The metabolism of NAD remained an area of intense research into the 21st century, with interest heightened after the discovery of the NAD-dependent protein deacetylases called sirtuins in 2000, by Shin-ichiro Imai and coworkers in the laboratory of Leonard P. Guarente. In 2009 Imai proposed the "NAD World" hypothesis that key regulators of aging and longevity in mammals are sirtuin 1 and the primary NAD synthesizing enzyme nicotinamide phosphoribosyltransferase (NAMPT). In 2016 Imai expanded his hypothesis to "NAD World 2.0" which postulates that extracellular NAMPT from adipose tissue maintains NAD in the hypothalamus (the control center) in conjunction with myokines from skeletal muscle cells.