BACKGROUND: The hormone klotho, encoded by the gene klotho, is primarily 
expressed in the kidney and choroid plexus of the brain. Higher klotho 
concentrations have been linked to better physical performance; however, it is 
unknown whether klotho relates to frailty status in older adults.
METHODS: Plasma klotho was measured in 774 participants aged ≥65 years enrolled 
in InCHIANTI, a prospective cohort study comprising Italian adults. Frailty 
status was assessed at 3 and 6 years after enrollment. Frailty was defined as 
presence of at least three out of five criteria of unintentional weight loss, 
exhaustion, sedentariness, muscle weakness, and slow walking speed; prefrailty 
was defined as presence of one or two criteria; and robustness was defined as 
zero criteria. We assessed whether plasma klotho concentrations measured at the 
3-year visit related to frailty.
RESULTS: Each additional natural logarithm of klotho (pg/mL) was associated with 
lower odds of frailty versus robustness after adjustment for covariates (odds 
ratio [OR] 0.46; 95% confidence interval 0.21, 0.98; p-value = .045). Higher 
klotho was particularly associated with lower odds of exhaustion (OR 0.57; 95% 
CI 0.36, 0.89; p-value = .014). Participants with higher klotho also had lower 
estimated odds of weight loss and weakness, but these findings were not 
statistically significant.
CONCLUSIONS: Higher plasma klotho concentrations were associated with lower 
likelihoods of frailty and particularly exhaustion. Future studies should 
investigate modifiable mechanisms through which klotho may affect the frailty 
syndrome.