The Soukas laboratory focuses on identification and characterization of genetic pathways that promote healthy aging and reduce aging-associated metabolic diseases such as type 2 diabetes, obesity, and cancer. The lab uses a combination of genetic approaches in vertebrate and invertebrate model systems to determine how genetic pathways can be manipulated to have favorable effects on metabolism and aging. At present, three projects are ongoing:

1) Mechanisms by which metformin improves glucose and lipid homeostasis, prolongs lifespan, and blocks the growth of cancer. Metformin is the most commonly used medication for type 2 diabetes worldwide. In recent years, it has become clear that metformin also has anti-cancer properties and can prolong lifespan of model organisms. We recently published in Cell (PMC5390486) that metformin effects at mitochondria lead to alterations in nuclear transport, inactivating mTORC1, thereby, inhibiting cancer growth, and prolonging lifespan. Remarkably, this pathway is conserved from the invertebrate C. elegans to human.

2) Connecting starvation survival to obesity and type 2 diabetes. Starvation is among the most ancient of selection pressures. Starvation defenses activated when nutrients become scarce permit animals to survive until nutrients are plentiful again. We identified a thrifty genetic pathway that activates doubling to tripling of starvation survival when protein translation genes are inhibited. Turning off protein synthesis tripled fat stores and starvation survival while turning off proteasomal genes, which encode gene products that degrade proteins, led to very low body fat stores and tremendous shortening of starvation
survival. Surprisingly, the proteostasis machinery controls starvation survival by activating the master starvation regulator AMPK (Published in Cell Reports PMC5578715).

3) Manipulating insulin signaling to reduce aging-associated diseases and to promote healthy aging and healthy metabolism. Recent work in the aging field has shown that activation of autophagy, or “self-eating” is mechanistically required in almost every genetic, dietary, and pharmacologic manipulation that extends lifespan. Conversely, mutations in essential autophagy-related genes lead to human diseases such as diabetes, inflammatory bowel disease, and cancer. By studying the insulin-signaling component mTOR complex 2, we determine that it promotes health by reducing mitochondrial permeability. When mTOR complex 2 acts, it promotes mitochondrial health, permitting autophagy to have beneficial effects on longevity in invertebrates and to reduce ischemia-reperfusion injury in mTOR complex 2 signaling liver- specific knockout mice (published in Cell PMC6610881). This work has implications for metabolism, aging, heart attack, stroke, and organ transplantation. More recently, we have found that mTOR complex 2 has complicated roles in metabolism. Specifically, mTOR complex 2 promotes insulin resistance in animals fed a high fat diet by signaling through the downstream AGC family kinase Sgk1 (published in Cell Reports PMC8576737). As such inactivation of mTOR complex 2 has disparate effects on mitochondrial health and insulin resistance, so further work is dissecting how we can promote health by leveraging targets downstream of the kinase.