Skip to main content
eScholarship
Open Access Publications from the University of California

Scholarly Works (3 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2019)

Aging and aging related diseases are closely related to wellness and lifespan of aged population. Modulating aging can be achieved by specific gene mutations, intrinsic signaling regulation (e.g. by dietary restriction) and pharmacological perturbations. Recent studies on the role of metabolism and endogenous metabolites in aging process provided hope for new anti-aging approaches to counter aging and aging related diseases. Here we identified a novel anti-aging metabolite, α-ketobutyrate (α-KB), that extends the lifespan of adult Caenorhabditis elegans and aged mice. Utilizing drug affinity responsive target stability assay, in-vitro enzymatic kinetics analysis, and epistasis, we demonstrated that α-KB depends on pyruvate dehydrogenase perturbation as a competitive alternative substrate to extend lifespan. Consistently, rewired pyruvate metabolism was detected in both α-KB treatment and genetic inhibition of pyruvate dehydrogenase in mammalian models. Furthermore, AMP-activated protein kinase (AMPK) pathway activation is required to induce longevity by α-KB. In an Alzheimer’s disease C. elegans model, epistasis demonstrated that α-KB requires pyruvate dehydrogenase and AMPK to delay the age dependent paralysis progression. Besides lifespan extension, α-KB also improves fitness in aged mice, including maintaining healthy hair growth. In the search of its mechanism and additional hair regenerative compounds, we discovered the essential role of autophagy in hair growth cycle and potential application of autophagy activators in hair loss therapy. As a shared effector of anti-aging signaling pathways, including TOR and AMPK pathways, autophagy is successfully induced by known aging modulators, α- ketoglutarate, α-KB, rapamycin, and metformin in mouse skin and confers their hair regeneration effect. Co-treatment of specific autophagy inhibitors blocks the stimulation of hair regeneration, which further confirmed the requirement of autophagy activation by these agents. Consistently, dynamically regulated autophagy level is detected during hair cycle: upregulation from telogen throughout anagen phase and downregulation from catagen until telogen. Our finding that α-KB combats aging and aging related disorders in worms and mice has implications for human anti-aging remedies development.

    Cover page: Modulating Aging and Aging-related Symptoms Using Endogenous Small Molecules
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2018)
      Cover page: Hair Regeneration by Small Molecules That Activate Autophagy
      • Article
      • Peer Reviewed
      UC San Francisco Previously Published Works (2019)
      Hair plays important roles, ranging from the conservation of body heat to the preservation of psychological well-being. Hair loss or alopecia affects millions worldwide, but methods that can be used to regrow hair are lacking. We report that quiescent (telogen) hair follicles can be stimulated to initiate anagen and hair growth by small molecules that activate autophagy, including the metabolites α-ketoglutarate (α-KG) and α-ketobutyrate (α-KB), and the prescription drugs rapamycin and metformin, which impinge on mTOR and AMPK signaling. Stimulation of hair growth by these agents is blocked by specific autophagy inhibitors, suggesting a mechanistic link between autophagy and hair regeneration. Consistently, increased autophagy is detected upon anagen entry during the natural hair follicle cycle, and oral α-KB prevents hair loss in aged mice. Our finding that anagen can be pharmacologically activated in telogen skin when natural anagen-inducing signal(s) are absent has implications for the treatment of hair loss patients.
        Cover page: Stimulation of Hair Growth by Small Molecules that Activate Autophagy
        Top