地球上的生物終會衰老，而世人都在追尋不老的解藥，什麼是老化?人為什麼會變老？其實老化指的是細胞或生理機能上的效率逐漸衰退的情形，而這樣的情況當日趨嚴重時，往往就會造成生物個體的死亡。然而，現實生活中其實有許多因子可以決定老化發生的快慢，其中包括了營養物質攝取的多寡、溫度、氧化壓力等，都是能夠影響並促成老化的發生。當細胞在進行呼吸作用時，常會產生一些活性氧自由基(reactive oxygen species)，然而這樣的自由基在細胞內不單只是做為一個訊息傳遞的重要因子，當其過度產生的時候，其實對於細胞本體來說也是一種傷害而促會使老化的發生。Sestrin是一個受到p53調控的蛋白質，並且在許多物種身中俱有高度的保留性，其俱有還原抗氧化蛋白peroxiredoxins的能力。近年來Jun Hee Lee等人透過實驗發現果蠅裡中的Sestrin這樣的蛋白與老化相關病症的進程有關，然而對於其在個體壽命上的調控卻不是那麼的清楚。此研究中，我們發現了當線蟲(C. elegans)缺乏sesn-1基因時，除壽命具有明顯縮短的情形外，還伴隨著活性氧自由基的累積和提早老化的現象。除此之外，生物體內的sesn-1 基因在對抗生活中的逆境上也扮演了非常重要的角色。當sesn-1 基因過度表現的時候，線蟲的壽命可以被延長。這些結果指出了，其實sesn-1基因在正常壽命上的存在是必須的，而隨著年齡的增長，老化的表徵明顯發生在線蟲的肌肉細胞，並可能引發肌肉衰減綜合症，而這樣的發生可能是由於氧化自由基的大量累積所造成。

Aging is a process of gradual function decline leading to death. Human aging always accompanied with many diseases such as cancer, chronic inflammation, cardiovascular diseases and various degenerative diseases, such as sarcopenia. The rate of aging can be influenced by environmental factors, such as the level or quality of nutrients, temperature, and sensory cues. Reactive oxygen species (ROS) not only contribute to oxidative stress and cell damage leading to aging but also serve as signaling molecules at last. Sestrin, a p53-regulated protein, is evolutionally conserved in all multicellular organisms and required for regenerating the hyperoxidized forms of typical 2-Cys peroxiredoxins. It has been reported that Sestrins also have a function in preventing aging-related pathologies in Drosophila. However, whether Sestrin per se can regulate longevity is still unclear. In this study, we demonstrated that loss-of-function of sesn-1 in C. elegans (cSesn) play a key role in preventive defence of many life stressors, eg. heat, hydrogen peroxide and heavy metals, also, mutant worms express higher in ROS level and show a decline in the function of body wall muscle. Surprisingly, loss of sesn-1 does not weaken in the innate immunity functions of the worms. When the sesn-1 is overexpressed, we found that it can prolong the lifespan of C. elegans and this also can be seen in the rescued worms. All these results suggested that sesn-1 is required for normal lifespan and its function in muscle cells would prevent muscle dysregulattion or sarcopenia over a lifetime.

Bakkar, N. and D. C. Guttridge (2010). "NF-kappaB signaling: a tale of two pathways in skeletal myogenesis." Physiol Rev 90(2): 495-511.
Bischof, L. J., C. Y. Kao, et al. (2008). "Activation of the unfolded protein response is required for defenses against bacterial pore-forming toxin in vivo." PLoS Pathog 4(10): e1000176.
Biteau, B., J. Labarre, et al. (2003). "ATP-dependent reduction of cysteine-sulphinic acid by S. cerevisiae sulphiredoxin." Nature 425(6961): 980-984.
Blackman, M. R., J. D. Sorkin, et al. (2002). "Growth hormone and sex steroid administration in healthy aged women and men: a randomized controlled trial." JAMA 288(18): 2282-2292.
Bolanowski, M. A., R. L. Russell, et al. (1981). "Quantitative measures of aging in the nematode Caenorhabditis elegans. I. Population and longitudinal studies of two behavioral parameters." Mech Ageing Dev 15(3): 279-295.
Brenner, S. (1974). "The genetics of Caenorhabditis elegans." Genetics 77(1): 71-94.
Brown, W. T. (1990). "Genetic diseases of premature aging as models of senescence." Annu Rev Gerontol Geriatr 10: 23-42.
Budanov, A. V. and M. Karin (2008). "p53 target genes sestrin1 and sestrin2 connect genotoxic stress and mTOR signaling." Cell 134(3): 451-460.
Budanov, A. V., A. A. Sablina, et al. (2004). "Regeneration of peroxiredoxins by p53-regulated sestrins, homologs of bacterial AhpD." Science 304(5670): 596-600.
Chae, H. Z., K. Robison, et al. (1994). "Cloning and sequencing of thiol-specific antioxidant from mammalian brain: alkyl hydroperoxide reductase and thiol-specific antioxidant define a large family of antioxidant enzymes." Proc Natl Acad Sci U S A 91(15): 7017-7021.
Chavez, V., A. Mohri-Shiomi, et al. (2009). "Ce-Duox1/BLI-3 generates reactive oxygen species as a protective innate immune mechanism in Caenorhabditis elegans." Infect Immun 77(11): 4983-4989.
Chavez, V., A. Mohri-Shiomi, et al. (2007). "Oxidative stress enzymes are required for DAF-16-mediated immunity due to generation of reactive oxygen species by Caenorhabditis elegans." Genetics 176(3): 1567-1577.
Collins, J. J., C. Huang, et al. (2008). "The measurement and analysis of age-related changes in Caenorhabditis elegans." WormBook: 1-21.
Croll, N. A., J. M. Smith, et al. (1977). "The aging process of the nematode Caenorhabditis elegans in bacterial and axenic culture." Exp Aging Res 3(3): 175-189.
de Magalhaes, J. P. (2005). "Open-minded scepticism: inferring the causal mechanisms of human ageing from genetic perturbations." Ageing Res Rev 4(1): 1-22.
Faber, P. W., J. R. Alter, et al. (1999). "Polyglutamine-mediated dysfunction and apoptotic death of a Caenorhabditis elegans sensory neuron." Proc Natl Acad Sci U S A 96(1): 179-184.
Finch, C. E., M. C. Pike, et al. (1990). "Slow mortality rate accelerations during aging in some animals approximate that of humans." Science 249(4971): 902-905.
Forman, H. J., M. Maiorino, et al. (2010). "Signaling functions of reactive oxygen species." Biochemistry 49(5): 835-842.
Fraser, G. E. (2009). "Vegetarian diets: what do we know of their effects on common chronic diseases? (vol 89, pg 1607S, 2009)." American Journal of Clinical Nutrition 90(1): 248-248.
Fridovich, I. (1978). "The biology of oxygen radicals." Science 201(4359): 875-880.
Garigan, D., A. L. Hsu, et al. (2002). "Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation." Genetics 161(3): 1101-1112.
Garsin, D. A., J. M. Villanueva, et al. (2003). "Long-lived C. elegans daf-2 mutants are resistant to bacterial pathogens." Science 300(5627): 1921.
Gensler, H. L. and H. Bernstein (1981). "DNA damage as the primary cause of aging." Q Rev Biol 56(3): 279-303.
Girard, L. R., T. J. Fiedler, et al. (2007). "WormBook: the online review of Caenorhabditis elegans biology." Nucleic Acids Res 35(Database issue): D472-475.
Gruber, J., S. Schaffer, et al. (2008). "The mitochondrial free radical theory of ageing--where do we stand?" Front Biosci 13: 6554-6579.
Hammerman, M. R. (1987). "Insulin-like growth factors and aging." Endocrinol Metab Clin North Am 16(4): 995-1011.
Harman, D. (1956). "Aging: a theory based on free radical and radiation chemistry." J Gerontol 11(3): 298-300.
Herndon, L. A., P. J. Schmeissner, et al. (2002). "Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans." Nature 419(6909): 808-814.
Ho, K. Y., W. S. Evans, et al. (1987). "Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations." J Clin Endocrinol Metab 64(1): 51-58.
Honda, Y., M. Tanaka, et al. (2010). "Trehalose extends longevity in the nematode Caenorhabditis elegans." Aging Cell 9(4): 558-569.
Hosono, R., Y. Sato, et al. (1980). "Age-dependent changes in mobility and separation of the nematode Caenorhabditis elegans." Exp Gerontol 15(4): 285-289.
Hsu, A. L., Z. Feng, et al. (2009). "Identification by machine vision of the rate of motor activity decline as a lifespan predictor in C. elegans." Neurobiol Aging 30(9): 1498-1503.
Huang, C., C. Xiong, et al. (2004). "Measurements of age-related changes of physiological processes that predict lifespan of Caenorhabditis elegans." Proc Natl Acad Sci U S A 101(21): 8084-8089.
Huang, M. E., A. G. Rio, et al. (2003). "A genomewide screen in Saccharomyces cerevisiae for genes that suppress the accumulation of mutations." Proc Natl Acad Sci U S A 100(20): 11529-11534.
Hughes, S. E., K. Evason, et al. (2007). "Genetic and pharmacological factors that influence reproductive aging in nematodes." PLoS Genet 3(2): e25.
Johnson, T. E. (1987). "Aging Can Be Genetically Dissected into Component Processes Using Long-Lived Lines of Caenorhabditis-Elegans." Proceedings of the National Academy of Sciences of the United States of America 84(11): 3777-3781.
Johnson, T. E. (1987). "Aging can be genetically dissected into component processes using long-lived lines of Caenorhabditis elegans." Proc Natl Acad Sci U S A 84(11): 3777-3781.
Johnson, T. M., Z. X. Yu, et al. (1996). "Reactive oxygen species are downstream mediators of p53-dependent apoptosis." Proc Natl Acad Sci U S A 93(21): 11848-11852.
Kenyon, C. (2005). "The plasticity of aging: insights from long-lived mutants." Cell 120(4): 449-460.
Lapointe, J. and S. Hekimi (2010). "When a theory of aging ages badly." Cell Mol Life Sci 67(1): 1-8.
Lee, J. H., A. V. Budanov, et al. (2010). "Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies." Science 327(5970): 1223-1228.
Lee, T. H., S. U. Kim, et al. (2003). "Peroxiredoxin II is essential for sustaining life span of erythrocytes in mice." Blood 101(12): 5033-5038.
Leiers, B., A. Kampkotter, et al. (2003). "A stress-responsive glutathione S-transferase confers resistance to oxidative stress in Caenorhabditis elegans." Free Radic Biol Med 34(11): 1405-1415.
Levine, A. J. (1997). "p53, the cellular gatekeeper for growth and division." Cell 88(3): 323-331.
Li, S., C. M. Armstrong, et al. (2004). "A map of the interactome network of the metazoan C. elegans." Science 303(5657): 540-543.
Link, C. D. (1995). "Expression of human beta-amyloid peptide in transgenic Caenorhabditis elegans." Proc Natl Acad Sci U S A 92(20): 9368-9372.
Lints, F. A. (1989). "The rate of living theory revisited." Gerontology 35(1): 36-57.
Liu, H., D. M. Bravata, et al. (2007). "Systematic review: the safety and efficacy of growth hormone in the healthy elderly." Ann Intern Med 146(2): 104-115.
Low, I. and T. Wieland (1974). "The interaction of phalloidin. Some of its derivatives, and of other cyclic peptides with muscle actin as studied by viscosimetry." FEBS Lett 44(3): 340-343.
Lu, T. and T. Finkel (2008). "Free radicals and senescence." Exp Cell Res 314(9): 1918-1922.
Lu, T., Y. Pan, et al. (2004). "Gene regulation and DNA damage in the ageing human brain." Nature 429(6994): 883-891.
Marroquin, L. D., D. Elyassnia, et al. (2000). "Bacillus thuringiensis (Bt) toxin susceptibility and isolation of resistance mutants in the nematode Caenorhabditis elegans." Genetics 155(4): 1693-1699.
Martin, G. M. and J. Oshima (2000). "Lessons from human progeroid syndromes." Nature 408(6809): 263-266.
Martin, G. M., A. C. Smith, et al. (1985). "Increased chromosomal aberrations in first metaphases of cells isolated from the kidneys of aged mice." Isr J Med Sci 21(3): 296-301.
Mates, J. M., J. A. Segura, et al. (2008). "Intracellular redox status and oxidative stress: implications for cell proliferation, apoptosis, and carcinogenesis." Arch Toxicol 82(5): 273-299.
Michael Morcos, e. a. (2008). "Glyoxalase-1 prevents mitochondrial protein modification and enhances lifespan in Caenorhabditis elegans." Aging Cell 7: 260-269.
Murakami, S. and H. Murakami (2005). "The effects of aging and oxidative stress on learning behavior in C. elegans." Neurobiol Aging 26(6): 899-905.
Neumann, C. A., D. S. Krause, et al. (2003). "Essential role for the peroxiredoxin Prdx1 in erythrocyte antioxidant defence and tumour suppression." Nature 424(6948): 561-565.
Olahova, M., S. R. Taylor, et al. (2008). "A redox-sensitive peroxiredoxin that is important for longevity has tissue- and stress-specific roles in stress resistance." Proc Natl Acad Sci U S A 105(50): 19839-19844.
Pavlides, S., A. Tsirigos, et al. (2010). "The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism." Cell Cycle 9(17): 3485-3505.
Pletcher, S. D., A. A. Khazaeli, et al. (2000). "Why do life spans differ? Partitioning mean longevity differences in terms of age-specific mortality parameters." J Gerontol A Biol Sci Med Sci 55(8): B381-389.
Powell, J. R. and F. M. Ausubel (2008). "Models of Caenorhabditis elegans infection by bacterial and fungal pathogens." Methods Mol Biol 415: 403-427.
Schaffer, S., J. Gruber, et al. (2011). "The effect of dichloroacetate on health- and lifespan in C. elegans." Biogerontology 12(3): 195-209.
Sedeek, M., R. L. Hebert, et al. (2009). "Molecular mechanisms of hypertension: role of Nox family NADPH oxidases." Curr Opin Nephrol Hypertens 18(2): 122-127.
Sedensky, M. M. and P. G. Morgan (2006). "Mitochondrial respiration and reactive oxygen species in C. elegans." Exp Gerontol 41(10): 957-967.
Sonntag, W. E., C. D. Lynch, et al. (1999). "Pleiotropic effects of growth hormone and insulin-like growth factor (IGF)-1 on biological aging: inferences from moderate caloric-restricted animals." J Gerontol A Biol Sci Med Sci 54(12): B521-538.
Szilard, L. (1959). "On the Nature of the Aging Process." Proc Natl Acad Sci U S A 45(1): 30-45.
Tan, M. W., S. Mahajan-Miklos, et al. (1999). "Killing of Caenorhabditis elegans by Pseudomonas aeruginosa used to model mammalian bacterial pathogenesis." Proc Natl Acad Sci U S A 96(2): 715-720.
Tan, M. W., L. G. Rahme, et al. (1999). "Pseudomonas aeruginosa killing of Caenorhabditis elegans used to identify P. aeruginosa virulence factors." Proc Natl Acad Sci U S A 96(5): 2408-2413.
Tatar, M. (2009). "Can we develop genetically tractable models to assess healthspan (rather than life span) in animal models?" J Gerontol A Biol Sci Med Sci 64(2): 161-163.
Thompson, J. D., D. G. Higgins, et al. (1994). "CLUSTAL W: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice." Nucleic Acids Res 22(22): 4673-4680.
Timmons, L., D. L. Court, et al. (2001). "Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans." Gene 263(1-2): 103-112.
Velasco-Miguel, S., L. Buckbinder, et al. (1999). "PA26, a novel target of the p53 tumor suppressor and member of the GADD family of DNA damage and growth arrest inducible genes." Oncogene 18(1): 127-137.
Vousden, K. H. and D. P. Lane (2007). "p53 in health and disease." Nat Rev Mol Cell Biol 8(4): 275-283.
Wallace, D. C. (2005). "A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a dawn for evolutionary medicine." Annu Rev Genet 39: 359-407.
Ward, S. and J. S. Carrel (1979). "Fertilization and sperm competition in the nematode Caenorhabditis elegans." Dev Biol 73(2): 304-321.
Waterfield, N. R., B. W. Wren, et al. (2004). "Invertebrates as a source of emerging human pathogens." Nat Rev Microbiol 2(10): 833-841.
Watts, G. D., J. Wymer, et al. (2004). "Inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia is caused by mutant valosin-containing protein." Nat Genet 36(4): 377-381.
Wei, J. Z., K. Hale, et al. (2003). "Bacillus thuringiensis crystal proteins that target nematodes." Proceedings of the National Academy of Sciences of the United States of America 100(5): 2760-2765.
Wood, Z. A., E. Schroder, et al. (2003). "Structure, mechanism and regulation of peroxiredoxins." Trends Biochem Sci 28(1): 32-40.