Therapeutic modulation of autophagy: which disease comes first?

Abstract

The relentless efforts of thousands of researchers have allowed deciphering the molecular machinery that regulates and executes autophagy, thus identifying multiple molecular targets to enhance or block the process, rendering autophagy "druggable". Autophagy inhibition may be useful for preserving the life of cells that otherwise would succumb to excessive self-digestion. Moreover, autophagy blockade may reduce the fitness of cancer cells or interrupt metabolic circuitries required for their growth. Autophagy stimulation is probably useful for the prevention or treatment of aging, cancer (when stimulation of immunosurveillance is the therapeutic goal), cardiovascular disease, cystic fibrosis, infection by intracellular pathogens, obesity, and intoxication by heavy metals, just to mention a few examples. Epidemiological evidence suggests broad health-improving effects for lifestyles, micronutrients, and drugs that favor autophagy. In this review, we discuss the role of autophagy in disease pathogenesis while focusing on the question, which disease will become the first clinically approved indication for therapeutic autophagy modulation.

Fig. 1

Indications for autophagy inhibition. a Hypothetical desirable and side effects of autophagy inhibition are shown in green and red, respectively. b For reducing unacceptable side effects, it may be necessary to administer autophagy inhibitors at a reduced dose and in short-term or intermittent schedules

Fig. 2

Indications for autophagy enhancement. For a detailed discussion, consult main text

Fig. 3

General considerations on strategies for autophagy induction. Life style modifications (exercise, fasting, diet), natural caloric restriction mimetics (CRMs), old drugs for which autophagy induction has been discovered, as well as completely new drugs may be used to stimulate autophagy for therapeutic purposes