- 1Department of Neurology, The Second Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China
- 2Department of Pediatric Surgery, Qilu Hospital of Shandong University, Jinan, China
- 3Cheeloo College of Medicine, Shandong University, Jinan, China
- 4Department of Human Genetics, School of Medicine, Emory University, Atlanta, GA, United States
Objective: Serum klotho protein is a protein with
anti-aging effects. Since the relationship between serum klotho and
Stroke remains rather ambiguous, this research probed into the potential
correlation between serum klotho concentration and Stroke.
Methods: This study employed a cross-sectional
design and incorporated population data from the NHANES from 2007 to
2016. Weighted univariate and multivariate logistic regression models
were utilized to inspect the relationship between klotho and Stroke.
Stratified analyses and interaction tests were carried out to explore
the latent correlation between klotho and Stroke. Finally, a fitted
smooth curve was adopted to depict the non-linear relationship.
Results: In this study, after excluding all the
missing data, a total of 12,414 participants were encompassed, including
450 Stroke individuals. After adjusting for all covariates, higher
klotho was associated with a lower prevalence of Stroke. According to
the subgroup analyses and interaction tests, age, gender, race, BMI,
hypertension, diabetes mellitus, family members, drinker and smoker were
not significantly correlated with the influence of klotho and Stroke.
After adjusting for all covariates, higher klotho was associated with a
lower prevalence of stroke [OR: 0.68, 95% CI: 0.47–0.99].
Conclusion: This study disclosed the negative
correlation between serum klotho protein levels and the prevalence of
Stroke. Further prospective studies are requisite to investigate the
impact of serum klotho protein levels on Stroke and determine the causal
relationship.
1 Introduction
Stroke represents the second leading global cause of mortality, surpassed only by acute ischemic heart disease (1).
This severe acute cerebrovascular disease not only threatens survival
but frequently induces debilitating sequelae including motor deficits,
cognitive impairment, and affective disorders, imposing substantial
socioeconomic burdens and quality-of-life deterioration (2). With the current development of an aging population, the prevalence rate of stroke is continuously rising (3).
Furthermore, stroke is currently emerging gradually among the young
population (attributed to factors including patent foramen ovale,
dyslipidemia, hormonal therapies, and genetic predisposition) (4, 5).
Since stroke is a global public health problem, researchers have never
stopped their research on the specific etiology, pathogenesis,
predictive means and treatment measures of stroke. And they have been
endeavoring to prevent the occurrence of stroke and handle it in a
timely manner through some laboratory test indicators and other
approaches.
The klotho gene, first identified through longevity
studies in murine models (1997), has emerged as a pleiotropic regulator
of aging processes. In mice, the overexpression of the klotho gene
prolongs lifespan, while its mutation reduces it (6).
The human klotho gene is situated at chromosome 13q12. It demonstrates
effects such as anti-aging and anti-inflammation and is correlated with
numerous age-related diseases (7, 8).
The klotho protein encoded by the klotho gene is predominantly a
single-channel transmembrane protein, and its soluble component can be
cleaved to form α-klotho and dissolve in the blood, featuring three
distinct functional types: membrane-bound α-klotho, truncated soluble
α-klotho, and secreted α-klotho (6).
Unless otherwise specified, the term “klotho” specifically refers to
α-klotho. In previous studies, it has been found to be associated with
kidney diseases (9), cardiovascular diseases (10, 11), and diabetes mellitus (12).
Additionally, in the field of neurology, it has also been discovered
that its reduction might be related to Alzheimer’s disease and other
degenerative disorders (13).
In 2014, Dubal and colleagues discovered that mice with higher serum
klotho levels exhibited stronger cognitive function across all age
groups, independent of the aging process (14).
Subsequently, the team of Castner demonstrated through experiments in
rodents and primates that klotho enhances synaptic plasticity and
cognitive capacity. Notably, their research revealed that a single
low-dose (but not high-dose) administration of klotho could improve
memory function in aged non-human primates (15).
Emerging evidence from animal studies has demonstrated that beyond its
well-documented cardiovascular effects, klotho protein plays a
significant role in mediating ischemic preconditioning mechanisms. This
endogenous neuroprotective function not only reduces stroke prevalence
but also exhibits therapeutic potential through multifaceted
cerebroprotective actions, including attenuation of oxidative stress and
modulation of apoptotic pathways (16, 17).
Despite these advances, critical knowledge gaps persist
regarding klotho’s clinical relevance in cerebrovascular disease.
Whether serum klotho levels demonstrate an independent association with
stroke risk beyond traditional cardiovascular risk factors. The number
of related clinical studies is limited, and the sample sizes therein are
relatively small. We hypothesize that: Serum klotho concentration
inversely correlates with stroke prevalence in adults. This association
remains significant after comprehensive adjustment for confounders
including lipid profiles and metabolic comorbidities. Hence, we carried
out this research, conducting a large-sample study in the NHANES, which
is representative of the national population, in the hope of testing
these hypotheses between serum klotho and the prevalence of Stroke in
the clinical setting.
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