Fountain of youth-Targeting autophagy in aging

Abstract

As our society ages inexorably, geroscience and research focusing on healthy aging is becoming increasingly urgent. Macroautophagy (referred to as autophagy), a highly conserved process of cellular clearance and rejuvenation has attracted much attention due to its universal role in organismal life and death. Growing evidence points to autophagy process as being one of the key players in the determination of lifespan and health. Autophagy inducing interventions show significant improvement in organismal lifespan demonstrated in several experimental models. In line with this, preclinical models of age-related neurodegenerative diseases demonstrate pathology modulating effect of autophagy induction, implicating its potential to treat such disorders. In humans this specific process seems to be more complex. Recent clinical trials of drugs targeting autophagy point out some beneficial effects for clinical use, although with limited effectiveness, while others fail to show any significant improvement. We propose that using more human-relevant preclinical models for testing drug efficacy would significantly improve clinical trial outcomes. Lastly, the review discusses the available cellular reprogramming techniques used to model neuronal autophagy and neurodegeneration while exploring the existing evidence of autophagy's role in aging and pathogenesis in human-derived in vitro models such as embryonic stem cells (ESCs), induced pluripotent stem cell derived neurons (iPSC-neurons) or induced neurons (iNs).

Keywords: aging; autophagy; autophagy-modifying drugs; clinical trial; direct reprogramming; disease modeling; neurodegenerative diseases; rejuvenation.

FIGURE 1

Cellular reprogramming models derived from human somatic cells to study aging and rejuvenation via autophagy modulation. Schematic figure summarizing cellular reprogramming models derived from human somatic cells to study neuronal rejuvenation via autophagy modulation. Human-derived in vitro 2D neuronal models can be generated from embryonic stem cells (ESCs) (A) or by post-differentiation reprogramming (B) from pluripotent stem cells (iPSCs) derived from somatic human cells. In addition, direct reprogramming (C) allows the generation of induced neurons (iNs). 3D brain organoids can be generated by 3 routes: from ESCs, iPSCs and iNs. The use of known (mTOR, AMPK, ATG5, BECN1, and TFEB) and yet undiscovered therapeutic autophagy targets (D) allows the rejuvenation (E) of neuron and brain organoid models for modeling neuronal aging. AMPK, AMP-activated protein kinase; BECN1, Beclin-1; ESC, embryonic stem cell; FOXO, forkhead box class o family member protein; iPSC, induced pluripotent stem cell; mTOR, mammalian target of rapamycin; TFEB, transcription factor EB.