Accumulation of germline mutations with lateacting deleterious effects

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

Telomere: structure and function (In Greek, Telos means end; meros, part) Telomere Centromere AGGGTTAGGG-3’ TCCC-5’ Telemere is constructed by an enzyme (telemerase) which is active in embryonic cells but becomes inactive in the adult cells. Therefore, the length of telemere is fixed in adult cells.

Werner Syndrome: 遺傳性的早衰症

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

Aging vs. long life: the molecules involved Nature 424: 620 (2003)

老化研究的挑戰 • Aging in laboratory animal is not equivalent to aging in wild animal

Reduction of daf-2 activity extends lifespan of C. elegans Is daf-2 a “bad guy” to the worm?

The longevity of Caenorhabditis elegans in soil Biol. Lett. 2005 1, 247 -249. The median adult survivorship of daf-2 worms was 1. 8 days in sand (open square) and 27 days on agar (open circle). The median adult survivorship of wild-type was 4. 5 days in sand (filled square) and 12 days on agar (filled-circle).

以線虫的ROS/SOD為例： Worm has 5 SOD genes What happen if we delete all SOD in worm? ROS increases? Short life span?

No difference! Is ROS not important for worm’s life span ？ Superoxide dismutase is dispensable for normal animal lifespan PNAS 109: 5785– 5790; 2012.

SOD deleted worm consumes less oxygen than wild type worm

Low dose of paraquat (ROS generator) even increase life span of wild type worm!

老化研究的挑戰 • 老鼠或線蟲都不等於人； • Aging death is a stochastic nature • Aging in laboratory animal is not equivalent to aging in wild animal • 沒有快速和可靠的藥物篩選系統；

Sir 2 (histone deacetylase) has been shown as one longevity gene in yeast. Could we identify small chemicals as sir 2 activator ? High throughput screening needs a simple, automatic enzyme activity assay!

Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003; 425: 191 -196. Resveratrol improves health and survival of mice on a high-calorie diet. Nature. 2006; 444: 337 -342. Resveratrol delays age-related deterioration and mimics transcriptional aspects of dietary restriction without extending life span Cell Metab. 2008 ; 8: 157 -68.

In 2004, Sinclair co-founded Sirtris Pharmaceuticals with Christoph Westphal. Michelle Dipp since led the acquisition of Sirtris by Glaxo. Smith. Kline in 2008 for $720 million.

Sirt 1 activation by resveratrol is substrate sequence-selective. (Aging 5: 151 -4; 2013) Evidence for a Common Mechanism of SIRT 1 Regulation by Allosteric Activators (Science 335: 1216 -19: 2013)

Caloric Restriction Delays Disease Onset and Mortality in Rhesus Monkeys Science 325: 201 -203; 2009

“CR regimen implemented in young and older age rhesus monkeys at the National Institute on Aging (NIA) has not improved survival outcomes. ” Nature 489: 318 -321; 2012

What differences in experimental design between these two studies? Sugar content Eating behavior Genetics

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