The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation

Mar 29, 2026Cytokine

The IGF-1 aging switch: a two-phase model for how aging cells drive inflammation and targeted aging control

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Longevity & Aging on OpenScience ↗PubMed ↗DOI ↗

Abstract

Insulin-like growth factor-1 (IGF-1) signaling is associated with both tissue repair and chronic inflammation.

The duration of IGF-1 exposure, whether acute or chronic, influences cellular outcomes, potentially determining whether cells repair or enter stable senescence.
Transient IGF-1 signaling may support cellular homeostasis and repair, while sustained activation could lead to cellular aging through DNA damage and inflammation.
IGF-binding protein-5 (IGFBP-5) plays a critical role in promoting senescence in certain cells by connecting inflammatory signals to mechanisms that halt cell division.
Human conditions of IGF-1 deficiency and excess demonstrate the health risks related to imbalanced IGF-1 signaling.
New evidence suggests that extracellular vesicles might enable the spread of senescence signals despite overall regulation of IGFBP levels.

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Insulin-like growth factor-1 (IGF-1) signaling plays a paradoxical role in aging, acting as both a mediator of tissue repair and a driver of chronic inflammation through the senescence-associated secretory phenotype (SASP). In this review, we propose a biphasic senescence switch model in which the temporal pattern of IGF-1 exposure, acute versus chronic, determines cellular fate. Transient IGF-1 signaling supports homeostasis and repair, whereas sustained activation promotes stable senescence via reactive oxygen species (ROS)-mediated DNA damage, p53/p21 pathway activation, and a potent pro-inflammatory SASP. Central to this process is IGF-binding protein-5 (IGFBP-5), which amplifies senescence in vascular and stromal cells by linking coagulation and inflammatory signals to p53-dependent arrest. The contrasting human conditions of IGF-1 deficiency (Laron syndrome) and excess (acromegaly) illustrate the lifespan and disease risks associated with dysregulated IGF-1 signaling. Emerging evidence highlights the role of extracellular vesicles in bypassing soluble IGFBP regulation, enabling paracrine propagation of senescence even under systemic IGF-1 modulation. Ultimately, we position the IGF-1/IGFBP axis as a prime target for precision senomodulation, advocating for combined strategies that temporally tune endocrine signaling with senolytic and senomorphic therapies to mitigate chronic inflammation, delay age-related dysfunction, and extend healthspan.

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The IGF-1 senescence switch: a biphasic model for SASP-driven aging and precision senomodulation

Abstract

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