A geroscience approach for osteosarcopenia: Autophagy and senescence as therapeutic targets

Natanael Perez Cordero, Patricia V. Schoenlein, Sadanand Fulzele, William D. Hill

Research output: Chapter in Book/Report/Conference proceedingChapter

Abstract

Chronic diseases like osteoporosis are most common among the older population. With an ever-growing number of older patients due to an increase in lifespan, management and treatment of chronic diseases have been a primary focus of modern medicine centered on increasing not just patient lifespan but also their “Health-Span.” Autophagy and senotheraputics are among the areas under intensive research due to their antiaging properties, like alleviating stem cell dysfunction. As the geroscience hypothesis proposes, aging seems to be the primary culprit behind many, if not all chronic diseases, including osteosarcopenia. Targeting certain elements of the aging physiology like cellular senescence has proven to increase bone and muscle formation and alleviate or postpone degenerative diseases like osteosarcopenia. Both general and selective autophagy can mediate antisenescence properties depending on the stimuli triggering it and the cell type. Due to this cell and the context-dependent role of autophagy, multiple molecular mechanisms are likely involved. Underlying molecular pathways are now being delineated, and agents are being identified that can block senescence or inhibit the Senescence Associated Secretory Phenotype (SASP), which is the release of proinflammatory products by senescent cells into the extracellular milieu. Senostatics like Ruxolitinib (JAK/STAT pathway inhibitor) and metformin (an AMPK activator that is commonly used to treat Type 2 Diabetes Mellitus) have proven to inhibit the SASP and improve overall bone and muscle formation. At the same time, senolytics like Dasatinib (tyrosinase kinase inhibitor), Quercetin (a flavanol present in many fruits and vegetables), Navitoclax (targets the Bcl-2 family of antiapoptotic factors) and Fisetin (more potent flavonoid than Quercetin) can eradicate senescent cells. Overall, a reduction in the percentage of senescent cells or their function (i.e., SASP) in osteogenic and myogenic stem cell populations allows bone and muscle formation by returning the lineage commitment to osteoblast and myoblast differentiation instead of adipocytic differentiation. Unfortunately, the lack of reliable biomarkers, in addition to the lack of knowledge regarding the off target effects of these senotherapeutic drugs, has delayed the process of extensive randomized human clinical trials. Here we will examine the potential of autophagy, senostatics, and senolytics in treating chronic diseases like osteosarcopenia and discuss the drawbacks that still need solving to better understand how these approaches may impact human disease processes.

Original languageEnglish (US)
Title of host publicationOsteosarcopenia
PublisherElsevier
Pages51-75
Number of pages25
ISBN (Electronic)9780128200889
ISBN (Print)9780128204207
DOIs
StatePublished - Jan 1 2022

Keywords

  • ASP
  • Autophagy
  • Mesenchymal stem cell
  • Osteoporosis
  • Osteosarcopenia
  • Senescence
  • Senolytics
  • Senomorphics
  • Senostatics
  • Senotherapeutic

ASJC Scopus subject areas

  • General Medicine

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