Why do some people live much longer than others? What allows these individuals to escape age-associated diseases that contribute to mortality in the elderly? Is this a result of favorable genes or merely a healthy life style? If genes do play a role, what are the mechanisms?
To address these questions, we recruited over 1500 Ashkenazi Jews. The Ashkenazi Jewish population is unique as it is derived from a small number (several thousands) of founders. External factors such as ecclesiastical edicts prohibiting all social contact with Jews, the Crusades, the establishment of the Pale of Settlement, numerous Pogroms, and ethnic bigotry resulted in social isolation and inbreeding of the Ashkenazi Jews, and led this population through a genetic bottleneck resulting in founder effects. This population has been utilized for identification of several genes, a prominent example being the breast cancer gene.
The subjects fall into three groups; probands, subjects with exceptional longevity (1:10000 in the general population); their offspring; and a control group consisting of spouses of the offspring and other Ashkenazi Jewish people recruited from the Einstein Aging Study. We studied the genetic and metabolic profile. We found certain physiological characteristics such as high levels of high-density lipoprotein (HDL) as well as significantly larger particle sizes of HDL and low-density lipoprotein (LDL) in the proband and the offspring groups compared to the control group. This phenotype is associated with a lower prevalence of hypertension, CVD, the metabolic syndrome, and homozygosity of the I405V and C(-641)A variant in the CETP and ApoC III genes, respectively. Recently, we discovered a connection between the CETP variant and cognitive function. We showed that the protective genotype of I405V, namely VV, is associated with the highest scores on the MMSE test for cognitive function. Furthermore, we expanded our research to a newly discovered serum protein, adiponectin (ADIPOQ), expressed and secreted exclusively by adipose tissue. We demonstrated for the first time that exceptionally long-lived probands have markedly higher levels of serum ADIPOQ. We also demonstrated that the distribution of ADIPOQ levels in the offspring group is bimodal, suggesting that a subset of the offspring may have inherited the favorable ADIPOQ trait. We demonstrated association of a common ADIPOQ polymorphism with ADIPOQ levels and with exceptional longevity, suggesting that genetic determinants of ADIPOQ may contribute to this rare phenotype of exceptional longevity. Recently, we studied telomere length in our population, demonstrating longer telomeres in our longest living subjects and their offspring compared to control. These finding may indicate longer telomeres at birth or slower attrition rate in their length. Most important, since the trait of longer telomeres is associated with protective lipoprotein profile and less age-related disease, this test may be used as a predictor for longevity.
Finally, we performed whole genome association analysis to identify mutations in new, uncharacterized genes that may be linked to diseases of aging, such as cardiovascular disease and cancer. We hope this can explain this rare trait and often-desirable state defined as longevity.
Recent Publications:
Barzilai, N., Gabriely, I., Gabriely, M., Iankowitz, N., and Sorkin, J.D. (2001) Offspring of centenarians have a favorable lipid profile. J. Am. Geriatr. Soc. 49(1), 76-9.
Barzilai, N. and Shuldiner, A.R. (2001) Searching for human longevity genes: the future history of gerontology in the post-genomic era. J. Gerontol. A. Biol. Sci. Med. Sci. 56(2), M83-7.
Atzmon, G., Gabriely, I., Greiner, W., Davidson, D., Schechter, C., and Barzilai, N. (2002) Plasma HDL levels highly correlate with cognitive function in exceptional longevity. J. Gerontol. A. Biol. Sci. Med. Sci. 57(11), M712-5.
Barzilai, N., Atzmon, G., Schechter, C., Schaefer, E.J., Cupples, A.L., Lipton, R., Cheng, S., and Shuldiner, A.R. (2003) Unique lipoprotein phenotype and genotype associated with exceptional longevity. JAMA. Oct 15; 290(15), 2030-40.
Barzilai, N. (2003) Discovering the secrets of successful longevity. J. Gerontol. A. Biol. Sci. Med. Sci. 58(3), 225-6.
Crandall, J. and Barzilai, N. (2003) Treatment of diabetes mellitus in older people: oral therapy options. J. Am. Geriatr. Soc. 51(2), 272-4.
Atzmon, G., Schechter, C., Greiner, W., Davidson, D., Rennert, G., and Barzilai, N. (2004) Clinical Phenotype of Families with Longevity. J. Am. Geriat. Soc. 52(2), 274-277.
Globerson, A. and Barzilai, N. (2005) The voyage to healthy longevity: from experimental models to the ultimate goal. Mech. Ageing Dev. 126(2), 225-9.
Atzmon, G., Rincon, M., Rabizadeh, P., and Barzilai, N. (2005) Biological evidence for inheritance of exceptional longevity. Mech. Ageing Dev.126(2), 341-5.
Arking, D.E., Atzmon, G., Arking, A., Barzilai, N., Dietz, H.C. (2005) Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ. Res. 96(4), 412-8.
Atzmon G, Rincon M, Schechter C, Shuldiner An, Lipton R, Bergman A, Barzilai N: Lipoprotein Genotype and Conserved Pathway for Exceptional Longevity in Humans. PLoS Biol. 2006 Apr;4(4):e113.
Barzilai N, Atzmon, G, Derby C, Shuldiner, AR. Lipton, RB. (2006) A genotype of exceptional longevity is associated with preservation of cognitive function. Neurology. 67(12):2170-5.
Terry DF, Wyszynski DF, Nolan VG, Atzmon G, Schoenhofen EA, Pennington JY, Andersen SL, Wilcox MA, Farrer LA, Barzilai N, Baldwin CT, Asea A. (2006) Serum heat shock protein 70 level as a biomarker of exceptional longevity. Mech Ageing Dev. 127(11):862-8.
Iwata N, Zhang J, Atzmon G, Leanza S, Cho J, Chomyn A, Burk RD, Barzilai N, Attardi G. (2007) Aging-related occurrence in Ashkenazi Jews of leukocyte heteroplasmic mtDNA mutation adjacent to replication origin frequently remodeled in Italian centenarians. Mitochondrion. 7(4):267-72.
Bergman A, Atzmon G, Ye K, MacCarthy T,Barzilai N. Buffering mechanisms in aging: a systems approach toward uncovering the genetic component of aging. PLoS Comput Biol. 2007
Suh Y, Atzmon G, Cho M-O, Hwang D, Liu B, Leahy D,Barzilai N*, Cohen P. Functionally-significant insulin-like growth factor-I receptor mutations in centenarian. Proc Natl Acad Sci U S A. 2008 Mar 4;105(9):3438-42.
Muzumdar R, Allison DB, Huffman DM, Ma X, Atzmon G, Einstein FH, Fishman S, Poduval AD, McVei T, Keith SW, Barzilai N. Visceral Adipose Tissue Modulates Mammalian Longevity. Aging Cell. 2008 Mar 18.
Atzmon G, Pollin TI, Crandall J, Tanner K, Schechter CB, Scherer PE, Rincon M, Siegel G, Katz M, Lipton RB, Shuldiner AR, and Barzilai N. Adiponectin levels and genotype: A potential regulator of life-span in humans. J Gerontol A Biol Sci Med Sci. 2008;63(5):447-53.
