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

eLife

Nathaniel Luketich¹  Hikaru Mamiya¹  Jian Cui²  Aaron Barchowsky³  Sunita Shinde⁴  Amrita Sahu⁴  Sruthi Sivakumar⁵  Abish Pius⁶  Zachary Clemens⁷  Fabrisia Ambrosio⁸  Purushottam Dixit⁹  Joerg D Hoeck^1,10  Sebastian Kreuz^1,10  Michael Franti^1,10 

[1] Department of Bioengineering, University of Pittsburgh, Pittsburgh, United States;Department of Computational & Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, United States;Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, United States;Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, United States;Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, United States;Department of Bioengineering, University of Pittsburgh, Pittsburgh, United States;Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, United States;Department of Computational & Systems Biology, School of Medicine, University of Pittsburgh, Pittsburgh, United States;Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, United States;Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, United States;Department of Physical Medicine & Rehabilitation, University of Pittsburgh, Pittsburgh, United States;Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, United States;Department of Bioengineering, University of Pittsburgh, Pittsburgh, United States;McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, United States;Department of Physics, University of Florida, Gainesville, United States;Department of Research Beyond Borders, Regenerative Medicine, Boehringer Ingelheim Pharmaceuticals, Inc, Rhein, Germany;

关键词: skeletal muscle;    hallmarks of aging;    klotho;    muscle stem cells;    sarcopenia;    adeno-associated virus;    Mouse;   

DOI  :  10.7554/eLife.61138

来源: eLife Sciences Publications, Ltd

【 摘 要 】

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.

【 授权许可】

CC BY