Klotho Levels Decline with Age, But Are Unaffected by Physical Fitness at a Given Age – Fight Aging!

Klotho is a longevity-associated gene. Klotho functions within the cell, but a portion of the full protein is also released into the bloodstream. In humans, higher levels of circulating klotho correlate with lower incidence of age-related disease and mortality. In mice, interventions such as gene therapies that increase klotho levels have been shown to extend life, while reducing klotho levels shortens life. Klotho is thought to act within the kidney, where it is protective, slowing age-related decline of kidney function. Increased klotho levels produce cognitive improvement in mice and non-human primates, however, and higher levels in humans are associated with lesser degrees of cognitive decline in later life. This may be the case because kidney function is important to all organs, or it may be that klotho acts directly on the brain in some way yet to be rigorously determined. Some groups are pursuing delivery of klotho as a basis for therapies.

You might recall a recent discussion of circulating klotho protein in the bloodstream as a biomarker of the effectiveness of lifestyle interventions to modestly slow aging. Today’s open access paper provides a counterpoint, in that it shows that while klotho levels and physical capabilities both decline with age, the degree of physical fitness at a given age doesn’t appear to correlate with klotho levels. So, per these results, increasing one’s physical fitness in later life wouldn’t be expected to raise klotho levels. This is interesting, because circulating klotho has been shown to correlate with a number of parameters that one would expect to be helped by greater fitness. Levels of chronic inflammation, for example, are higher in people with less circulating klotho.

Relationship between klotho and physical function in healthy aging

Accumulating data suggests that the “anti-aging” protein Klotho may play a key role in the development of functional impairments. α-Klotho, hereby referred to as Klotho, is a large transmembrane glycoprotein that is predominantly expressed in the distal convoluted tubules of the kidneys. A landmark study found that Klotho-deficient mice exhibited a shortened lifespan and a premature aging phenotype that included functional impairments, such as severe muscle wasting, hypokinesis, an abnormal walking pattern, and decreased stride length. In support of these findings, experimental models have shown that Klotho is involved in several key processes that regulate skeletal muscle function, such as muscle regeneration, mitochondrial biogenesis, oxidative stress, and inflammation. Importantly, total circulating Klotho levels have been shown to decline with increasing age, and several epidemiological studies in older adults – all of which included those with chronic diseases – have revealed a strong association between lower Klotho levels and increased disability in activities of daily living, increased risk of frailty, lower performance in the short physical performance battery.

The majority of studies investigating the relationship between circulating Klotho and physical function focused solely on older adults and have included those with comorbidities. The problem is that it is currently unclear whether circulating levels of Klotho are associated with physical function in individuals without comorbidities, and whether they are also associated with impairments in physical function earlier in life. The present study therefore sought to examine the relationship between serum Klotho levels and physical function indices in a community-based cohort of healthy adults across various age categories. Elucidating this relationship enables us to examine the natural history of age-related declines in circulating Klotho and its relationship with physical function in the absence of any chronic disease. We hypothesized that serum Klotho levels are associated with higher measures of physical function in all age groups.

In this cross-sectional study, serum Klotho was measured in 80 adults. Participants (n = 20, 50% men per group) were chosen into four age groups: 20-34, 35-49, 50-64, and ≥ 65 years, and were further grouped based on performance (low vs. high) on grip strength and chair stand tests. Klotho levels were lower in the ≥ 65 years group and the 50-64 years group compared to 20-34 years. No differences were observed in Klotho between the low and high performers. The ≥ 65 years group walked a shorter distance during the 6-min walk test (6MWT) compared to 20-34 years. Klotho was correlated with age, body fat, and 6MWT distance. Klotho levels decline as early as the fifth decade of life, potentially before the onset of age-related impairment in exercise capacity.