TY - JOUR TI - The biphasic and age-dependent impact of klotho on hallmarks of aging and skeletal muscle function AU - Clemens, Zachary AU - Sivakumar, Sruthi AU - Pius, Abish AU - Sahu, Amrita AU - Shinde, Sunita AU - Mamiya, Hikaru AU - Luketich, Nathaniel AU - Cui, Jian AU - Dixit, Purushottam AU - Hoeck, Joerg D AU - Kreuz, Sebastian AU - Franti, Michael AU - Barchowsky, Aaron AU - Ambrosio, Fabrisia A2 - Suh, Yousin A2 - Tyler, Jessica K A2 - Remondini, Daniel VL - 10 PY - 2021 DA - 2021/04/20 SP - e61138 C1 - eLife 2021;10:e61138 DO - 10.7554/eLife.61138 UR - https://doi.org/10.7554/eLife.61138 AB - 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. KW - skeletal muscle KW - hallmarks of aging KW - klotho KW - muscle stem cells KW - sarcopenia KW - adeno-associated virus JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -