The hippo pathway: a molecular bridge between environmental cues and pace of life.

Abstract

The pace of life (POL) is shaped by a complex interplay between genetic and environmental factors, influencing growth, maturation, and lifespan across species. The Hippo signaling pathway, a key regulator of organ size and cellular homeostasis, has emerged as a central integrator of environmental cues that modulate POL traits. In this review, we explore how the Hippo pathway links environmental factors-such as temperature fluctuations and dietary energy availability-to molecular mechanisms governing metabolic balance, hormonal signaling, and reproductive timing. Specifically, we highlight the regulatory interactions between the Hippo pathway and metabolic sensors (AMPK, mTOR, SIRT1 and DLK1-Notch), as well as hormonal signals (IGF-1, kisspeptin, leptin, cortisol, thyroid and sex steroids), which together orchestrate key life-history traits, including growth rates, lifespan and sexual maturation, with a particular emphasis on their role in reproductive timing. Furthermore, we consider its role as a potential coordinator of POL-related molecular processes, such as telomere dynamics and epigenetic mechanisms, within a broader regulatory network. By integrating insights from molecular biology and eco-evolutionary perspectives, we propose future directions to dissect the Hippo pathway's role in POL regulation across taxa. Understanding these interactions will provide new perspectives on how organisms adaptively adjust life-history strategies in response to environmental variability.