METHODS AND COMPOSITIONS FOR ALTERING HEALTH, WELLBEING, AND LIFESPAN

• US 20100173024A1
• Filed: 12/01/2009
• Published: 07/08/2010
• Est. Priority Date: 12/01/2008
• Status: Abandoned Application

• Current Assignee: Lifespan Extension, LLC
• Original Assignee: Lifespan Extension, LLC
• Inventors: McDaniel, David H.
• Application Number:
  US12/629,040
• Publication Number:
  US 20100173024A1
• Time in Patent Office: Days
• US Class Current: 424/729
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/05 Phenols cannabinoids A61K31/658
• CPC Class Codes: A61K 31/122 having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
• CPC Class Codes: A61K 31/16 Amides, e.g. hydroxamic acids
• CPC Class Codes: A61K 31/166 having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
• CPC Class Codes: A61K 36/13 Coniferophyta (gymnosperms)
• CPC Class Codes: A61K 36/74 Rubiaceae (Madder family)
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system

Abstract

Described herein are the results of comprehensive genetic expression and other molecular analysis of the effect of antioxidants on biological systems, including specifically different human cells. Based on these analyses, methods and compositions are described for modifying or influencing the lifespan of cells, tissues, organs, and organisms. In various embodiments, there are provided methods for modulating the activity of the gene maintenance process in order to influence the length and/or structural integrity of the telomere in living cells, as well as methods for modulating the rate/efficiency of the cellular respiration provided by the mitochondria, mitochondrial biogenesis, and maintenance of the mitochondrial membrane potential. Exemplary lifespan altering compounds include natural and synthetic antioxidants, such as plant antioxidant and polyphenol compounds derived from coffee cherry, tea, berry, and so forth, including but not limited to caffeic acid, chlorogenic acid, ferulic acid, quinic acid, proanthocyanidins, ubiquinone, idebenone, or a synthetic form or derivatives thereof.

Claims

1. A method for modulating the lifespan of a cell, tissue, organ or organism, or of increasing or decreasing cellular respiration and/or capacity and/or biogenesis of mitochondria in a cell, tissue, organ or organism, comprising contacting the cell, tissue, organ or organism with at least one lifespan modulating agent selected from the group consisting of:

idebenone, or an analog or derivative thereof;

a cocoa extract;

a coffee cherry extract;

quinic acid, or an analog or derivative thereof;

ferulic acid, or an analog or derivative thereof;

a proanthocyanidin, anthocyanidin, procyanidin, or cyanidin;

chlorogenic acid, or an analog or derivative thereof;

a tea extract;

or

resveratrol or a composition derived from or chemically related to resveratrol.

6. The method of claim 1, wherein modulating the lifespan comprises modulating the level and/or activity of at least one gene selected from the group consisting of those listed in Data Table 7 and those listed as part of Array 2.

9. The method of claim 6, wherein modulating comprises modulating the level and/or activity of:

(a) ten or more of the genes listed as part of Array 2;

(b) the genes listed as part of Array 1;

(c) VEGFA, HMOX1, CCL4L1, DDC, NOS2A, S1RT1, TERT, PTGS2, or IF144;

(d) four or more of TERT, TERC, NRF2, POT1, TRF1, TRF2, TIN2, TPP1, RAP1, TNKS, TNKS 2, TERF2, TERF2IP, POLG, POLB, POLD3, POLE, POLI, POLL, PARP2, PPARG, SHC1, PTOP, IFI44, NFKB1, HSPA1A, HSPA1B, HSPA1L, MTND5, HPGD, IDH2, MDH1, MDH2, ME1, ME2, ME3, MTHD1, MTHFD1L, MTHFR, NADK, NADSYN1, NDUFA2, NDUFA3, NDUFA4, NDUFA4L2, NDUFA5, NDUFA6, NDUFA7, NDUFA9, NDUFA10, NDUFA12, NDUFB2, NDUFB3, NDUFB5, NDUFB6, NDUFB7, NDUFB8, NDUFB9, NDUFC2, NDUFS2, NDUFS4, NDUFS5, NDUFS7, NDUFS8, NDUFV2, NDUFV3, NOX1, NOX3, NOX4, NOX5, NOXA1, NOXO1, NQO1, FOXO1, FOXO3, FOXO4, LMNA, NHP2L1, RAD50, RAD51, KL and KU70;

(e) BCL2, SOD1, TP53, and SOD2;

(f) BCL2, SOD1, TP53, SOD2, BCL2L1, TIMM22, TOMM40, IMMPIL, CDKN2A, GADPH, ACTB, HRP1, and HGDC;

(g) PARP1, PARP2, TERT, TEP1, TPS3, JUN, PARP3, PARP4, TERF2, TINF2, and CDKN2A;

(h) PARP1, PARP2, TERT, TEP1, and TP53;

(i) TERF2, POT1, TERT, and TPP1;

(j) PAPR1, PARP2, PARP3, and PARP4;

(k) PARP2, CYP19A1, TEP1, BCL2, HSPA1A, ACE, TP53, and NFKB1;

(l) IGF1, IGF2, PPARG, IL10, APOE, TERT, TNF, HLA-DRA, DDC, CCL4L1, NOS2A, and GH1;

(m) PARP1, IL6, SIRTT1, KRAS, and HSPA1L;

(n) IGF1, IL6, PPARG, IL10, TERT, TNF, TEP1, HSPA1A, SIRT1, TP53, GH1, NOS2A, and PPC;

(o) another list of genes described herein;

or

(p) a combination of two or more of (a) through (o).

10. The method of claim 1, wherein modulating the lifespan comprises modulating the activity or level of at least one of the telomere length maintenance genes or modulating the activity or level of telomerase.

36. The method of claim 1, wherein the method comprises increasing the lifespan of a cell through modulating biogenesis of, or respiratory efficiency of mitochondria, lengthening telomeres, and/or modulating at least one gene affecting the same.

37. The method of claim 1, comprising increasing or decreasing proliferation or biogenesis of mitochondria through modulation of at least one of PGC1α

, SIRT1, SIRT3, SIRT4, SIRT5, NRF1 and/or Tfam.

38. The method of claim 1, further comprising inducing mitochondrial regeneration, or new mitochondrial biosynthesis in at least one cell.

2-5. -5. (canceled)

7-8. -8. (canceled)

11-26. -26. (canceled)

27. A method for modulating response or resistance to stress of a cell, tissue, organ or organism, comprising modulating the level and/or activity of at least one gene selected from the group consisting of those listed in Data Table 7 and those listed as part of Array 2.

28. The method of claim 27, wherein modulating comprises modulating the level and/or activity of:

(a) ten or more of the genes listed as part of Array 2;

(b) the genes listed as part of Array 1;

(c) VEGFA, HMOX1, CCL4L1, DDC, NOS2A, SIRT1, TERT, PTGS2, or IF144;

(d) four or more of TERT, TERC, NRF2, POT1, TRF1, TRF2, TIN2, TPP1, RAP1, TNKS, TNKS 2, TERF2, TERF21P, POLG, POLB, POLD3, POLE, POLI, POLL, PARP2, PPARG, SHC1, PTOP, IF144, NFKB1, HSPA1A, HSPA1B, HSPA1L, MTND5, HPGD, IDH2, MDH1, MDH2, ME1, ME2, ME3, MTHD1, MTHFD1L, MTHFR, NADK, NADSYN1, NDUFA2, NDUFA3, NDUFA4, NDUFA4L2, NDUFA5, NDUFA6, NDUFA7, NDUFA9, NDUFA10, NDUFA12, NDUFB2, NDUFB3, NDUFB5, NDUFB6, NDUFB7, NDUFB8, NDUFB9, NDUFC2, NDUFS2, NDUFS4, NDUFS5, NDUFS7, NDUFS8, NDUFV2, NDUFV3, NOX1, NOX3, NOX4, NOX5, NOXA1, NOXO1, NQO1, FOXO1, FOXO3, FOXO4, LMNA, NHP2L1, RAD50, RAD51, KL and KU70;

(e) BCL2, SOD1, TP53, and SOD2;

(f) BCL2, SOD1, TP53, SOD2, BCL2L1, TIMM22, TOMM40, IMMPIL, CDKN2A, GADPH, ACTB, HRP1, and HGDC;

(g) PARP1, PARP2, TERT, TEP1, TPS3, JUN, PARP3, PARP4, TERF2, TINF2, and CDKN2A;

(h) PARP1, PARP2, TERT, TEP1, and TP53;

(i) TERF2, POT1, TERT, and TPP1;

(j) PAPR1, PARP2, PARP3, and PARP4;

(k) PARP2, CYP19A1, TEP1, BCL2, HSPA1A, ACE, TP53, and NFKB1;

(l) IGF1, IGF2, PPARG, IL10, APOE, TERT, TNF, HLA-DRA, DDC, CCL4L1, NOS2A, and GH1;

(m) PARP1, IL6, SIRTT1, KRAS, and HSPA1L;

(n) IGF1, IL6, PPARG, IL10, TERT, TNF, TEP1, HSPA1A, SIRT1, TP53, GH1, NOS2A, and PPC;

(o) another list of genes described herein;

or

(p) a combination of two or more of (a) through (o).

29. The method of claim 27, wherein modulating comprises increasing the level of activity of the at least one listed gene.

30. The method of claim 27, wherein modulating comprises decreasing the level of activity of the at least one listed gene.

31-35. -35. (canceled)

39. A method for modulating, preventing, delaying, or reversing acute cell death or apoptosis, or prolonging the survival of a cell, tissue, organ or organism comprising modulating the level and/or activity of at least one gene selected from the group consisting of those listed in Data Table 7 and those listed as part of Array 2.

40. The method of claim 39, wherein modulating acute cell death or apoptosis comprises increasing or upregulating acute cell death or apoptosis.

41. A method for modulating, enhancing, maintaining or producing a more youthful or function of the skin and/or associated tissues, comprising modulating the level and/or activity of at least one gene selected from the group consisting of those listed in Data Table 7 and those listed as part of Array 2.

42. (cancel)

43. A collection of lifespan-influencing nucleic acid molecules, which collection comprises a plurality of nucleic acid molecules selected from those listed in Data Table 7 or Array 2, or fragments of those listed in Data Table 7 or Array 2.

44-45. -45. (canceled)

47-48. -48. (canceled)

49. A method of screening compounds useful for modulating lifespan, comprising:

contacting a test compound with a host cell expresses a lifespan-influencing protein encoded by an isolated nucleic acid molecule listed in Data Table 7 or listed as part of Array 2 and

detecting a change in the expression of the nucleotide sequence or a change in activity of encoded protein, wherein such a change indicates the test compound is useful for modulating lifespan.

50. The method of claim 49, which is a high throughput method, comprising:

contacting in parallel a test compound with a collection of host cells each of which expresses a different lifespan-influencing protein encoded by an isolated nucleic acid molecule in listed in Data Table 7 or listed as part of Array 2; and

detecting a change in the expression of at least one of the nucleotide sequences or a change in activity of at least one of the encoding proteins, wherein such a change indicates the test compound(s) are useful for modulating lifespan.

51. (canceled)

52. A method for identifying an agent with potential to influence mitochondrial damage, comprising:

contacting an cell with an agent; and

detecting the level of a nucleic acid molecule corresponding to

(1) ACTB, BCL2, BCL2L1, CDKN2A, COX10, COX18, CPT1B, CPT2, DNAJC19, EGF, EGR2, FIS1, GAPDH, GRPEL1, HSP90AA1, LRPPRC, MFN1, MFN2, NOS3, OPA1, PARP3, PARP4, PPARGC1A, SIRT2, SIRT4, SLC25A1, SLC25A1, SLC24A2, SLC25A3, SLC25A4, SCL25A5, SLC25A10, SLC25A12, SLC25A13, SLC25A14, SLC25A15, SLC25A16, SLC25A17, SLC25A19, SLC25A2, SLC25A20, SLC25A21, SLC25A22, SLC25A23, SLC25A24, SLC25A25, SLC25A27, SLC25A3, SLC25A30, SLC25A31, SLC25A37, SLC25A4, SLC25A5, TIMM10, TIMM17A, TIMM17B, TIMM22, TIMM23, TIMM44, TIMM50, TIMM8A, TIMM8B, TIMM9, TOMM20, TOMM22, TOMM34, TOMM40, TOMM40L, TOMM70A, UCP1, UCP2, UCP3 or another gene indicated herein as beneficial for mitochondrial health or maintenance when increased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein an increase in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to reverse or inhibit mitochondrial damage;

or

(2) AIFM2, AIP, BAK1, BBC3, BID, BNIP3, CLK1, HSPA1A, HSPA1B, HSPA1L, IMMP1L, IMMP2L, MIPEP, PARP1, PARP2, PMAIP1, RPL13A, SOD1, SOD2, SFN, SH3GLB1, UXT or another gene indicated herein as beneficial for mitochondrial health or maintenance when decreased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein a decrease in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to reverse or inhibit mitochondrial damage;

or

(3) ACTB, BCL2, BCL2L1, CDKN2A, COX10, COX18, CPT1B, CPT2, DNAJC19, EGF, EGR2, FIS1, GAPDH, GRPEL1, HSP90AA1, LRPPRC, MFN1, MFN2, NOS3, OPA1, PARP3, PARP4, PPARGC1A, SIRT2, SIRT4, SLC25A1, SLC25A1, SLC24A2, SLC25A3, SLC25A4, SCL25A5, SLC25A10, SLC25A12, SLC25A13, SLC25A14, SLC25A15, SLC25A16, SLC25A17, SLC25A19, SLC25A2, SLC25A20, SLC25A21, SLC25A22, SLC25A23, SLC25A24, SLC25A25, SLC25A27, SLC25A3, SLC25A30, SLC25A31, SLC25A37, SLC25A4, SLC25A5, TIMM10, TIMM17A, TIMM17B, TIMM22, TIMM23, TIMM44, TIMM50, TIMM8A, TIMM8B, TIMM9, TOMM20, TOMM22, TOMM34, TOMM40, TOMM40L, TOMM70A, UCP1, UCP2, UCP3 or another gene indicated herein as beneficial for mitochondrial health or maintenance when increased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein a decrease in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to increase or accelerate mitochondrial damage;

or

(4) AIFM2, AIP, BAK1, BBC3, BID, BNIP3, CLK1, HSPA1A, HSPA1B, HSPA1L, IMMP1L, IMMP2L, MIPEP, PARP1, PARP2, PMAIP1, RPL13A, SODI, SOD2, SFN, SH3GLB1, UXT or another gene indicated herein as beneficial for mitochondrial health or maintenance when decreased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein an increase in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to increase or accelerate mitochondrial damage.

56. The method of claim 52, wherein mitochondrial damage comprises mtDNA depletion or reduced mitochondrial respiratory activity.

53-55. -55. (canceled)

57. A method for identifying an agent with potential to influence DNA damage or telomere shortening, comprising:

contacting an cell with an agent; and

detecting the level of a nucleic acid molecule corresponding to;

(1) AK3, APEX1, APEX2, ATF2, ATM, ATR, ATRX, BARDI, BLM, BRIP1, CCNH, CDK7, CDKN2A, CHEK1, CHEK2, CSF2, CTPS, DDB1, DDB2, DHFR, DMC1, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, EXO1, FANCA, FANCC, FANCF, FANCG, FEN1, GADD45A, GADD45G, GTF2H1, GTF2H2, GTF2H3, GTF2H4, JUN, LIG1, LIG3, LIG4, MAP2K6, MAPKAPK2, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH4, MSH5, MSH6, NBN, NEIL1, NEIL2, NEIL3, NFKB1, NFKBIA, HK1, NUDT1, NUDT2, ODC1, PAPSS1, PAPSS2, PARP1, PARP3, PCNA, PMS1, PMS2, PNKP, POLB, POLD3, POLE, POLI, POLL, PRKDC, RAD1, RAD18, RAD21, RAD23A, RAD50, RAD51C, RAD51L1, RAD51L3, RAD52, RAD54B, RAD54L, RBBP8, SESN1, SLC23A2, TDG, TYMS, UBE2V2, UNG2, WRN, XAB2, XPA, XPC, XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, XRCC6, ZNRD1 or another gene indicated herein as beneficial for DNA or telomere maintenance when increased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein an increase in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to reverse or inhibit DNA damage or telomere shortening;

or

(2) B2M, BRCA1, BRCA2, BTG2, CIDEA, CIDEB, DDIT3, DKC1, GTSE1, MDM2, PCBP4, PDCD8, PINX1, PPPIR15A, RAD17, RELA, TELO2, TEP1 or another gene indicated herein as beneficial for DNA or telomere maintenance when decreased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein a decrease in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to reverse or inhibit DNA damage or telomere shortening;

or

(3) AK3, APEX1, APEX2, ATF2, ATM, ATR, ATRX, BARD1, BLM, BRIP1, CCNH, CDK7, CDKN2A, CHEK1, CHEK2, CSF2, CTPS, DDB1, DDB2, DHFR, DMC1, ERCC1, ERCC2, ERCC3, ERCC4, ERCC5, ERCC6, ERCC8, EXO1, FANCA, FANCC, FANCF, FANCG, FEN1, GADD45A, GADD45G, GTF2H1, GTF2H2, GTF2H3, GTF2H4, JUN, LIG1, LIG3, LIG4, MAP2K6, MAPKAPK2, MLH1, MLH3, MRE11A, MSH2, MSH3, MSH4, MSH5, MSH6, NBN, NEIL1, NEIL2, NEIL3, NFKB1, NFKB1A, HK1, NUDT1, NUDT2, ODC1, PAPSS1, PAPSS2, PARP1, PARP3, PCNA, PMS1, PMS2, PNKP, POLB, POLD3, POLE, POLI, POLL, PRKDC, RAD1, RAD18, RAD21, RAD23A, RAD50, RAD51C, RAD51L1, RAD51L3, RAD52, RAD54B, RAD54L, RBBP8, SESN1, SLC23A2, TDG, TYMS, UBE2V2, UNG2, WRN, XAB2, XPA, XPC, XRCC1, XRCC2, XRCC3, XRCC4, XRCC5, XRCC6, ZNRD1 or another gene indicated herein as beneficial for DNA or telomere maintenance when increased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein a decrease in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to accelerate or cause or enhance DNA damage or telomere shortening;

or

(4) B2M, BRCA1, BRCA2, BTG2, CIDEA, CIDEB, DDIT3, DKC1, GTSE1, MDM2, PCBP4, PDCD8, PINX1, PPP1R15A, RAD17, RELA, TELO2, TEP1 or another gene indicated herein as beneficial for DNA or telomere maintenance when decreased, or the level or activity of a protein encoded thereby, in the presence and absence of the agent, wherein an increase in the level or activity in the presence of the agent as compared to in the absence of the agent indicates that the agent has potential to accelerate or cause or enhance DNA damage or telomere shortening.

58-60. -60. (canceled)

61. A method inducing expression of TERT, POT1, TPP1 and TERF2 in a cell, by applying to the cell or an organism comprising the cell a composition comprising between about 0.000001% and about 10% (by weight) coffee cherry extract.

63. The method of claim 61, wherein the composition further comprises green tea extract, a component of green tea extract, or idebenone.

62. (canceled)

64-65. -65. (canceled)

66. A method inducing expression of PARP1, BCL2 and p53 in a cell, by applying to the cell or an organism comprising the cell a composition comprising between about 0.000001% and about 10% (by weight) coffee cherry extract.

67-68. -68. (canceled)

69. A method of inducing expression of NOS2A, NOS1, and NOS3 in a cell, by applying to the cell or an organism comprising the cell a composition comprising between about 0.000001% and about 10% (by weight) coffee cherry extract.

70. (canceled)

71. A method of inducing expression of CCL4L1 in a cell, by applying to the cell or an organism comprising the cell a composition comprising between about 0.000001% and about 10% (by weight) coffee cherry extract.

72-73. -73. (canceled)