The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function

Abstract

Aging is accompanied by disrupted information flow, resulting from accumulation of molecular mistakes. These mistakes ultimately give rise to debilitating disorders including skeletal muscle wasting, or sarcopenia. To derive a global metric of growing 'disorderliness' of aging muscle, we employed a statistical physics approach to estimate the state parameter, entropy, as a function of genes associated with hallmarks of aging. Escalating network entropy reached an inflection point at old age, while structural and functional alterations progressed into oldest-old age. To probe the potential for restoration of molecular 'order' and reversal of the sarcopenic phenotype, we systemically overexpressed the longevity protein, Klotho, via AAV. Klotho overexpression modulated genes representing all hallmarks of aging in old and oldest-old mice, but pathway enrichment revealed directions of changes were, for many genes, age-dependent. Functional improvements were also age-dependent. Klotho improved strength in old mice, but failed to induce benefits beyond the entropic tipping point.

The fidelity of genetic information transfer with aging segregates according to biological processes

“…A higher Shannon entropy indicates that the probability distribution of gene expression becomes more uniform, thereby decreasing the ability to reliably predict gene expression. Consistent with our previous work using bulk RNA-seq data from skeletal muscle (10), we found that entropy at the level of single cells increases over time (Figure 1B).…”

Klotho: An Emerging Factor With Ergogenic Potential

“…Therefore, Klotho replacement therapy can target multiple organ systems that are integral to physical function, including the heart, vasculature, and potentially skeletal muscle. A recent study by Clemens and colleagues (5) found that Klotho treatment via adeno-associated virus (AAV) in old (21-24 mo.) mice significantly reduced skeletal muscle fibrosis, reduced intramuscular lipid accumulation, enhanced muscle mitochondrial structure, and improved muscle strength and endurance.…”

“…Klotho deficient mice exhibit a shortened lifespan and a premature aging syndrome that includes phenotypic features of sarcopenia and physical dysfunction such as severe muscle wasting, hypokinesis, an abnormal walking pattern, decreased stride length, muscle weakness, and decreased running endurance (1)(2)(3). Conversely, restoration of Klotho in Klotho deficient mice can reverse these aging phenotypes and extend life span (1,(4)(5)(6). In humans, several epidemiological studies have revealed a link between Klotho levels and physical function indices (7)(8)(9)(10)(11).…”

“…Accumulating data suggest that Klotho may play a key role in the development of sarcopenia and its progression into physical dysfunction. Moreover, research in animal models suggests that enhancing Klotho levels may improve skeletal muscle strength, quality, and recovery following injury and may therefore represent a novel ergogenic agent (5,33,34).…”

“…The term “ergogenic” comes from the Greek prefix ergo- meaning “work” and the suffix -gen meaning “production.” As such, any intervention or therapeutic agent that enhances or restores the ability to produce work can be described as “ergogenic.” Accumulating data suggest that Klotho may play a key role in the development of sarcopenia and its progression into physical dysfunction. Moreover, research in animal models suggests that enhancing Klotho levels may improve skeletal muscle strength, quality, and recovery following injury and may therefore represent a novel ergogenic agent ( 5 , 33 , 34 ).…”