(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2014/004902 A2 3 January 2014 (03.01.2014) P O P C T (51) International Patent Classification: Penelope; 3 av d'Evian, CH-1 006 Lausanne (CH). A61K 31/366 (2006.01) A61P 25/00 (2006.01) AUWERX, Johan; 8 rue Roger de Lessert, CH-1 168 A61K 45/06 (2006.01) A61P 3/04 (2006.01) Buchillon (CH). A61K 31/00 (2006.01) A61P 3/06 (2006.01) (74) Agents: STEELE, Alan, W. et al; Foley Hoag LLP, Pat C07D 493/00 (2006.01) A61P 3/10 (2006.01) ent Group, 155 Seaport Boulevard, Boston, MA 02210- C07D 493/06 (2006.01) A61P 35/00 (2006.01) 2600 (US). A61P 9/00 (2006.01) A61P 43/00 (2006.01) A61P 29/00 (2006.01) (81) Designated States (unless otherwise indicated, for every kind of national protection available): AE, AG, AL, AM, (21) International Application Number: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, PCT/US20 13/0483 10 BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, (22) International Filing Date: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, 27 June 2013 (27.06.2013) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, (25) Filing Language: English MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (26) Publication Language: English OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, (30) Priority Data: TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. 61/665,137 27 June 2012 (27.06.2012) US 61/712,886 12 October 20 12 ( 12.10.20 12) US (84) Designated States (unless otherwise indicated, for every 61/791,137 15 March 2013 (15.03.2013) us kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: AMAZENTIS SA [CH/CH]; Pare Scientifique UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, EPFL, PSE-C, CH-1024 Ecublens (CH). TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, (72) Inventor; and EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, LV, (71) Applicant : RINSCH, Christopher, L. [US/CH]; 60 Rue MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, de Lausanne, CH-1 110 Morges (CH). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, KM, ML, MR, NE, SN, TD, TG). (72) Inventors: BLANCO-BOSE, William; Chemin Chante- merle 13T, CH-1010 Lausanne (CH). SCHNEIDER, Published: Bernard; Av. des Cerisiers 37, CH-1009 Pully (CH). — without international search report and to be republished MOUCHIROUD, Laurent; Avenue de Cour 126, CH- upon receipt of that report (Rule 48.2(g)) 1007 Lausanne (CH). RYU, Dongryeol; Ch de Bourg-des- sus 20, CH-1 020 Renens VD (CH). ANDREUX, < o (54) Title: ENHANCING AUTOPHAGY OR INCREASING LONGEVITY BY ADMINISTRATION OF UROLITHINS OR PRE CURSORS THEREOF o (57) Abstract: Disclosed are methods, compounds, and compositions useful for increasing autophagy and promoting longevity. The methods, compounds, and compositions relate to urolithins and urolithin precursors and use thereof. Certain urolithins are represen ted by Formula I, while certain urolithin precursors are represented by Formula rv. The urolithin may be urolithin A, urolithin B, o urolithin C, or urolithin D. The urolithin precursor may be ellagic acid or an ellagitannin. The methods include in vivo, ex vivo, and in vitro uses of the compounds and compositions. Enhancing Autophagy or Increasing Longevity by Administration of Urolithins or Precursors Thereof RELATED APPLICATIONS This application claims benefit of priority to U.S. Provisional Patent Application No. 61/791,137, filed March 15, 2013; U.S. Provisional Patent Application No. 61/712,886, filed October 12, 2012; and U.S. Provisional Patent Application No. 61/665,137, filed June 27, 2012. BACKGROUND Autophagy is a lysosomal degradation pathway in both animals and plants that is essential for development, differentiation, homeostasis, and survival. In animals, autophagy serves principally as an adaptive mechanism to protect organisms against diverse pathologies, including infection, cancer, neurodegeneration, heart disease, and aging. The repertoire of routine housekeeping functions performed by autophagy includes elimination of defective proteins and organelles, prevention of the accumulation of abnormal protein aggregates, and elimination of intracellular pathogens. The autophagy pathway is uniquely capable of degrading entire organelles, such as mitochondria, peroxisomes, and endoplasmic reticulum. Multiple reports indicate that proteins required for autophagy induction, such as sirtuin 1, have reduced expression in aged tissues; levels of autophagy have been shown to diminish with age. Reduced levels of autophagy have also been associated with obesity, diabetes, cancer, neurodegenerative diseases, cardiovascular disease, osteoarthritis, and age- related macular degeneration. A number of compounds that stimulate autophagy have been identified, including rapamycin, resveratrol, metformin, spermidine, and glucosamine. Urolithins are ellagitannin- and ellagic acid-derived metabolites produced, e.g., by mammalian colonic microflora, including human colonic microflora. Urolithins are known to exhibit anti-oxidant activity. SUMMARY OF THE INVENTION An aspect of the invention is a method of increasing autophagy in an animal, comprising the step of administering to an animal in need thereof an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the animal. An aspect of the invention is a method of increasing longevity in an animal, comprising the step of administering to an animal in need thereof an effective amount of a urolithin or a precursor thereof, thereby increasing longevity of the animal. An aspect of the invention is a method of increasing autophagy in a cell, comprising the step of contacting a cell with an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the cell. An aspect of the invention is a method of increasing longevity of a cell, comprising the step of contacting a cell with an effective amount of a urolithin or a precursor thereof, thereby increasing longevity of the cell. An aspect of the invention is a method of increasing autophagy of eukaryotic cells in vitro, comprising the step of contacting eukaryotic cells in vitro with an effective amount of a urolithin or a precursor thereof, thereby increasing autophagy in the eukaryotic cells in vitro. An aspect of the invention is a method of increasing longevity of eukaryotic cells in vitro, comprising the step of contacting eukaryotic cells in vitro with an effective amount of a urolithin or a precursor thereof, thereby increasing longevity of the eukaryotic cells in vitro. An aspect of the invention is a composition comprising a urolithin or a precursor thereof; and a compound selected from the group consisting of rapamycin, resveratrol, metformin, and spermidine. An aspect of the invention is a compound of Formula II Formula II wherein X1, X2, X3, X4, X5, X6, X7, and X8 are independently selected from the group consisting of H and OH; and with the proviso that the compound is not a compound of Formula II wherein X1, X2, X3, X4, X5, X6, X7, and X8 are H; X1 is OH, and X2, X3, X4, X5, X6, X7, and X8 are H; X2 is OH, and X1, X3, X4, X5, X6, X7, and X8 are H (urolithin B); X3 is OH, and X1, X2, X4, X5, X6, X7, and X8 are H; X4 is OH, and X1, X2, X3, X5, X6, X7, and X8 are H; X5 is OH, and X1, X2, X3, X4, X6, X7, and X8 are H; X6 is OH, and X1, X2, X3, X4, X5, X7, and X8 are H; X7 is OH, and X1, X2, X3, X4, X5, X6, and X8 are H; X8 is OH, and X1, X2, X3, X4, X5, X6, and X7 are H; X1 and X2 are OH, and X3, X4, X , X6, X7, and X are H; X1 and X5 are OH, and X2, X3, X4, X6, X7, and X8 are H; X1 and X7 are OH, and X2, X3, X4, X5, X6, and X8 are H; X1 and X8 are OH, and X2, X3, X4, X5, X6, and X7 are H; X2 and X3 are OH, and X1, X4, X5, X6, X7, and X are H; X2 and X4 are OH, and X1, X3, X5, X6, X7, and X8 are H; X2 and X5 are OH, and X1, X3, X4, X6, X7, and X8 are H; X2 and X6 are OH, and X1, X3, X4, X5, X7, and X are H (urolithin A); X2 and X7 are OH, and X1, X3, X4, X5, X6, and X8 are H; X3 and X4 are OH, and X1, X2, X5, X6, X7, and X8 are H; X3 and X5 are OH, and X1, X2, X4, X6, X7, and X8 are H ; X3 and X6 are OH, and X1, X2, X4, X5, X7, and X8 are H; X5 and X6 are OH, and X1, X2, X3, X4, X7, and X8 are H; X5 and X8 are OH, and X1, X2, X3, X4, X6, and X7 are H; X6 and X7 are OH, and X1, X2, X3, X4, X5, and X8 are H; X1, X2, and X5 are OH, and X3, X4, X6, X7, and X8 are H; X1, X2, and X6 are OH, and X3, X4, X5, X7, and X8 are H; X1, X5, and X8 are OH, and X2, X3, X4, X6, and X7 are H; X2, X4, and X6 are OH, and X1, X3, X5, X7, and X8 are H; X2, X4, and X7 are OH, and X1, X3, X5, X6, and X8 are H; X2, X6, and X7 are OH, and X1, X3, X4, X5, and X8 are H (urolithin C); X2, X6, and X8 are OH, and X1, X3, X4, X5, and X7 are H; X2, X7, and X8 are OH, and X1, X3, X4, X5, and X6 are H; X1, X2, X5, and X6 are OH, and X3, X4, X7, and X8 are H; X1, X2, X5, and X7 are OH, and X3, X4, X6, and X8 are H; X1, X2, X6, and X7 are OH, and X3, X4, X5, and X8 are H (urolithin D); X1, X6, X7, and X8 are OH, and X2, X3, X4, and X5 are H; X2, X3, X6, and X7 are OH, and X1, X4, X5, and X8 are H; X2, X4, X5, and X are OH, and X1, X3, X6, and X7 are H; X2, X4, X6, and X7 are OH, and X1, X3, X5, and X8 are H; X1, X2, X4, X5, and X7 are OH, and X3, X6, and X8 are H; X1, X2, X6, X7, and X8 are OH, and X3, X4, and X5 are H; and X1, X2, X3, X6, X7, and X8 are OH, and X4 and X5 are H.