The Endicott Laboratory

We study the biological mechanisms by which rare genetic variants confer resilience to aging-associated diseases, including cancer, obesity/diabetes, fatty liver disease, and sarcopenia. We seek to leverage these insights to develop safe, scalable interventions that recapitulate their benefits.

We are currently focused on two beneficial loss-of-function mutations (ghr and gdf8).

1. GHR. Medical doctors, scientists, and popular news outlets have all been baffled by the recent finding that rare individuals with Laron Syndrome (loss-of-function mutation in ghr) almost never develop spontaneous cancers, despite normal cancer rates in their second-degree relatives (such as cousins), who are living in similar environmental conditions. This powerfully demonstrates that LS constitutes a genetic basis for resilience against developing cancer in humans, but the cellular mechanisms that lead to cancer resilience in people with LS are not known. LS patients have growth hormone (GH)-resistant dwarfism, in addition to their cancer resilience. These phenotypes are mirrored in ghr knock out (KO) mice (the standard mouse model for LS), which have a 50% reduction in adult body size, low rates of cancer, improved insulin sensitivity, and a ~20% lifespan extension, compared to their normal littermates. These findings present the key question: Downstream of the loss of ghr, what are the cellular and sub-cellular changes that reduce the likelihood of oncogenic transformation?

In our recent work, we have found that three kinds of long-lived and cancer-resistant mouse stocks (including ghr KOs, pou1f1 mutants, and PTEN overexpressors) have a constitutive activation of a highly selective protein recycling mechanism, called chaperone-mediated autophagy (CMA). CMA degrades, and thereby regulates the abundance of, several oncogenic proteins, including CIP2A12, MDM213, mutant TP5314, TPT115, and HK216.

We (and others) have found that CMA selectively degrades a subset of the proteome to downregulate fundamental anabolic processes, i.e. glycolysis, de novo lipogenesis, translation, and production of cytoplasmic acetyl-coA, and that these pathways are downregulated in the livers of ghr KO mice.

We have leveraged a multi-disciplinary research program, using a combination of quantitative proteomics, biochemistry, microscopy, cell biology, and mouse studies to address fundamental questions pertaining to chaperone-mediated autophagy (CMA):

1. How is CMA regulated at the endocrine, cellular, and sub-cellular levels?
2. What are the targets of CMA, and how does their degradation affect metabolism, health, and longevity?

2. GDF8 (Myostatin). Myostatin (gene symbol MSTN) is a circulating hormone that inhibits satellite cell (muscle stem cell) division and self-renewal. Thus, myostatin negatively limits muscle size, strength, and regeneration after exercise. Myostatin is a secreted ligand of the TGFβ family, and it has both paracrine and endocrine functions. Humans with rare inherited loss of function mutations in MSTN are unusually muscular and strong, even as infants, and they show no major deleterious phenotypes. People carrying a single nucleotide polymorphism in MSTN are disproportionally represented in some kinds of strength-based professional sports. Mice that are heterozygous knockouts for MSTN have enhanced muscle volume, increased strength, and live 15% longer than normal controls. Homozygous knockouts have a normal lifespan, but they show signs of improved healthspan in old age, such as improved cardiac function, reduced fibrosis in the myocardium, increased bone mineral density, and reduced circulating insulin and glucose.

We have invented a virus-like particle (VLP) that displays unique MSTN epitopes at high valency. This VLP induces an immunogenic response against the full-length MSTN protein in genetically normal mice of both sexes, enhances muscle volume, boosts grip strength, and reduces fat mass. USA patent pending.