Autophagy is the name given to a complex collection of processes responsible for identifying and recycling damaged or otherwise unwanted structures in the cell. Typically, a structure flagged for recycling is engulfed by an autophagosome, which is transported to and fuses with a lysosome, and the structure is broken down inside the lysosome by enzymes. An optimal level of autophagy for the maintenance of cell function only occurs in response to stress, including heat, cold, lack of nutrients, toxins, oxidative damage to important molecules, and so forth. Thus mild stresses that inflict relatively little damage to a cell can improve the function of cells, tissues, and organs, leading to a greater resistance to the damage and dysfunction of aging. Most of the well studied interventions shown to modestly slow aging and extend life in animals involve an increased operation of autophagy.
Researchers and the longevity industry continue to work towards the development of drugs capable of upregulating autophagy to produce health benefits in older people. These efforts include examples in the well studied category of mTOR inhibitors, drugs that can mimic some of the beneficial metabolic response to exercise and calorie restriction, as well as a good number of unrelated programs at various stages of preclinical and clinical development. Meanwhile, there is a continued effort to better understand and measure autophagy. One of the challenges is that autophagy consists of many different steps, an assay can only obtain insight into one step, and increased activity in any given step can be a sign of increased function, but it can also be a sign that autophagy is dysfunctional and backed up.
Links between autophagy and healthy aging
Several if not all manifestations of aging can be postponed by a healthy lifestyle involving a balanced diet coupled with regular exercise and sufficient sleep. Similarly, various genetic and pharmacological longevity interventions can exert beneficial effects across species in a conserved manner, extending both lifespan and healthspan. While all these interventions-ranging from genetic perturbations to pharmacological supplementation to lifestyle changes-affect diverse biological processes, a common candidate mechanism underpinning at least some of their benefits is autophagy, a cellular recycling process essential for maintaining cellular homeostasis.
In this review, we summarize how autophagy is affected by various pharmacological and lifestyle factors, with a focus on studies in which autophagy has been shown to play a causal role in promoting healthy aging. Specifically, we review the molecular mechanisms through which pharmacological agents, dietary restriction, exercise, sleep adjustments, as well as temperature modulation affect autophagy to extend lifespan and often also healthspan in model organisms and humans.
Still, major gaps remain in human research due to limited assays to monitor autophagy and the scarcity of longitudinal studies linking autophagy dynamics to health outcomes. Closing this gap is a key challenge in converting discoveries from model organisms into interventions that consistently enhance healthy aging in humans. By summarizing current findings and highlighting remaining uncertainties, this review aims to provide a roadmap for translating insights on autophagy from model organisms into strategies to promote healthy aging in humans.
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