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(12) Patent Application Publication (10) Pub. No.: US 2003/0207315A1 Burmer Et Al

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(12) Patent Application Publication (10) Pub. No.: US 2003/0207315A1 Burmer Et Al US 20030207315A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2003/0207315A1 Burmer et al. (43) Pub. Date: Nov. 6, 2003 (54) ANT-AGING NUCLEIC ACID AND PROTEIN Related U.S. Application Data TARGETS (63) Continuation of application No. 09/875,534, filed on Sep. 28, 2000, now abandoned. (75) Inventors: Glenna C. Burmer, Seattle, WA (US); Joseph P. Brown, Seattle, WA (US); (60) Provisional application No. 60/156,666, filed on Sep. David K. Pritchard, Seattle, WA (US) 29, 1999. Correspondence Address: Publication Classification TOWNSEND AND TOWNSEND AND CREW, (51) Int. Cl. .................................................. C12O 1/68 LLP (52) U.S. Cl. .................................................................. 435/6 TWO EMBARCADERO CENTER EIGHTH FLOOR (57) ABSTRACT SAN FRANCISCO, CA 94111-3834 (US) This invention relates to the discovery of nucleic acids and Assignee: LifeSpan BioSciences, Inc., Seattle, WA proteins associated with aging processes. The identification (73) of these aging-associated nucleic acids and proteins have (US) diagnostic uses in detecting the aging Status of a cell (21) Appl. No.: 10/454,565 population as well as application for treating or delaying cellular and physiological changes that occur with aging or (22) Filed: Jun. 3, 2003 the onset of diseases typically associated with aging. US 2003/0207315 A1 Nov. 6, 2003 ANT-AGING NUCLEIC ACID AND PROTEIN 0006 Cells that have exhausted their potential for pro TARGETS liferative growth are said to have undergone "Senescence.” Although a variety of theories have been proposed to explain CROSS-REFERENCE TO RELATED the phenomenon of cellular Senescence in vitro, experimen APPLICATIONS tal evidence Suggests that the age-dependent loSS of prolif erative potential may be the function of a genetic program 0001. This present application claims priority to U.S. (Orgel, L. E., Proc. Natl. Acad. Sci. (U.S.A.) 49:517 (1963); Application No. 60/156,666 filed Sep. 29, 1999, which is De Mars, R., et al., Human Genet. 16:87 (1972); M. Buch herein incorporated by reference. wald, Mutat. Res. 44:401 (1977); Martin, G. M., et al., Amer: J. Pathol. 74:137 (1974); Smith, J.R., et al., Mech. Age. Dev. FIELD OF THE INVENTION 13:387 (1980); Kirkwood, T. B. L., et al., Theor: Biol. 53:481 (1975). These genes associate with Senescence may also 0002 This invention relates to the discovery of nucleic include genes that are differentially expressed in aging acids and proteins associated with aging processes. The tissue. identification of these aging-associated nucleic acids and proteins have diagnostic uses in detecting the aging Status of 0007 Two main strategies have been used to identify a cell population as well as application for treating or genes that are involved in the aging process. In relatively delaying cellular and physiological changes that occur with Simple, genetically-tractable model organisms. Such as Sac aging or the onset of diseases typically associated with charomyces cerevisae, Drosophila melanogaster, and C. aging. elegans, genetic Screens have been used to identify genes that, when mutated, confer enhanced longevity. In complex BACKGROUND OF THE INVENTION organisms, molecular Screens have been used to identify genes that are differentially expressed during aging. For 0003) Aging is characterized by various changes in cel example, Studies have compared expression patterns lular and physiological processes and an increase in the between young and Senescent human diploid fibroblasts or incidence of age-related diseaseS Such as cancer, heart between tissue Sample derived from young versus old Sub disease, cataracts, neurodegenerative diseases, osteoporosis, jects. These studies have often identified different sets of arthritis, and hearing loSS. Cellular changes that occur with genes and the results have been difficult to compare due to aging include oxidation of lipids and proteins, damage to methodological differences, including variations in the DNA, loss of proliferative capacity, telomere shortening, methods used to derive cDNA libraries, cell cultures con decline in RNA and protein Synthesis, accumulation of ditions, types of tissue used. cellular debris, and breakdown in cell to cell Signaling. Physiological changes with aging include changes in skin 0008. The present invention identifies aging-associated tone, loSS of muscle Strength and muscle wasting, loSS of hair nucleic acid and protein Sequences which are differentially and hair pigment, decreased elasticity of arteries, athero expressed in multiple types of tissue. The high-density array Sclerosis, disrupted endocrine functions, loSS of organ func technology employed herein has quantified the differential tion, decreased metabolism and decline in the immune expression of 6,000 genes acroSS multiple tissue types response. during aging. Thus, the present invention provides nucleic acid and protein Sequences associated with aging and meth 0004. The identification of protein and nucleic acid ods of identifying modulators of these Sequences. Sequences that are differentially expressed in aging tissues, e.g., Sequences that are associated with the loSS of prolifera SUMMARY OF THE INVENTION tive potential, has important diagnostic and therapeutic Significance. For example, Such Sequences can be used as 0009. The present invention provides isolated nucleic diagnostic markers or indicators to determine the aging acids and proteins associated with aging. Such Sequences Status of tissues and can also serve as targets for intervention can be used for diagnostic and therapetic purposes. For to slow or ameliorate the onset of age-related diseases or example, the Sequences can be used to diagnose the aging cellular and physiological changes associated with aging. Status of tissues and in diagnosing tissues Susceptible to age-related diseases. Moreover, the Sequences can be used to 0005 With respect to proliferative capacity of cells, treat cellular and phyiological changes that occur during normal human diploid cells have a finite potential for aging. For example, drugs or modulators that alter either proliferative growth (Hayflick, L., et al., Exp. Cell Res. expression levels or the function of aging-associated differ 25:585 (1961); Hayflick, L., Exp. Cell Res. 37:614 (1965)). entially expressed genes can be used to slow aging-related Indeed, under controlled conditions, in vitro cultured human changes or the development of age-associated diseases. cells can maximally proliferate only to about 80 cumulative Gene therapy can also be used to alter the expression levels population doublings. The proliferative potential of Such of aging-associated genes or proteins. The ability to slow or cells has been found to be a function of the number of modify aging-associated gene expression can, for example, cumulative population doublings which the cell has under gone (Hayflick, L., et al., Exp. Cell Res. 25:585 (1961); lower the incidence and retard the progression of age-related Hayflick, L., et al., Exp. Cell Res. 37: 614 (1985)). This diseases. potential is also inversely proportional to the in Vivo age of 0010. In one aspect, the present invention provides a the cell donor (Martin, G. M., et al., Lab. Invest. 23:86 method for identifying a modulator of expression of an (1979); Goldstein, S., et al., Proc. Natl. Acad. Sci. (U.S.A.) age-associated gene, the method comprising: culturing the 64:155 (1969); Schneider, E. L., Proc. Natl. Acad. Sci. cell in the presence of the modulator to form a first cell (U.S.A) 73:3584 (1976); LeGuilty, Y., et al., Gereontologia culture; contacting RNA from the first cell culture with a 19:303 (1973)). probe which comprises a polynucleotide Sequence associ US 2003/0207315 A1 Nov. 6, 2003 ated with aging, determining whether the amount of the 0014 Similarly, the present invention provides a method probe which hybridizes to the RNA from the first cell culture for modulating the aging of a cell in a patient in need thereof, is increased or decreased relative to the amount of the probe the method comprising administering to the patient a com which hybridizes to RNA from a second cell culture grown pound that modulates the aging of the cell. In one embodi in the absence of the modulator, and further, the method can ment, the compound increases or decreases the expression comprise detecting a phenotype indicative of altered aging level of a nucleic acid associated with aging. In this embodi properties in the cell population that is treated with the ment, the nucleic acid can, for example, comprise at least modulator. In one embodiment of this method, the probe about 10 nucleotides from a polynucleotide Sequence comprises at least about 10 nucleotides from a polynucle Selected from the group consisting of the Sequences Set out otide Sequence Selected from the group consisting of the in Table 1. Sequences Set out in Table 1 which show increased expres Sion with aging. In an alternative embodiment, the probe DEFINITIONS comprises at least about 10 nucleotides from a polynucle 0015 “Amplification' primers are oligonucleotides com otide Sequence Selected from the group consisting of the prising either natural or analog nucleotides that can Serve as Sequences Set out in Table 1 which show decreased expres the basis for the amplification of a Select nucleic acid Sion with aging. In another embodiment, the method of Sequence. They include, for example, both polymerase chain identifying a modulator of expression of aging-associated reaction primers and ligase chain reaction
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