My research group has been focused for the last 5 years on two areas: (1.) the role of PI 3-kinase in insulin-like signaling and extreme longevity, extending to a 10-fold increase in lifespan for C. elegans nematodes carrying a null mutation; and (2.) protein aggregation as a unifying feature of many or all age-progressive diseases. We have pursued specific aggregate proteins that favor the formation of aggregates (by promoting protein coallescence) or disrupt their clearance (through interference with proteasomes and autophagosomes). We use proteomics to identify proteins in aggregates of Alzheimer's and other human neurodegenerative diseases; their known or predicted structures allow molecular-dynamic simulations of protein-protein and protein-drug interactions. Predictions from in silico studies are then tested in vivo using models of Alzheimer’s and other human neurodegenerative diseases, in the nematode C. elegans, in cultured human cells, and in mouse models of neuropathy. Molecular genetics and bioinformatics provide complementary tools to discover and understand functional interactions.

Water under the bridge (previous research):
From the start of my research career, I have been fascinated by the genetic regulation of longevity and age-associated diseases. My group characterized a number of mutations that have large effects on lifespan in the nematode C. elegans. We also used gene mapping combined with bioinformatics approaches to discover and characterize the natural variation in genes that modulate lifespan. We found that Rec-8 protein (a cohesin) alters lifespan in nematodes and yeast, and a colleague then showed that it also contributed to the exceptional longevity of bowhead whales. In mammalian genetics, we were the first to identify the Pirin gene on the X chromosome as a determinant of post-menopausal bone loss in women, a discovery subsequently confirmed in a Chinese population. We also pioneered studies of homologous recombination (HR) and its roles in the etiology and subsequent progression of myeloma, prostate and breast cancers. Data from our laboratory, and subsequently many others, support the hypothesis that HR generates genetic diversity from which more highly oncogenic clones emerge by cell selection. We have exploited the heavy dependence of cancer cells on HR to develop synergistic combinations of chemotherapeutic drugs.

Chair, 9 NIH/NIA Review Boards and site-visit teams (1987, 2006, 2011, 2013, 2017, 2018); member of 30 NIH/NIA Initial Review Board meetings (1983 - present).

Chair, CAVHS Research and Development Committee (2016 - present)

Chair, CAVHS Strategic Planning Committee (2018 - present)

Member, 10 Merit Review, Career Development, Promotion, and Research Career Scientist review boards (2000 - present)

Associate Editor, Frontiers in Genetics (2014 - present)

Session Chair, Longevity Genes, Cold Spring Harbor Symposium on the Molecular Genetics of Aging (2014)

Chair of Program Committee and Session Chair, 3rd International Conference on the Genetics of Aging & Longevity (Sochi, 2014)

Chair of Program Committee and Session Chair, 2nd International Conference on the Genetics of Aging & Longevity (Moscow, 2012)

Organizing Committee, International Workshop, Genetics of Bone Disease (Davos, Switzerland 2003, 2006)