MTP Biology and Previous Associations. The gene product of MTP has been well characterized since the mid-1980s for its role in lipoprotein assembly and is an investigational target for treating combined hyperlipidemia and obesity (29, 30). MTP is thought to be the rate-limiting step in the production of lipoproteins (31), making it a particularly appealing target for next-generation lipid-lowering drugs. Structurally, the protein dimerizes with the ubiquitous protein disulfide isomerase and resides on the luminal surface of the endoplasmic reticulum where it facilitates the proper assembly of very low-density lipoprotein and chylomicron

fraction of the total genetic variance in human longevity and there may be dozens of genes with a similar association, much more expansive studies in the near future will likely yield a wealth of insight into the genetic basis of longevity, aging, and disease resistance.

most appreciative of the assistance provided by the American Asso- ciation of Retired Persons in the subject recruitment efforts led by T.T.P. We thank Carl Weissman for his operational expertise during the experimental stages of this work. Last, we are grateful for the assistance of the Rutgers University Cell and DNA Repository. Funding for this study was largely contributed by Elixir Pharmaceu- ticals. This work was supported by grants from the National Institute on Aging (R01-AG1875), the Ellison Medical Foundation, the Alz- heimer’s Association’s Templeton Discovery Award, the Institute for the Study of Aging, the Howard Hughes Medical Institute, and the French Ministry of Research. L.M.K. is an Investigator with the Howard Hughes Medical Institute.

We thank the many individuals involved in recruiting subjects for study and the laboratory and bioinformatic staff that carried out genotyping and analyses. We thank the study participants and families for generously agreeing to participate in our study. We

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