Nature Reviews Drug Discovery 4 569 580 2005

“老”是一種病嗎？ Nature Reviews Drug Discovery 4, 569 -580, 2005

Accumulation of germ-line mutations with late-acting deleterious effects 在平均年齡 30歲的族群中累積了許多 60歲才會發作的基因突變 …the forces of natural selection weakens with increasing age …. If a genetical disaster… happens late enough in individual life, its consequences may be completely unimportant. Even in such a crude and unqualified form, this dispensation may have a real bearing on the origin of innate deterioration with increasing age. Medawar, 1952

A B Young animal Elderly animal mutant gene action Increased fitness Reduced fitness Young animal Elderly animal mutant gene action Latent damage unmasked 到老年時才發作 Increased fitness Reduced fitness Latent damage 潛在的傷害 李承維

Survival 只有在動物園裡オ能看到老的斑馬。 老化是文明的產物！ Effective maintenance and repair Age

Science Vol. 299, pp 1342 – 1346; 2003 Wild-type (left specimen)and long-lived dwarf (right specimen) yeast, flies and mice with mutations that decrease glucose or insulin/IGF-I signaling.

Cellular senescence Human diploid fibroblast has limited replicative life span, termed replicative senescence or cellular senescence. Human diploid fibroblasts can divide ~60 -80 times. Experimental Cell Vol. 25 585 -621, 1961 周成功

Young vs. senescent fibroblasts • Senescent cells are generally larger, less motile, decreased saturation density. • Senescent cell is different from the quiescent cell in G 0. Senescence is irreversible process whereas G 0 cells can reenter cell cycle upon induction. • Senescent cells resist apoptosis, this may explain why senescent cells are not cleared and thus accumulate with age. Experimental Cell Research 212, p 167 -175, 1994

Aging is an autonomous property of normal cells Hayflick and Moorhead 40 th population doubling 10 th population doubling Male control Male, female Mixture Female control Male control 230 …… 李承維 …… …… 230 Female cell remain Female control

Human telomere shortening during replication Nature 345, 458 – 460; May 1990

Is cellular senescence the same as biological aging? • Cells cultured from old donors tend to senesce after fewer population-doublings than cells from young cell. • Interspecies comparison suggests that cell replicative life span and biological life span is genetically related.

Correlation between telomere length and human aging Nature 346, p. 866 – 868; Aug 1990

Cells from long-lived species are capable of replicating more times Sci Am. 1968 Mar; 218(3): 32 -7

What is the cause of Dolly’s death? • Dolly was cloned in 1997. • Analysis of telomere lengths in Dolly indicates that Dolly’s telomere length is similar to normal six-year-old sheep (1999). • Dolly die on 14 Feb, 2003 Toni Barros Dolly, 1997 -2003

Werner Syndrome • Autosomal recessive; Life Span in Years: 60 • Loss of WRN, a Rec. Q family helicase. • Reduced replicative life span of cultured cells. Increased mutation rate, particularly DNA deletions. Rapid telomere shortening during cellular replicative life span.

Telomerase is expressed in immortal and cancer cells

粒腺體：細胞內的火力發電廠！ Mitochondria Jim Thomas Copyright © Mc. Graw-Hill Companies Permission required for reproduction or display

G 3 P DHAP 4 H+ Transhydrogenise NAD+ I II NADH Q 4 H+ IV III O 2 NADH+ H+ NADPH NADP+ 2 G-SH G-S-S-G . O 2 - ½ O 2 H 2 O + 2 H+ . O 2 - H 2 O 2 + O 2 2 H 2 O 李承維 2 H+ Cyt c

誰看起來比較老？ One for the Ages: A Prescription That May Extend Life, The New York Times

One for the Ages: A Prescription That May Extend Life, The New York Times

Is it too late?

Science Vol. 301, p. 1731 – 1733; 2003

Science Vol. 301, p. 1731 – 1733; 2003

For fly, it’s never too late！ (但是必須持之有恒，才不會功虧一簣) Science 301: 1731 (2003)

Nature 424: 260 (2003)

出芽酵母菌的老化現象 Nature 408, 255 -262; 2000

Caloric restriction in yeast Caloric restriction Nature 408, 255 -262; 2000

The Fountain of Youth Lucas CRANACH (1546)

尋找可以使酵母菌長壽的藥物？ Search for drugs can activate Sir 2 activity

Nature 425, 191 -196; 2003

Nature 425, 191 -196; 2003

Nature 425, 191 -196; 2003 Average lifespan for wild type (WT) untreated, 19. 0 generations; wild type plus resveratrol (WT+R), 37. 8; glucose (calorie)-restricted plus resveratrol (WT+CR+R), 39. 9.

Fountain of youth juice. Scott Bauer

Dieter Weber 圖表參考自Nat Rev Drug Discov. 2006 Jun; 5(6): 493 -506. “ Rhubard “: 大黃 or 香港稱為芋莢

? ? ? Nature Reviews Drug Discovery 5, 493 -506 ; June 2006 The increases in lifespan for various species treated with resveratrol Nature Review of Drug Discovery June 2006

Baur, J. A. et al. Nature 444: 337 – 342, 2006

Resveratrol可以保護高熱量飲食引起的 早衰死亡! (New York Times Nov. 7, 2006) Nature Reviews Drug Discovery 5, 493 -506 ; June 2006

Resveratrol 不會讓胖子變瘦 Nature 444, p. 337 – 342; 2006

Resveratrol 能讓胖子精力充沛 Nature 444, p. 337 – 342; 2006

Resveratrol Delays Age-Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span Cell Metabolism 8, 157– 168, 2008

Looking for genes affect life span in mice!

Adipocyte: the origin of aging signal in mice? Extended longevity in mice lacking the insulin receptor in adipose tissue. Science 299: 572– 574; 2003

Suppression of Aging in Mice by the Hormone Klotho SCIENCE 309: 1829 -1833; 2005

Klotho is a circulating hormone and also a coreceptor for FGF 23 Biochimica et Biophysica Acta 1790 (2009) 1049– 1058

Two families demonstrating vertical transmission of extreme longevity Perls et al (2002) J. Amer. Geriatric Soc. 50, 359.

“The CISD 2 gene is located on human chromosome 4 q, where a genetic component for longevity maps” 本作品由Cold Spring Harbor Laboratory Press同意課程：「生物、演化與人」使 用，本資料庫亦無再授權他人使用之權 利，您如需利用本作品，請另行向權利 人取得授權

Genes Dev. 23: 1183 -1194; 2009 “Cisd 2 is primarily localized in the mitochondria and that mitochondrial degeneration appears to have a direct phenotypic consequence that triggers the accelerated aging process in Cisd 2 knockout mice”

Morris Water Maze 周成功

Rampon et al. , (2000)Nature Neuroscience 3, 238 - 244 (2000)

Nature 419, p. 794 -795 ; 2002

作品 授權條件 作者/來源 Kelloggs&Comstock http: //commons. wikimedia. org/wiki/File: 11 -stageswomanhood-1840 s. jpg 2010/09/29 visited Rory Curtis et al, Ageing and metabolism: drug discovery opportunities , Nature Reviews Drug Discovery 4, 569 -580; July 2005 Xtreambar http: //commons. wikimedia. org/wiki/File: Peter_Brian_Meda war. jpg 2010/09/29 visted Frank Gaillard http: //commons. wikimedia. org/wiki/File: Huntington. jpg 2010/09/30 visited http: //commons. wikimedia. org/wiki/File: George_Sumner_ Huntington. jpg 2010/09/30 visited 臺灣大學動物所 李承維

作品 作者/來源 授權條件 Valter D. LONGO, Caleb E. Finch, Evolutionary Medicine: From Dwarf Model Systems to Healthy Centenarians? , Science Vol. 299, pp 1342 – 1346; 2003 Hayflick and P. S. Moorhead , The serial cultivation of human diploid cell strains, Experimental Cell Vol. 25 585 -621; Dec 1961 L. Hayflick and P. S. Moorhead , The serial cultivation of human diploid cell strains, Experimental Cell Vol. 25 585 -621; Dec 1961 長庚大學 周成功 G. A. Mc. Farland R. Holliday (1994) Experimental Cell Research 212, p 167 -175 臺灣大學動物所 李承維

作品 授權條件 作者/來源 臺灣大學動物所 李承維 Calvin B. Harley, A. Bruce Futcher & Carol W. Greider, Telomeres shorten during ageing of human fibroblasts, Nature 345, 458 – 460; May 1990 Nicholas D. Hastie et al, Telomere reduction in human colorectal carcinoma and with ageing , Nature 346, 866 – 868; Aug 1990

作品 授權條件 作者/來源 L Hayflick (1968) Human cells and aging. Sci Am. 218: 327. Toni barros http: //commons. wikimedia. org/wiki/File: Dolly_face_closeu p. jpg 2010/09/30 visted Genes and Genetics, National Library of Medicine發行。 http: //www. ncbi. nlm. nih. gov/bookshelf/br. fcgi? book=gnd& part=wernersyndrome Fiona S. Wyllie et al, Telomerase prevents the accelerated cell ageing of Werner syndrome fibroblasts, Nature Genetics 24, 16 – 17; 2000 Kim NW et al, Specific association of human telomerase activity with immortal cells and cancer, Science 23, 266; Dec 1994

作品 授權條件 作者/來源 Kim NW et al, Specific association of human telomerase activity with immortal cells and cancer, Science 23, 266; Dec 1994 Jim Thomas http: //commons. wikimedia. org/wiki/File: Cell_parts. png 2010/09/16 visited Mariana Ruiz Villarreal http: //commons. wikimedia. org/wiki/File: Animal_mitochon drion_diagram_en. svg 2010/09/13 visited Masur http: //commons. wikimedia. org/wiki/File: Mitochondrial_ele ctron_transport_chain_short_PL. svg 2010/10/11 visited 臺灣大學動物所 李承維 Weindruch R, Walford RL, Fligiel S, Guthrie D. The retardation of aging in mice by dietary restriction: Longevity, cancer, immunity and lifetime energy intake. J Nutr. 1986; 116: 641– 654.

作品 作者/來源 授權條件 http: //www. nytimes. com/2006/10/31/health/nutrition/31 agi n. html? _r=2 2010/10/26 visited http: //www. nytimes. com/imagepages/2006/10/31/health/20 061031_AGING_GRAPHIC. html 2010/10/26 visited William Mair et al, Demography of Dietary Restriction and Death in Drosophila, Science Vol. 301, p. 1731 – 1733; 2003 長庚大學 周成功 Cynthia Kenyon et al, A C. elegans mutant that lives twice as long as wild type, Nature 366, 461 – 464; December 1993

作品 授權條件 作者/來源 Cynthia Kenyon et al, A C. elegans mutant that lives twice as long as wild type, Nature 366, 461 – 464; December 1993 David Gems & Joshua J. Mc. Elwee, Ageing: Microarraying mortality, Nature 424, 259 -261; 2003 Leonard Guarente & Cynthia Kenyon, Genetic pathways that regulate ageing in model organisms , Nature 408, 255262; 2000 http: //commons. wikimedia. org/wiki/File: Cranach_Jungbrun nen. jpg 2010/09/30 visited 本作品由得利影視同意課程：「生物、演化與人」使用， 本資料庫亦無再授權他人使用之權利，您如需利用本作 品，請另行向權利人取得授權

作品 作者/來源 授權條件 Konrad T. Howitz, Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan, Nature 425, 191196; 2003 Konrad T. Howitz, Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan, Nature 425, 191196; 2003 Scott Bauer http: //www. forestryimages. org/browse/detail. cfm? imgnum= 1322073 2010/10/26 visited Dieter Weber http: //commons. wikimedia. org/wiki/File: Rheum_rhabar barum. 2006 -04 -27. uellue. jpg 2010/10/26 visited Joseph A. Baur & David A. Sinclair, Therapeutic potential of resveratrol: the in vivo evidence, Nature Reviews Drug Discovery 5, 493 -506 ; June 2006

作品 授權條件 作者/來源 http: //commons. wikimedia. org/wiki/File: Cornelis_de_V os_-_Triumph_of_Bacchus. jpg 2010/09/30 visited Joseph A. Baur & David A. Sinclair, Therapeutic potential of resveratrol: the in vivo evidence, Nature Reviews Drug Discovery 5, 493 -506 ; June 2006 Joseph A. Baur et al, Resveratrol improves health and survival of mice on a high-calorie diet, Nature 444, 337 – 342; 2006 Thomas B. L. Kirkwood & Caleb E. Finch, Ageing: The old worm turns more slowly, Nature 419, 794 -795 ; 2002 Kevin J. Pearson et al, Resveratrol Delays Age. Related Deterioration and Mimics Transcriptional Aspects of Dietary Restriction without Extending Life Span, Cell Metabolism, Volume 8, 157 -168; 2008

作品 授權條件 作者/來源 Matthias Blüher et al, Extended Longevity in Mice Lacking the Insulin Receptor in Adipose Tissue, Science 299: 572– 574; 2003 Makoto Kuro-o, Klotho and aging, Biochimica et Biophysica Acta (BBA) - General Subjects Vol. 1790, P. 1049 -1058; 2009 Thomas Perls MD et al, The Genetics of Exceptional Human Longevity, J. Amer. Geriatric Soc. 50, 359; 2002 Thomas Perls MD et al, The Genetics of Exceptional Human Longevity, J. Amer. Geriatric Soc. 50, 359; 2002 本作品由Cold Spring Harbor Laboratory Press同意課程： 「生物、演化與人」使用，本資料庫亦無再授權他人使 用之權利，您如需利用本作品，請另行向權利人取得授 權 Yi-Fan Chen et al, Cisd 2 deficiency drives premature aging and causes mitochondria-mediated defects in mice, Genes Dev. 23: 1183 -1194; 2009

作品 作者/來源 授權條件 Yi-Fan Chen et al, Cisd 2 deficiency drives premature aging and causes mitochondria-mediated defects in mice, Genes Dev. 23: 1183 -1194; 2009 Thomas Perls MD et al, The Genetics of Exceptional Human Longevity, J. Amer. Geriatric Soc. 50, 359; 2002 長庚大學 周成功 台灣大學生態學與演化生物研究所 李艾陵 Rampon et al. , Enrichment induces structural changes and recovery from nonspatial memory deficits in CA 1 NMDAR 1 -knockout mice, Nature Neuroscience 3, 238 - 244 ; 2000 圖表參考自Joseph A. Baur & David A. Sinclair, Therapeutic potential of resveratrol: the in vivo evidence, Nature Reviews Drug Discovery 5, 493 -506 ; June 2006