The autophagy-senescence axis as a threshold model of aging and therapeutic targeting

TL;DR

This paper explains how autophagy and cellular aging interact in a stage-dependent way, offering a new model for developing targeted therapies for age-related diseases.

Contribution

The paper introduces a threshold model to unify the dual roles of autophagy in aging and disease progression.

Findings

Autophagy prevents senescence at low stress levels but supports it at high stress levels.

Key signaling pathways like mTORC1 and p53 regulate the autophagy-senescence transition.

Targeting autophagy with precision can lead to stage-specific anti-aging therapies.

Abstract

Autophagy and cellular senescence are fundamental stress-response programs that critically shape aging and disease progression, yet their functional relationship has remained paradoxical. Autophagy is traditionally viewed as a cytoprotective process that preserves cellular homeostasis and delays senescence. In contrast, emerging evidence demonstrates that autophagy is also indispensable for the survival and pathological activity of established senescent cells. In this review, we propose a “threshold model” to reconcile these opposing roles and to provide a unified framework linking signal transduction, organelle quality control, and therapeutic intervention. According to this model, autophagy exerts stage-dependent functions governed by stress intensity and disease progression. Below a critical damage threshold, robust autophagic flux suppresses senescence initiation by maintaining mitochondrial integrity, limiting oxidative stress, and preserving proteostasis. Once this threshold is exceeded, autophagy is functionally reprogrammed to sustain the metabolic and biosynthetic demands of senescent cells, including production of the senescence-associated secretory phenotype (SASP). We highlight key signaling nodes that regulate this transition, including mTORC1, AMPK, p53, and p62, as well as spatial and organelle-specific mechanisms such as the TOR–autophagy spatial coupling compartment (TASCC), mitophagy failure, lipophagy blockade, and aberrant nucleophagy. These processes converge on innate immune pathways, notably cGAS–STING and NF-κB signaling, to drive chronic inflammation and tissue dysfunction. Importantly, we extend this mechanistic framework to clinical translation, synthesizing evidence from ongoing trials in cancer, neurodegeneration, metabolic liver disease, and fibrosis. We argue that effective targeting of the autophagy–senescence axis requires precision gerontology, integrating dynamic biomarkers to guide stage-specific interventions—autophagy activation for prevention and autophagy inhibition or senolysis for established disease. This threshold-based perspective provides a rational foundation for next-generation therapeutic strategies targeting aging and age-related disorders.

•Autophagy and senescence have opposing but interconnected roles in aging and disease.•Autophagy suppresses senescence at early stages but supports senescent cell survival later.•A threshold model explains stress- and stage-dependent autophagy reprogramming.•Precision targeting of autophagy enables stage-specific anti-aging and disease therapies.

Autophagy and senescence have opposing but interconnected roles in aging and disease.

Autophagy suppresses senescence at early stages but supports senescent cell survival later.

A threshold model explains stress- and stage-dependent autophagy reprogramming.

Precision targeting of autophagy enables stage-specific anti-aging and disease therapies.

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