The Genetics of Longevity

Genetics May Be Biggest Factor in Longevity: 444 families. Thomas Perls found that brothers and sisters of those who lived to be 100 had about half the risk of dying throughout their lives, compared with people who did not have a long-living brother or sister. Compared with the general population, brothers of centenarians were at least 17 times more likely to make it to 100 themselves and sisters were at least 8 times more likely. Boston U. Proceedings of the National Academy of Sciences 6/02

Specific Findings:

Apolipoprotein-E with No e4, Right Male Sex Chromosome Version, Lack Mental Illness in Youth Increase Longevity, Decrease AD: Chance of longevity without Alzheimers is higher if no mental disorders in their youth and younger adulthood, absence of e4 version of apolipoprotein-E, and if they carry a particular version of a gene on the male sex chromosome. Study 100 mentally healthy 90yo+ and 100 18-25yos matched ethnically and 100 dead of AD. 42% of AD with e4, vs. 12% of 18-25yos, and 7% of healthy 90yo+. The healthy 90+ group had half the level of mental illness in youth and younger adulthood than did the 18-25yo controls. George Zubenko, Univ. Pittsburgh 10/02 American Journal of Geriatric Psychiatry.

Catalase Increase in Transgenic Mouse Increased Lifespan: A transgenic mouse strain was constructed (MCAT) with a C57BL/6J background that has about a 50-fold increase in expression in cardiac mitochondria and skeletal muscle of catalase enzyme activity. The MCAT strain was found to have reduced severity of age-dependent arteriosclerosis and increased genomic stability, as indicated by a decrease in oxidative stress and mitochondrial deletions in heart and muscle tissues. Lifespan were increased about 17-21% compared to wild-type controls through a delay in the onset of aging. Oxidative stress and aging: catalase is a longevity determinant enzyme. Cutler RG. Kronos, Phoenix, Arizona. . Rejuvenation Res. 2005 Fall;8(3):138-40.

DOPA Decarboxylase Major Longevity Role in Fruit Flies, Maybe Humans: Three natural variants in the gene for DOPA decarboxylase (DDC), an enzyme required for the production of dopamine and serotonin, together accounted for 15 percent of the genetic contribution to variation in life span among strains of the fruit fly Drosophila melanogaster, North Carolina State University. Trudy Mackay, July 27, 2003, online edition Nature Genetics.

IGF-1 Gene Mutation Associated with Longevity: Mutation in genes that share similarities with those in humans involved in the insulin/insulin-like growth factor I (IGF-I) signal response pathway can significantly extend life span in diverse species, including yeast, worms, fruit flies, and rodents. Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans. Barbieri M, Bonafe M, Franceschi C, Paolisso G. Am J Physiol Endocrinol Metab. 2003 Nov;285(5):E1064-71. Similar, with 26% increased life-span in mice heterozygous for mutation. Horm Res. 2004;62 Suppl 1:89-92.

Insulin Receptor Gene Blocking on Fat Cells Increases Mouse Life 18%: Fat-specific insulin receptor knock-out (KIRKO) mice created, blocks the action of insulin at just the fat cells. Since insulin is needed to help fat cells store fat, these animals had less fat and were protected against obesity and diabetes. Ron Kahn. Harvard. At three months of age, mice had up to 70 per cent less body fat than normal, despite the fact that they ate 55 per cent more food per gram of body weight. 1/24/03 Science (vol 299, p 572)

Lipoprotein Polymorphism Associated with Exceptional Longevity: Large HDL & LDL in Older: 241 Ashkenazi Jews with an average age of 98 and their children were tested and compared to Jewish and non-Jewish controls. HDL and LDL were larger than normal. Genotyped for the codon 405 isoleucine to valine (I405V) variation in the cholesteryl ester transfer protein (CETP) gene. Probands and offspring had a 2.9- and 3.6-fold (in men) and 2.7- and 1.5-fold (in women) increased frequency, respectively, of homozygosity for the 405 valine allele of CETP (VV genotype), respectively, compared with controls (P<.001 for both). Those probands with the VV genotype had increased lipoprotein sizes and lower serum CETP concentrations. Unique lipoprotein phenotype and genotype associated with exceptional longevity. Barzilai N, et al. JAMA. 2003 Oct 15;290(15):2030-40

Methionine Synthase Polymorphism Linked to Longevity in Humans: The functional polymorphism methionine synthase (MTR) c.2576Aright curved arrow G (D919G) influences homocysteine and folate metabolism and has been reported to be of protective function against oncological, neurodegenerative and vascular diseases. In a study of 329 healthy individuals to confirm whether this polymorphism might be of epidemiological impact on disease-free longevity, the prevalence of the G-allele was significantly higher in the older than in the younger individuals (p=0.005) supporting the thesis that MTR c.2576Aright curved arrow G is beneficial to disease-free longevity. The MTR genotype on male subjects became relevant at a younger age as opposed to female subjects suggesting a gender-dependent effect. The methionine synthase polymorphism c.2756Aright curved arrow G (D919G) is relevant for disease-free longevity. Linnebank M, et al. University Hospital Bonn, Germany. . Int J Mol Med. 2005 Oct;16(4):759-61

Methionine Sulfoxide Reductase Increases Life Span: Aging is associated with a loss of methionine sulfoxide reductase (Msr) activities in a number of animal tissues, and mutations in mice leading to a decrease in the Msr levels lead to a decrease in the maximum life span, whereas overexpression of Msr leads to a dramatic increase in the maximum life span.  Msr catalyzes the reduction of MetO (methionine sulfoxide) back to methionine residues. Methionine oxidation and aging. Stadtman ER, et al. Biochim Biophys Acta 2005 Jan 17;1703(2):135-40. Methionine oxidation may play an important role in Alzheimer's and Parkinson's diseases. Oxidative alteration of Met to Met(O) is reversed by Msr (MsrA enzymes reduce S-MetO and MsrB enzymes reduce R-MetO). MsrA null mice exhibit ataxic tip toe walking, is more sensitive to oxidative stress, and has a 40% shorter life span than wild-type (WT) mice. Biochim Biophys Acta 2005 Jan 17;1703(2):213-9

Mitochondrial Gene 5x More Common in Centenarians: 52 Italian centenarians, the researchers found a common mutation in the same main control region. Looking at mitochondrial DNA in white blood cells, they found that 17 percent of the 52 had a specific mutation called C150T transition, compared with only 3.4 percent of 117. Evidence was obtained for the contribution of somatic events, under probable nuclear genetic control, to the striking selective accumulation of the mutation in centenarians. In another study, among leukocyte mtDNA samples from 20 monozygotic and 18 dizygotic twins, 60-75 years old, 30% (P = 0.0007) and 22% (P = 0.011). Strikingly higher frequency in centenarians and twins of mtDNA mutation causing remodeling of replication origin in leukocytes. Zhang J, Asin-Cayuela J, Fish J, Michikawa Y, Bonafe M, Olivieri F, Passarino G, De Benedictis G, Franceschi C, Attardi G. Proc Natl Acad Sci U S A 2003 Feb 4;100(3):1116-21

Mitochondrial DNA Polymorphism in Longevity:In study of 225 >90yo vs controls, haplogroup H was less frequent than among the middle-aged subjects ( P=0.001) and infants ( P=0.00001), whereas haplogroups U and J were more frequent. Haplogroup clusters also differed between Vitality 90+ and both the middle-aged subjects ( P=0.002) and infants ( P=0.00001), the frequency of haplogroup cluster HV being lower in the former and that of UK and WIX being higher. Mitochondrial DNA polymorphisms associated with longevity in a Finnish population. Niemi AK, Hervonen A, Hurme M, Karhunen PJ, Jylha M, Majamaa K. Hum Genet 2003 Jan;112(1):29-33

P-53 Polymorphism Increases Both Cancer Risk and Longevity: Longevity may depend on a balance between tumor suppression and tissue renewal. Mice with constitutively activated p53 are almost cancer free but their life span is reduced and accompanied by early tissue atrophy. The codon 72 polymorphic variants of p53 have markedly different apoptotic potential. In a prospective study of 1226 people aged 85 years and over, carriers of the Pro/Pro genotype had a 41% increased survival (p = 0.032) despite a 2.54 fold increased (p = 0.007) proportional mortality from cancer. Variation in the human TP53 gene affects old age survival and cancer mortality. van Heemst D, Mooijaart SP, et al. Exp Gerontol. 2005 Jan-Feb;40(1-2):11-5. Ed: Of course, others with the P-53 polymorphism would have died of cancer before their chance of reaching age 85 and being included in the study.

Sirtuin Variants Not Associated with Longevity in Germans: The SIR2/Sirt1 gene has been demonstrated as regulating lifespan in many model organisms, including yeast, Caenorhabditis elegans and rodents. In a study of common allelic variations in the SIRT1 gene of 1573 long-lived individuals (centenarians and nonagenarians) and matched younger controls, there was no evidence for an association was detected between any of the tested SNPs and the longevity phenotype at the allele, genotype or haplotype levels. Sirtuin 1 (SIRT1) sequence variation is not associated with exceptional human longevity. Flachsbart F, et al. University Hospital Schleswig-Holstein, Kiel, Germany. Exp Gerontol 2005 Oct 26.

Sir2 Protein May Help: Sirtuin controls the enzyme that converts acetate, a source of calories, into acetyl-CoA, a key component of cellular respiration. it could help explain why restricting regular sources of calories -- sugars and fats -- leads to extended lifespan in many kinds of organisms." sirtuin protein in bacteria is a crucial modifier of an enzyme known as acetyl-CoA synthetase, which converts acetate into acetyl-CoA in a two-step process. Acetyl-CoA then can directly fuel the citric acid cycle, the central energy-producing step in cellular respiration. known to play an important role in keeping regions of chromosomes turned off. By modifying the histone proteins that keep DNA tightly coiled, sirtuins prevent certain regions of chromosomes from being exposed to cells' DNA-reading machinery. U Wisc, Hopkins, Sci Daily 1/7/03

Telomeres Shorter with MAOA Polymorphisms: Telomere shortening and increased MAOA gene activity both occur with aging. In a stratified random household sample of 433 adults, their telomere lengths were distributed (6.4-11.63 kb). The rate of shortening per year was 69 base pairs, and the gender difference in length was not significantly different. The lognormal distribution of telomere lengths was linear. The high-activity allele of the MAOA promoter polymorphisms were negatively associated with telomere length (P=0.013). Telomeric length varies with age and polymorphisms of the MAOA gene promoter in peripheral blood cells obtained from a community in Taiwan. Lung FW, Fan PL, et al. National Cheng-Kung University, Tainan, Taiwan. Psychiatr Genet. 2005 Mar;15(1):31-35. Ed: It's amazing what they can measure now.

Telomeres: Elderly with Short Telomeres Die Sooner: Richard Cawthon, University of Utah measured the telomeres in a randomly-chosen group of 150 patients aged 60 or over. Those with shorter telomeres were eight times as likely to die from an infectious disease and three times more likely to suffer a fatal heart attack. A telomere is a repeated sequence of five bases that preserves the integrity of genes during DNA replication. In healthy people, telomeres do not shrink significantly until old age because the enzyme telomerase ensures regeneration. The Lancet (vol 361, p 393, 1/31/03

Telomeres: In Animals, Most Telomere Loss Early in Life: Hall ME, et al, University of Glasgow. Proc R Soc Lond B Biol Sci. 2004 Aug 7;271(1548):1571-6.