According to some estimates, slowing the rate of aging just enough to postpone the age of onset of multiple age-related chronic diseases by two to three years would save hundreds of billions of dollars in health care costs. Furthermore, lowering age-specific mortality rates from multiple causes by slowing the rate of aging may be easier to achieve than lowering them to the same extent by developing a separate, more specific intervention for each of a multitude of age-related life-threatening diseases of which atherosclerotic heart disease, cancer, stroke, lung infections, and chronic obstructive pulmonary disease are among the most common
We are studying the genetics of human aging. Different physiological functions within the same individual decline at different rates with age, and the magnitude and rank order of these functional declines vary among individuals. These dichotomies suggest that there are two or more distinct processes of senescence. On the other hand, a single environmental intervention, restriction of calories in the diet, has been shown to extend life span and postpone the age of onset of multiple signs of senescence in every species tested to date, including mammalian species. Furthermore, mutations in any one of several genes of the nematode worm C. elegans approximately double its life span, and two of these genetic alterations combined in the same animal increase life span five-fold. Therefore, while aging is likely to be complex, with multiple environmental and genetic factors influencing it, it is reasonable to search for single genes in the human that simultaneously promote longevity and slow senescence.
To look for genes that regulate senescence, we will measure, in 40 large Utah families (the Utah Genetic Reference Families), several traits that change with age beginning in young adulthood and that show increasing variation among individuals as the age of the tested population increases. This is the behavior expected if the rate of change of the trait (its rate of senescence) varies among people. Examples of such traits are shortening of chromosomal telomeres, somatic mutations in mitochondrial DNA, and declines in lung function. Quantitative traits that do not change dramatically with age but vary in tandem with age-specific mortality rates from each of two or more causes will also be examined, since such traits may be markers of a fundamental aging process; examples are peripheral blood leukocyte counts and resting heart rates. Once the traits have been quantified in individuals, genetic linkage analyses can proceed rapidly and with great power, because thousands of genetic markers have already been typed in the families being studied.
To look for genes associated with longevity, patterns of longevity in families will be examined in a large genealogical database. First we will test whether some longevity follows maternal lineages, a result that would be consistent with a hypothesis that heritable mitochondrial genetic variants contribute to longevity. Mitochondria from any maternal lineages of interest will be collected for studies of function and for analysis of DNA sequence. Second, additional extended pedigrees will be identified in which the incidence of longevity is much higher than in the general population. DNA from very long-lived members of these families will be used in linkage analyses to investigate involvement of selected candidate genes, among them the human homologs of loci that are capable of conferring longevity in other species.
Richard Cawthon, MD, Ph.D.
Department of Human Genetics
University of Utah
15 N 2030 E RM 6110B
Salt Lake City, Utah 84112-5330
Njajou OT, Blackburn EH, Pawlikowska L, Mangino M, Damcott CM, Kwok PY, Spector TD, Newman AB, Harris TB, Cummings SR, Cawthon RM, Shuldiner AR, Valdes AM, Hsueh WC. A common variant in the telomerase RNA component is associated with short telomere length.PLoS One. 2010 Sep 27;5(9):e13048.
Atzmon G, Cho M, Cawthon RM, Budagov T, Katz M, Yang X, Siegel G, Bergman A, Huffman DM, Schechter CB, Wright WE, Shay JW, Barzilai N, Govindaraju DR, Suh Y. Evolution in health and medicine Sackler colloquium: Genetic variation in human telomerase is associated with telomere length in Ashkenazi centenarians. Proc Natl Acad Sci U S A. 2010 Jan 26;107 Suppl 1:1710-7. Epub 2009 Nov 13.
Xu, Q., C.G. Parks, L.A. DeRoo, R.M. Cawthon, D.P. Sandler, and H. Chen (2009). Multivitamin use and telomere length in women. Am J Clin Nutr. 89(6): p. 1857-63.
Smith, K.R., A. Gagnon, R.M. Cawthon, G.P. Mineau, R. Mazan, and B. Desjardins (2009). Familial aggregation of survival and late female reproduction. J Gerontol A Biol Sci Med Sci. 64(7): p. 740-4.
Sanders, J.L., J.A. Cauley, R.M. Boudreau, J.M. Zmuda, E.S. Strotmeyer, P.L. Opresko, W.C. Hsueh, R.M. Cawthon, R. Li, T.B. Harris, S.B. Kritchevsky, and A.B. Newman (2009). Leukocyte Telomere Length Is Not Associated With BMD, Osteoporosis, or Fracture in Older Adults: Results From the Health, Aging and Body Composition Study. J Bone Miner Res. 24(9): p. 1531-6.
Parks, C.G., D.B. Miller, E.C. McCanlies, R.M. Cawthon, M.E. Andrew, L.A. DeRoo, and D.P. Sandler (2009). Telomere length, current perceived stress, and urinary stress hormones in women. Cancer Epidemiol Biomarkers Prev. 18(2): p. 551-60.
Njajou, O.T., W.C. Hsueh, E.H. Blackburn, A.B. Newman, S.H. Wu, R. Li, E.M. Simonsick, T.M. Harris, S.R. Cummings, and R.M. Cawthon (2009). Association between telomere length, specific causes of death, and years of healthy life in health, aging, and body composition, a population-based cohort study. J Gerontol A Biol Sci Med Sci. 64(8): p. 860-4.
Kim, S., C.G. Parks, L.A. DeRoo, H. Chen, J.A. Taylor, R.M. Cawthon, and D.P. Sandler (2009). Obesity and weight gain in adulthood and telomere length. Cancer Epidemiol Biomarkers Prev. 18(3): p. 816-20.
Kerber, R.A., E. O’Brien, and R.M. Cawthon (2009). Gene expression profiles associated with aging and mortality in humans. Aging Cell. 8(3): p. 239-50.
Hosgood, H.D., 3rd, R. Cawthon, X. He, S. Chanock, and Q. Lan (2009). Genetic variation in telomere maintenance genes, telomere length, and lung cancer susceptibility. Lung Cancer.
Cawthon, R.M. (2009). Telomere length measurement by a novel monochrome multiplex quantitative PCR method. Nucleic Acids Res. 37(3): p. e21.
Terry, D.F., V.G. Nolan, S.L. Andersen, T.T. Perls, and R. Cawthon (2008). Association of longer telomeres with better health in centenarians. J Gerontol A Biol Sci Med Sci. 63(8): p. 809-12.
Kao, H.T., R.M. Cawthon, L.E. Delisi, H.C. Bertisch, F. Ji, D. Gordon, P. Li, M.M. Benedict, W.M. Greenberg, and B. Porton (2008). Rapid telomere erosion in schizophrenia. Mol Psychiatry. 13(2): p. 118-9.
Farzaneh-Far, R., R.M. Cawthon, B. Na, W.S. Browner, N.B. Schiller, and M.A. Whooley (2008). Prognostic value of leukocyte telomere length in patients with stable coronary artery disease: data from the Heart and Soul Study. Arterioscler Thromb Vasc Biol. 28(7): p. 1379-84.
Njajou, O.T., R.M. Cawthon, C.M. Damcott, S.H. Wu, S. Ott, M.J. Garant, E.H. Blackburn, B.D. Mitchell, A.R. Shuldiner, and W.C. Hsueh (2007). Telomere length is paternally inherited and is associated with parental lifespan. Proc Natl Acad Sci U S A. 104(29): p. 12135-9.
Hunt, S.C., Y. Xin, L.L. Wu, R.M. Cawthon, H. Coon, S.J. Hasstedt, and P.N. Hopkins (2006). Sodium bicarbonate cotransporter polymorphisms are associated with baseline and 10-year follow-up blood pressures. Hypertension. 47(3): p. 532-6.
Epel, E.S., J. Lin, F.H. Wilhelm, O.M. Wolkowitz, R. Cawthon, N.E. Adler, C. Dolbier, W.B. Mendes, and E.H. Blackburn (2006). Cell aging in relation to stress arousal and cardiovascular disease risk factors. Psychoneuroendocrinology. 31(3): p. 277-87.
Coon, H., Y. Xin, P.N. Hopkins, R.M. Cawthon, S.J. Hasstedt, and S.C. Hunt (2005). Upstream stimulatory factor 1 associated with familial combined hyperlipidemia, LDL cholesterol, and triglycerides. Hum Genet. 117(5): p. 444-51.
Hunt, S.C., H. Coon, S.J. Hasstedt, R.M. Cawthon, N.J. Camp, L.L. Wu, and P.N. Hopkins (2004). Linkage of serum creatinine and glomerular filtration rate to chromosome 2 in Utah pedigrees. Am J Hypertens. 17(6): p. 511-5.
Hasstedt, S.J., N.J. Camp, P.N. Hopkins, H. Coon, J.T. McKinney, R.M. Cawthon, and S.C. Hunt (2004). Model-fitting and linkage analysis of sodium-lithium countertransport. Eur J Hum Genet. 12(12): p. 1055-61.
Epel, E.S., E.H. Blackburn, J. Lin, F.S. Dhabhar, N.E. Adler, J.D. Morrow, and R.M. Cawthon (2004). Accelerated telomere shortening in response to life stress. Proc Natl Acad Sci U S A. 101(49): p. 17312-5.
Browner, W.S., A.J. Kahn, E. Ziv, A.P. Reiner, J. Oshima, R.M. Cawthon, W.C. Hsueh, and S.R. Cummings (2004). The genetics of human longevity. Am J Med. 117(11): p. 851-60.
Cawthon, R.M., K.R. Smith, E. O’Brien, A. Sivatchenko, and R.A. Kerber (2003). Association between telomere length in blood and mortality in people aged 60 years or older. Lancet. 361(9355): p. 393-5.
Camp, N.J., P.N. Hopkins, S.J. Hasstedt, H. Coon, A. Malhotra, R.M. Cawthon, and S.C. Hunt (2003). Genome-wide multipoint parametric linkage analysis of pulse pressure in large, extended utah pedigrees. Hypertension. 42(3): p. 322-8.
Hunt, S.C., S.J. Hasstedt, H. Coon, N.J. Camp, R.M. Cawthon, L.L. Wu, and P.N. Hopkins (2002). Linkage of creatinine clearance to chromosome 10 in Utah pedigrees replicates a locus for end-stage renal disease in humans and renal failure in the fawn-hooded rat. Kidney Int. 62(4): p. 1143-8.
Cawthon, R.M. (2002). Telomere measurement by quantitative PCR. Nucleic Acids Res. 30(10): p. e47.
Kerber, R.A., E. O’Brien, K.R. Smith, and R.M. Cawthon (2001). Familial excess longevity in Utah genealogies. J Gerontol A Biol Sci Med Sci. 56(3): p. B130-9.
Purandare, S.M., R. Cawthon, L.M. Nelson, S. Sawada, W.S. Watkins, K. Ward, L.B. Jorde, and D.H. Viskochil (1996). Genotyping of PCR-based polymorphisms and linkage-disequilibrium analysis at the NF1 locus. Am J Hum Genet. 59(1): p. 159-66.
Martinez, J.M., H.H. Breidenbach, and R. Cawthon (1996). Long RT-PCR of the entire 8.5-kb NF1 open reading frame and mutation detection on agarose gels. Genome Res. 6(1): p. 58-66.
Purandare, S.M., H. Huntsman Breidenbach, Y. Li, X.L. Zhu, S. Sawada, S.M. Neil, A. Brothman, R. White, R. Cawthon, and D. Viskochil (1995). Identification of neurofibromatosis 1 (NF1) homologous loci by direct sequencing, fluorescence in situ hybridization, and PCR amplification of somatic cell hybrids. Genomics. 30(3): p. 476-85.
Li, Y., P. O’Connell, H.H. Breidenbach, R. Cawthon, J. Stevens, G. Xu, S. Neil, M. Robertson, R. White, and D. Viskochil (1995). Genomic organization of the neurofibromatosis 1 gene (NF1). Genomics. 25(1): p. 9-18.
Viskochil, D., R. White, and R. Cawthon (1993). The neurofibromatosis type 1 gene. Annu Rev Neurosci. 16: p. 183-205.
O’Connell, P., R. Cawthon, G.F. Xu, Y. Li, D. Viskochil, and R. White (1992). The neurofibromatosis type 1 (NF1) gene: identification and partial characterization of a putative tumor suppressor gene. J Dermatol. 19(11): p. 881-4.
Li, Y., G. Bollag, R. Clark, J. Stevens, L. Conroy, D. Fults, K. Ward, E. Friedman, W. Samowitz, M. Robertson, and et al. (1992). Somatic mutations in the neurofibromatosis 1 gene in human tumors. Cell. 69(2): p. 275-81.
Fults, D., D. Brockmeyer, M.W. Tullous, C.A. Pedone, and R.M. Cawthon (1992). p53 mutation and loss of heterozygosity on chromosomes 17 and 10 during human astrocytoma progression. Cancer Res. 52(3): p. 674-9.
Viskochil, D., R. Cawthon, P. O’Connell, G.F. Xu, J. Stevens, M. Culver, J. Carey, and R. White (1991). The gene encoding the oligodendrocyte-myelin glycoprotein is embedded within the neurofibromatosis type 1 gene. Mol Cell Biol. 11(2): p. 906-12.
O’Connell, P., R.M. Cawthon, D. Viskochil, R. White, J.C. Carey, and A.M. Buchberg (1991). The NF1 translocation breakpoint region. Ann N Y Acad Sci. 615: p. 319-31.
Cawthon, R.M., L.B. Andersen, A.M. Buchberg, G.F. Xu, P. O’Connell, D. Viskochil, R.B. Weiss, M.R. Wallace, D.A. Marchuk, M. Culver, and et al. (1991). cDNA sequence and genomic structure of EV12B, a gene lying within an intron of the neurofibromatosis type 1 gene. Genomics. 9(3): p. 446-60.
Andersen, L.B., M.R. Wallace, D.A. Marchuk, R.M. Cawthon, H.M. Odeh, R. Letcher, R.L. White, and F.S. Collins (1991). A polymorphic cDNA probe on chromosome 17q11.2 located within the NF1 gene [D17S376]. Nucleic Acids Res. 19(1): p. 197.
Xu, G.F., P. O’Connell, D. Viskochil, R. Cawthon, M. Robertson, M. Culver, D. Dunn, J. Stevens, R. Gesteland, R. White, and et al. (1990). The neurofibromatosis type 1 gene encodes a protein related to GAP. Cell. 62(3): p. 599-608.
Viskochil, D., A.M. Buchberg, G. Xu, R.M. Cawthon, J. Stevens, R.K. Wolff, M. Culver, J.C. Carey, N.G. Copeland, N.A. Jenkins, and et al. (1990). Deletions and a translocation interrupt a cloned gene at the neurofibromatosis type 1 locus. Cell. 62(1): p. 187-92.
O’Connell, P., D. Viskochil, A.M. Buchberg, J. Fountain, R.M. Cawthon, M. Culver, J. Stevens, D.C. Rich, D.H. Ledbetter, M. Wallace, and et al. (1990). The human homolog of murine Evi-2 lies between two von Recklinghausen neurofibromatosis translocations. Genomics. 7(4): p. 547-54.
Martin, G.A., D. Viskochil, G. Bollag, P.C. McCabe, W.J. Crosier, H. Haubruck, L. Conroy, R. Clark, P. O’Connell, R.M. Cawthon, and et al. (1990). The GAP-related domain of the neurofibromatosis type 1 gene product interacts with ras p21. Cell. 63(4): p. 843-9.
Cawthon, R.M., R. Weiss, G.F. Xu, D. Viskochil, M. Culver, J. Stevens, M. Robertson, D. Dunn, R. Gesteland, P. O’Connell, and et al. (1990). A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 62(1): p. 193-201.
Cawthon, R.M., P. O’Connell, A.M. Buchberg, D. Viskochil, R.B. Weiss, M. Culver, J. Stevens, N.A. Jenkins, N.G. Copeland, and R. White (1990). Identification and characterization of transcripts from the neurofibromatosis 1 region: the sequence and genomic structure of EVI2 and mapping of other transcripts. Genomics. 7(4): p. 555-65.
O’Connell, P., R.J. Leach, D.H. Ledbetter, R.M. Cawthon, M. Culver, J.R. Eldridge, A.K. Frej, T.R. Holm, E. Wolff, M.J. Thayer, and et al. (1989). Fine structure DNA mapping studies of the chromosomal region harboring the genetic defect in neurofibromatosis type I. Am J Hum Genet. 44(1): p. 51-7.
O’Connell, P., R. Leach, R.M. Cawthon, M. Culver, J. Stevens, D. Viskochil, R.E. Fournier, D.C. Rich, D.H. Ledbetter, and R. White (1989). Two NF1 translocations map within a 600-kilobase segment of 17q11.2. Science. 244(4908): p. 1087-8.
Coleman, R.T., R.M. Cawthon, M.J. Malloy, J.P. Kane, P.F. Nakashima, and P.M. Frossard (1988). Bsm I RFLP at the human apolipoprotein AI-CIII gene complex locus. Nucleic Acids Res. 16(5): p. 2364.
Hamblin, M.W., P.I. Adriaenssens, K. Ariani, R.M. Cawthon, C.A. Stratford, G.L. Tan, and R.D. Ciaranello (1987). Ascorbic acid prevents nonreceptor “specific” binding of [3H]-5-hydroxytryptamine to bovine cerebral cortex membranes. J Pharmacol Exp Ther. 240(3): p. 701-11.
Cawthon, R.M. and X.O. Breakefield (1983). Differences in the structures of monoamine oxidases A and B in rat clonal cell lines. Biochem Pharmacol. 32(3): p. 441-8.
Cawthon, R.M., J.E. Pintar, F.P. Haseltine, and X.O. Breakefield (1981). Differences in the structure of A and B forms of human monoamine oxidase. J Neurochem. 37(2): p. 363-72.
Bonnefil, V., C.M. Castiglione, R.M. Cawthon, and X.O. Breakefield (1981). Effect of riboflavin on monoamine oxidase activity in cultured neuroblastoma cells. Cell Mol Neurobiol. 1(4): p. 351-9.
Cawthon, R.M. and X.O. Breakefield (1979). Differences in A and B forms of monoamine oxidase revealed by limited proteolysis and peptide mapping. Nature. 281(5733): p. 692-4.