Keywords: I have strong research experience in molecular biology and biochemistry. In 2012, I joined the group of Richard Miller to study the mechanism of aging using longevity mouse models. My work has provided encouraging evidence that ARIs (Aging Rate Indicators) may be altered by genes, CR diet, and drugs in many tissues of many varieties of slow aging mice. The slow aging is attributed to a multitude of causes including mutations (Ames, Snell, GHR-KO, or PAPPA-KO) and CR diet, mice treated with rapamycin (Rapa), acarbose (Aca), 17aE2, and canagliflozin (Cana).These genes and interventions lead to many physiological changes such as 1) an increase in uncoupling protein UCP1 in brown and white adipose tissue (WAT); 2) a change in fat-associated macrophage subsets that leads to diminished production of inflammatory cytokines; 3) an increase in muscle fibronectin type III domain containing 5 (FNDC5) and its cleavage product, the myokine irisin, thought to cause changes in fat cell differentiation; 4) elevated production of hepatic GPLD1 and plasma GPLD1; 5) elevation of hippocampal BDNF and DCX, used as indices of neurogenesis.

Representative Publications

Abstract Deletion of pregnancy-associated plasma protein-A (PAPP-A), a protease that cleaves some but not all IGF1 binding proteins, postpones late-life diseases and extends lifespan in mice, but the mechanism of this effect is unknown. Here we show that PAPP-A knockout (PKO) mice display a set of changes, in multiple tissues, that are characteristic of other varieties of slow-aging mice with alterations in GH production or GH responsiveness, including Ames dwarf, Snell dwarf and GHRKO mice. PKO mice have elevated UCP1 in brown and white adipose tissue (WAT), and a change in fat-associated macrophage subsets that leads to diminished production of inflammatory cytokines. PKO mice also show increased levels of muscle FNDC5 and its cleavage product, the myokine irisin, thought to cause changes in fat cell differentiation. PKO mice have elevated production of hepatic GPLD1 and plasma GPLD1, consistent with their elevation of hippocampal BDNF and DCX, used as indices of neurogenesis. In contrast, disruption of PAPP-A limited to muscle (“muPKO” mice) produces an unexpectedly complex set of changes, in most cases opposite in direction from those seen in PKO mice. These include declines in WAT UCP1, increases in inflammatory macrophages and cytokines in WAT, and a decline in muscle FNDC5 and plasma irisin. muPKO mice do, however, resemble global PKO mice in their elevation of hippocampal BDNF and DCX. The data for the PKO mice support the idea that these changes in fat, macrophages, liver, muscle, plasma and brain are consistent and biologically significant features of the slow-aging phenotype in mice. The results on the muPKO mice provide a foundation for further investigation of the complex, local and global circuits by which PAPP-A modulates signals ordinarily controlled by GH and/or IGF1.