Research Paper|Volume 11, Issue 15|pp 5628—5645

Rejuvenation of brain, liver and muscle by simultaneous pharmacological modulation of two signaling determinants, that change in opposite directions with age

Melod Mehdipour¹, Jessy Etienne¹, Chia-Chien Chen², Ranveer Gathwala¹, Maryam Rehman¹, Cameron Kato¹, Chao Liu¹, Yutong Liu¹, Yi Zuo², Michael J. Conboy¹, Irina M. Conboy¹

¹Department of Bioengineering and QB3 Institute, University of California, Berkeley, Berkeley, CA 94720, USA
²Department of Molecular, Cell and Developmental Biology, University of California, Santa Cruz, Santa Cruz, CA 95064, USA

Received: February 7, 2019Accepted: July 31, 2019Published: August 15, 2019

https://doi.org/10.18632/aging.102148

Copyright © 2019 Mehdipour et al. This is an open-access article distributed under the terms of the Creative Commons Attribution (CC BY) 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

We hypothesize that altered intensities of a few morphogenic pathways account for most/all the phenotypes of aging. Investigating this has revealed a novel approach to rejuvenate multiple mammalian tissues by defined pharmacology. Specifically, we pursued the simultaneous youthful in vivo calibration of two determinants: TGF-beta which activates ALK5/pSmad 2,3 and goes up with age, and oxytocin (OT) which activates MAPK and diminishes with age. The dose of Alk5 inhibitor (Alk5i) was reduced by 10-fold and the duration of treatment was shortened (to minimize overt skewing of cell-signaling pathways), yet the positive outcomes were broadened, as compared with our previous studies. Alk5i plus OT quickly and robustly enhanced neurogenesis, reduced neuro-inflammation, improved cognitive performance, and rejuvenated livers and muscle in old mice. Interestingly, the combination also diminished the numbers of cells that express the CDK inhibitor and marker of senescence p16 in vivo. Summarily, simultaneously re-normalizing two pathways that change with age in opposite ways (up vs. down) synergistically reverses multiple symptoms of aging.