Switzerland/USA

Michael N. Hall

2024 Balzan Prize for Biological Mechanisms of Ageing

For groundbreaking contributions to our understanding of the molecular mechanisms regulating cell growth. Michael Hall discovered two proteins, TOR1 and TOR2, that regulate cell growth and metabolism in response to nutrients. These play a central role in the ageing process and in the development of ageing-related diseases such as cancer, diabetes and cardiovascular disease.

In the early 1990s, Michael Hall set out to find the target of the immunosuppressive drug rapamycin, a natural compound produced by a bacterium found on Rapa Nui, or Easter Island. In doing so, he discovered two genes that play a central role in regulating cell growth. He named these Target of Rapamycin 1 and 2, now abbreviated as TOR1 and TOR2.

Michael Hall next focused on elucidating the cellular function of TOR. In a series of seminal papers, he showed that TOR proteins control cell growth by sensing nutrient availability. This caused a paradigm shift in the field, because at that time it was thought that cell size was limited only by nutrient availability and was not regulated. The discovery that TOR is a master regulator of cell growth and metabolism in response to nutrients transformed our understanding of cell growth and led to a molecular understanding of many growth-related cellular processes, including ageing.

Subsequently, he discovered that TOR1 and TOR2 form two large protein complexes known as TORC1 and TORC2 that are structurally and functionally distinct. These complexes are conserved from yeast to humans and are now known as mTORC1 and mTORC2 (mechanistic target of rapamycin 1 and 2). They match cell growth to the nutrient supply and many external signals (such as hormones) by controlling the balance between the activity of catabolic (degradative) and anabolic (constructive) metabolic pathways. mTORC1 and mTORC2 signal via two different signaling pathways to control distinct cellular processes. mTORC1 regulates cell growth and metabolism by controlling the synthesis of cellular components like proteins, fats and nucleic acids that are needed for cell growth. Activation of mTORC1 also inhibits autophagy, the process by which waste proteins and other cellular components are degraded. Impaired autophagy can be detrimental to cells and lead to ageing-related diseases like diabetes. In contrast, mTORC2 regulates cell proliferation and survival. Recently, in collaborative studies, Micheal Hall has provided high-resolution atomic structures of both mTORC1 and mTORC2 which enhance our understanding of how these complexes function.

Professor Hall’s work has had multiple impacts on the study of ageing. His discovery that TOR1 is inhibited by rapamycin explains why rapamycin extends lifespan in multiple animal models. Likewise, his groundbreaking demonstration that nutrients activate TOR1 provides a mechanistic explanation for how dietary restriction extends lifespan extension: it does so by inhibiting mTORC1 activity. Dysregulation of mTOR also results in many diseases of ageing including cancer, diabetes and cardiovascular disease. Indeed, he recently showed that dysregulated mTORC2 promotes cancer development via the synthesis of lipids essential for growth and energy production.

Michael Hall’s groundbreaking discovery of TOR proteins founded an important new field of research that is now extremely large. He has been at the forefront of this field for over thirty years. His studies have provided a mechanism for lifespan extension by dietary restriction and have helped elucidate fundamental and clinically important mechanisms in ageing-related biology.