While the concept that alteration of gene expression or function of a particular gene can alter lifespan has been demonstrated convincingly in lower animal models, it is important to determine if those same genes and mechanisms are relevant to the complex biology of mammals and humans. Evidence to support such a connection is the findings that abnormal nematode daf-16 (a transcription factor) or daf-2 (insulin/IGF-1 receptor homolog) causes juvenile animals to enter a state of diapause called dauer instead of achieving adulthood, thereby extending lifespan [33]. Both of these genes are part of the insulinIGF-I signaling pathway, which has been implicated in longevity in mice [34]. Notably, the expression of vitellogenin (yolk protein/apolipoprotein-like) genes (vit-2 and vit-5) decreases as lifespan increases [35]. This hypothesis has been independently examined in honeybees where the vitellogenin lipoprotein is associated with both modulation of immune function and longevity [36]. We suggest that modulation of apolipoprotein expression could represent one conserved mechanism of life extension influencing lifespan across species from nematodes to humans. Furthermore, one of the regulators of APOC3 expression is Forkhead Box O1 (FOXO-1), a forkhead transcription factor that mediates insulin action [29,30], which is the homolog of the nematodes daf-16 [33,37]. Deletion of the FOXO-1 binding site in mouse hepatocytes annuls the inhibitory action of insulin on hepatic expression of APOC3, and animals that constitutively express active FOXO-1 have participated in the morning to obtain a medical historyFor the Aged in New Haven, Connecticut, all under the aegis of the Association of Jewish Aging Services of North America in Washington, D.C. Statistical analyses involved pairwise crude comparisons of lipid levels and lipid particle sizes among the study groups using the Mann-Whitney U-test because the distributions were skewed. Calculations were carried out using SAS version 6.12 (SAS Institute, Cary, North Carolina, United States) and Stata version 8.2SE (StataCorp, College Station, Texas, United States). Analyses of lipid parameters were stratified by sex due to known differences between female and male lipid profiles and cardiovascular risks [49,50]. Results are expressed as mean (SE). 

Author contributions: NB conceived and designed the experiments. GA, MR, and NB performed the experiments. GA, CBS, ARS, RBL, AB, and NB analyzed the data. GA, MR, CBS, ARS, RBL, AB, and NB contributed reagents/materials/analysis tools. GA, MR, CBS, ARS, RBL, AB, and NB wrote the paper.

To consider false positive associations resulting from multiple tests of the 66 SNP (Table S1), a Bonferroni correction was applied to determine the proper level of statistical significance: p < 0.05/66 = 0.0007.

Funding: This work has been supported by grants from the Paul Beeson Physician Faculty Scholar in Aging Award, the Ellison Medical Foundation Senior Scholar Award, NIH RO1 (AG-1872801A1), the General Clinical Research Center (NIH M01-RR12248), and Diabetes Research and Training Center (NIH DK 20541) at the Albert Einstein College of Medicine and the Baltimore VA Geriatric Research and Education Clinical Center.

For a comparison of the difference in APOC3 C(641)A genotype frequencies between the groups, the chi-square test was performed. Genotype frequencies of all SNP were found to be in Hardy-Weinberg equilibrium. A corrected p-value less than 0.05 was considered the threshold for statistical significance. Given that this is a relatively homogeneous population, stratification was not applied, except to control for gender effects as noted above. The haplotype association test between cases (probands) and controls was performed.

Competing interests: The authors have declared that no competing interests exist.

References:

- Cournil A, Kirkwood TB (2001) If you would live long, choose your parents well. Trends in Genetics.
- Perls TT, Wilmoth J, Levenson R, Drinkwater M, Cohen M, et al. (2002) Life-long sustained mortality advantage of siblings of centenarians. Proc Natl Acad Sci U S A.
- Perls TT, Bubrick E, Wager CG, Vijg J, Kruglyak L (2003) Siblings of centenarians live longer. Lancet.
- Barzilai N, Shuldiner AR (2001) Searching for human longevity genes: The future history of gerontology in the post-genomic era. J Gerontol A Biol Sci Med Sci.
- Atzmon G, Schechter C, Greiner W, Davidson D, Rennert G, et al. (2004) Clinical phenotype of Families with longevity. J Am Geriatr Soc.
- Barzilai N, Atzmon G, Schechter C, Schaefer EJ, Cupples AL, et al. (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA.
- Geesaman BJ, Benson E, Brewster SJ, Kunkel LM, Blanche H, et al. (2003) Haplotype-based identification of a microsomal transfer protein marker associated with the human lifespan. Proc Natl Acad Sci U S A.
- Groenendijk M, Cantor RM, de Bruin TW, Dallinga-Thie GM (2004) The apolipoprotein I-CIII-AIV gene cluster. Atherosclerosis.
- Reaven GM (1998) Banting lecture. Role of insulin resistance in human disease. Diabetes.
- Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, et al. (1985) Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia.
- Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, et al. (2003) The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7 Report. JAMA.
- Wang JY, Yan SK, Chen BS, Xue H, et al.Epidemiology: 

Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: Analysis and visualization of LD and haplotype maps. Bioinformatics.