klotho is expressed mainly in the kidneys , parathyroid glands , brain choroid plexus , and testes ( 2 - 4 ) .
studies have confirmed klotho expression in other tissues , including the aorta , colon , thyroid gland , and pancreas , but the kidney remains the strongest klotho - producing organ ( 5 ) .
the latter functions as a co - receptor for fibroblast growth factor-23 ( fgf23 ) . the membrane - bound form ,
after losing its membrane domain , enters into the circulation as soluble klotho ( skl ) , acting as a hormone with anti - aging and anti - oxidative stress properties ; skl can also be directly generated by alterative splicing of the klotho transcript ( 2 , 5 ) .
klotho deficiency is an early biomarker for chronic kidney disease , and its upregulation could protect the kidney from fibrosis progression ( 6 ) .
the beneficial effect of physical activity in preventing premature mortality has been established by epidemiological studies showing that exercise may delay aging through various mechanisms .
klotho upregulates nitrous oxide ( no ) production and inhibits angiotensin ii - induced reactive oxygen species production within endothelial cells ( 7 ) . in an epidemiological study , handgrip strength , an indicator of total body muscle strength ,
the purpose of this study was to determine whether plasma klotho levels are inuenced by aerobic exercise .
for this purpose , plasma klotho levels were measured in a group of trained athletes .
in this study , 30 healthy football players ( males aged 18  22 years ) participated .
the controls were 28 healthy young males ( age range 18  27 years ) .
all subjects were nonsmokers and free of cardiovascular disease , as indicated by their medical history .
none of the subjects took cardiovascular medications or hormone replacement therapy , and they all maintained routine eating habits . in the experimental group , klotho concentration was measured the morning after a session of afternoon training , with blood samples collected from the antecubital vein .
all participants had abstained from caffeine and fasted for at least 8 h before sampling .
we did not measure the level of physical activity in the control group ; they were healthy young males with normal daily physical activity , but none were trained athletes .
plasma klotho concentrations were measured with the elisa technique , using a soluble klotho elisa assay kit based on the manufacturer s instructions ( human klotho elisa kit ; hangzhou eastbiopharm co. , ltd . , hangzhou , china ) .
the demographic characteristics and measurements of the athlete group and the controls , respectively , were as follows : age , 18  22 versus 18  27 years ; body mass index , 22.3  1.4 versus 24.9  1.3 kg / mg ; total cholesterol , 5.3  0.4 versus 5.7  0.3 mmol / l ; triglycerides , 1.5  0.1 versus 1.7  0.15
mmol / l ; serum calcium , 9.8  0.8 versus 9.7  0.6 ; serum phosphorus , 4.4  0.3 versus 4.93  0.34 ; systolic blood pressure , 117  5 versus 119  6 mmhg ; diastolic blood pressure , 70  4 versus 71  3 mmhg ; and plasma klotho , ng / ml 3.375  1.48 ng / ml versus 1.39  0.43 ng / ml ( p < 0.05 ) .
we found no significant differences between the groups for total cholesterol , triglycerides , and blood pressure .
the control subjects were within close range of the previously proposed klotho concentrations for normal individuals , while the athlete group had significantly higher plasma klotho concentrations .
the results of this study showed that aerobic exercise training induces an increase in plasma klotho levels .
plasma klotho levels were only measured one time , the day after exercise in the athlete group ; therefore , it is not known whether this elevation continues over time .
our study population and the controls were healthy young adult males , and their serum calcium and phosphate levels were within the normal range . in the study group , we collected the blood samples the morning after the last evening exercise , so we can not rule out the acute effect of exercise on plasma klotho levels .
it has been shown that aerobic exercise training induces increased plasma klotho concentrations and decreased arterial stiffness in postmenopausal women ( 9 ) .
exercise training might increase circulating klotho due to increases in peroxisome proliferator - activated receptors ( ppar ) and decreases in angiotensin ii type i receptor ( at1r ) signaling ( 10 ) .
aerobic exercise - induced increases in plasma klotho concentrations could be responsible for exercise - induced decreases in arterial stiffness ( 11 ) , enhancing vascular protection and ameliorating endothelin - induced arterial stiffness .
secreted klotho protects endothelial cells and smooth muscle cells through no production ( 12 ) and suppression of oxidative stress ( 13 - 15 ) .
no production regulates endothelial cell calcium inux ( 9 ) . transforming growth factor beta-1 ( tgf-1 ) and endothelin-1 ( et-1 ) receptor activation
negatively affect arterial stiffness , and their levels are decreased by exercise training ( 16 ) .
interestingly , in a cross - sectional study , low plasma klotho concentrations were independently associated with disability among the elderly ( 17 ) .
exercise - induced increment of serum klotho could be due to increased klotho secretion or increased splicing of membrane - bound klotho ( 9 ) .
the kidney is the major source of skl production ( 18 ) , and membrane - bound klotho is also a co - activator of fgf23 , which is prominently expressed in distal convoluted tubule ( dct ) and proximal convoluted tubule ( pct ) cells ; these locations are essential for its function as a phosphaturic substance ( 11 ) .
klotho deficiency is an early biomarker for chronic kidney disease ( ckd ) , and a progressive decline in urine klotho occurs with ckd progression ( 6 , 11 , 19 ) .
endogenous klotho may inuence the processes of inammation , oxidative stress , and vascular calcication and remodeling ( 20 ) .
secreted klotho directly blocks phosphate - induced dedifferentiation of vascular smooth muscle cells into osteoblast - like cells .
secreted klotho also prevents the transformation of endothelial cells to osteoblast - like cells ( 21 , 22 ) .
angiotensin ii downregulates renal klotho protein expression ( 23 ) , and at1r blockade increases circulating klotho .
further studies are needed in order to clarify the dynamics of klotho production and secretion , and to understand the mechanisms of exercise - induced klotho secretion or shedding .
 background : klotho is an anti - aging protein that is predominantly secreted by the kidneys.objectives:the aim of the study was to measure and compare the circulating klotho levels in the serum of trained athletes and in healthy , non - athlete controls.materials and methods : thirty trained football players were enrolled and their serum klotho levels were measured the morning after their last evening exercise training.results:the plasma free klotho concentration was significantly higher in the athlete group ( 3.375  1.48 ng / ml ) compared to the non - athletes ( 1.39  0.43 ng / ml ) ( p < 0.05 ) . 
 serum levels of cholesterol , triglycerides , calcium , and phosphorus were not significantly different between the two groups.conclusions:regular aerobic exercise could increase plasma klotho levels , and this could be an explanation for exercise - related anti - aging effects . 