particularly when moderate-to-severe depression co-occurs with CKD. Clinicians should be mindful of the combined impact on patients with CoI. Further research is needed to elucidate the underlying mechanisms and assess the effects specific to different CKD stages.
... In addition to population-based studies, there were several experimental findings that echo the results of our analysis. It is well known that Klotho is an aging-related marker [20]. Yu et al. asserted that characteristic dietary fiber compounds had a maintenance and improvement effect on learning and memory ability in aging mice, as well as improved antioxidant capacity and reduced inflammation levels. ...
Article
Full-text available
Background: Klotho is an aging-related marker closely associated with a number of diseases. A growing body of evidence suggests that dietary factors and lifestyle habits can impact serum Klotho levels. The effect of dietary fiber, a key component of a healthy diet, on the body's serum Klotho levels has not been fully elucidated. Objective: The aim of this study was to explore the relationship between dietary fiber intake and serum Klotho levels in people aged 40-79 years in the United States. Methods: A total of 11,282 participants were included in this study, all from the National Health and Nutrition Examination Survey from 2007 to 2016. Dietary fiber intake was assessed by uniformly trained interviewers using the 24 h dietary recall method. Serum Klotho was quantified using commercially available ELISA kits manufactured by IBL International, Japan. The relationship between dietary fiber intake and serum Klotho levels was analyzed using a multiple linear regression model. Subsequently, the non-linear dose-response relationship between the two was further explored using a restricted cubic spline (RCS) model. Results: After adjusting for potential confounders, serum Klotho levels increased by 1.9% (95% confidence interval [CI]: 0.8%, 3.0%) for each interquartile range increase in dietary fiber intake in all participants. Considering dietary fiber intake as a categorical variable, serum Klotho levels were found to be 4.7% higher in participants in the highest quartile of dietary fiber intake than in those in the lowest quartile (95% CI: 1.8%, 7.6%). RCS plots depicted a non-linear positive correlation between dietary fiber intake and serum Klotho levels. Subgroup analysis revealed that the relationship between dietary fiber intake and serum Klotho levels was more pronounced in older (percentage change: 7.0%; 95% CI: 2.5%, 11.7%) and overweight and obese participants (percentage change: 4.9%; 95% CI: 1.5%, 8.4%). Conclusions: The results of this study showed that dietary fiber intake was significantly associated with serum Klotho levels in participants. This finding is yet to be further confirmed by prospective studies.
... This may be a consequence of time lag of the compensation mechanism. Besides, sKl levels are found to be decreased in patients who have neuropsychiatric diseases causing poor sleep quality like depression and dementia [33], which may show another evidence for the relation of sleep quality and sKl levels. ...
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Purpose Sleep and Klotho seem to share common physiological pathways in aging. However, studies investigating this relationship are very few and none of them was done with a specific patient group. The aim of this study was to investigate the association of sleep quality and soluble Klotho levels in hemodialysis patients. Methods 100 hemodialysis patients were included in this study. Soluble Klotho levels were obtained from each patient and Pittsburgh Sleep Quality Index was performed by all patients. Association of soluble Klotho with sleep quality was calculated. Results Soluble Klotho levels were significantly inversely correlated with total sleep quality score (p < 0.001, r = − 0.444). Among the subscales, soluble Klotho levels were negatively correlated with subjective sleep quality (p < 0.001, r = − 0.365), sleep latency (p = 0.002, r = − 0.312), sleep disturbance (p = 0.002, r = − 0.303) and daytime dysfunction (p = 0.027, r = − 0.221). Patients who had good sleep quality scores were found to have higher soluble Klotho levels [4.15 (0.05–22.68) vs. 1.14 (0.32–17.63), p < 0.001]. In regression analysis, total sleep quality score, subjective sleep quality and age were found to be independent negative factors for soluble Klotho levels. Conclusion In this study, a significant association between sleep quality and soluble Klotho levels was revealed in hemodialysis patients. Improving sleep quality will lead to increased soluble Klotho levels, which may further slow down the aging process in hemodialysis patients.
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Introduction With the global rise in life expectancy, the incidence of dementia is increasing, often accompanied by depressive symptoms. Understanding the interplay between dementia and depression is crucial, as depression may not only co-occur with but also potentially exacerbate the progression of dementia. This study employs bibliometric analysis to map the global research landscape, identify prevailing themes, and discern future research directions. Methods We analyzed reviews and original research articles on dementia and depression extracted from the Web of Science Core Collection spanning from 2005 to 2024. Utilizing tools such as CiteSpace, VOSviewer, and an R-based bibliometric analysis package, we assessed trends in publication volume, citation frequency, contributing countries, leading institutions, predominant journals, influential authors, and emergent keywords. Results A total of 1972 publications were obtained, revealing a consistent increase in both the number of publications and their citation impact over the study period. The United States is the country with the most publications and the most extensive collaborations. The University of Toronto and the Journal of Alzheimer’s Disease were identified as key contributors to this field. This research area is currently focused on cognitive impairments, the role of gut microbiota, and non-drug interventions. Future directions emphasize the importance of early detection and intervention, a deeper understanding of the gut-brain axis, and the integration of technology in treatment strategies. Additionally, there is a growing interest in the physiological and psychological interplays such as oxidative stress and its implications. Conclusion This study underscores pathogenesis, comorbid conditions, and non-drug interventions as primary research focal points, suggesting these areas as potential pathways for therapeutic innovation. These insights are intended to deepen our understanding, enhance diagnostics, and improve the management of dementia and depression, providing guidance for future research aimed at addressing these escalating global health challenges.
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Background Circadian syndrome (CircS) is characterized by disrupted circadian rhythm. α-klotho, an anti-aging protein, has garnered particular attention recently. The study aimed to assess the associations of serum alpha klotho and CircS. Methods Data from National Health and Nutrition Examination Survey (NHANES) 2005-2016 were analyzed. CircS further encompasses sleep disorders and depression, in addition to the components of the metabolic syndrome (MetS). Multivariate logistic regression, subgroup analysis and restricted cubic spline plot were used to analyze the associations. Results We found a negative relationship between circulating α-klotho and the risk of CircS. Using multivariate logistic regression models, we assessed the association between α-klotho and CircS while adjusting for potential confounders. Compared to the first quartile of klotho, the second quartile group showed 16% decrease in CirS risk (OR=0.84, 95%CI = 0.74-0.96, P = 0.012), and the third quartile group exhibited 21% decrease in CirS risk (OR=0.79, 95%CI = 0.69-0.91, p<0.001) after adjusting all demographic and lifestyle variables. Subgroup analyses revealed significant interactions between α-klotho and alcohol consumption (p=0.008). Additionally, we observed inverse association between α-klotho and odds ratio of CirS in a restricted cubic spline plot. Conclusion In this large cross-sectional study, our results suggest that higher serum α-klotho levels are significantly associated with a reduced likelihood of circadian syndrome in U.S. adults. Further studies are needed to confirm these findings and elucidate the underlying mechanisms..
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The apolipoprotein E ε4 (APOE4) allele is the strongest genetic risk factor for Alzheimer disease (AD), the most common neurodegenerative condition. Unfortunately, APOE4 is not rare. Approximately 23% of the US population carries an allele. One copy increases risk of developing AD by 3-fold; 2 copies increases it by more than 12-fold. The APOE4 allele shortens the time to disease onset and reduces survival¹,2 in both sporadic and familial AD. Beyond AD, APOE4 increases the likelihood of cognitive decline in patients with other neurologic disorders,³ elderly people who are clinically normal,⁴ and even patients with head trauma as putatively mild as heading a ball in soccer.⁵ Neuroanatomic differences with APOE4 have been detected in AD-relevant brain regions in adolescence⁶ and as early as infanthood.⁷ Remarkably—despite the lifelong influences of APOE4—not all who carry the allele are fated for AD.
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Question: Does Klotho-VS heterozygosity protect against Alzheimer disease (AD) in individuals who carry APOE4? Findings: In this study, associations were evaluated across 22 AD cohorts (n = 20 928), 3 longitudinal cohorts (n = 3008), and 4 cohorts collecting β-amyloid measurements (cerebrospinal fluid, n = 556; brain, n = 251). In individuals who carry APOE4, Klotho-VS heterozygosity was associated with reduced AD risk and more favorable β-amyloid profiles in the brain and cerebrospinal fluid of older control participants. Klotho-VS heterozygosity was also associated with reduced AD conversion risk in individuals who carry APOE4. Meaning: Pathways associated with KL merit exploration for novel AD drug targets, and the KL-VS genotype should be considered in conjunction with APOE genotype to refine prediction models used in clinical trial enrichment.
Article
Hyalinosis is a vascular lesion affecting the renal vasculature and contributing to ageing-related renal function decline. We assessed whether arteriolar hyalinosis is caused by Klotho deficiency - a state known to induce both renal and vascular phenotypes associated with ageing. Histochemistry was used to assess hyalinosis in Klotho-/- kidneys, compared to Klotho+/- and wild-type littermates. Immunohistochemistry was used to investigate vascular lesion composition and the different layers of the vascular wall. Finally, spironolactone was used to inhibit calcification in kl/kl mice and vascular lesions were characterized in the kidney. Arteriolar hyalinosis was detected in Klotho-/- mice, which was present up to the afferent arterioles. Hyalinosis was accompanied by loss of α-smooth muscle actin expression, while the endothelial lining was mostly intact. Hyalinous lesions were positive for IgM and iC3b/c/d, indicating subendothelial leakage of plasma proteins. The presence of extracellular matrix proteins suggested increased production by smooth muscle cells. Finally, in Klotho-/- mice with marked vascular calcification, treatment with spironolactone allowed for replacement of calcification by hyalinosis. Klotho deficiency potentiates both endothelial hyperpermeability and smooth muscle cell de-differentiation. Absent a calcification-inducing stimulus, smooth muscle cells assume a synthetic phenotype in response to subendothelial leakage of plasma proteins. In the kidney, this results in arteriolar hyalinosis, which contributes to the decline in renal function. Klotho may play a role in preventing ageing-related arteriolar hyalinosis.