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DNA repair and extended longevity

Many authors have noted an association between defects in the DNA damage response and premature aging. If a DNA repair protein is deficient, unrepaired DNA damages tend to accumulate.[1] Such accumulated DNA damages appear to cause features of premature aging (segmental progeria) (see Defects in DNA repair cause features of premature aging).

On the other hand, genetic alterations that increase DNA repair or decrease damage in DNA, may cause extended longevity. Table 1 lists DNA repair proteins whose increased expression is connected to extended longevity.

Table 1. DNA repair proteins that, when highly- or over-expressed, cause (or are associated with) extended longevity.
Protein Pathway Description
NDRG1 Direct reversal long-lived Snell dwarf, GHRKO, and PAPPA-KO mice have increased expression of NDRG1; higher expression of NDRG1 can promote MGMT DNA repair protein stability and enhanced DNA repair[2][3]
NUDT1 (MTH1) Oxidized nucleotide removal degrades 8-oxodGTP; prevents the age-dependent accumulation of DNA 8-oxoguanine[4] A transgenic mouse in which the human hMTH1 8-oxodGTPase is expressed,[5] giving over-expression of hMTH1, increases the median lifespan of mice to 914 days vs. 790 days for wild-type mice.[4] Mice with over-expressed hMTH1 have behavioral changes of reduced anxiety and enhanced investigation of environmental and social cues
PARP1 Base excision repair,[6] nucleotide excision repair,[7] microhomology-mediated end joining,[8] single-strand break repair[9] PARP1 activity in blood cells of thirteen mammalian species (rat, guinea pig, rabbit, marmoset, sheep, pig, cattle, pigmy chimpanzee, horse, donkey, gorilla, elephant and man) correlates with maximum lifespan of the species.[10]
SIRT1 Nucleotide excision repair, homologous recombination, non-homologous end joining[11] Increased expression of SIRT1 in male mice extends the lifespan of mice fed a standard diet, accompanied by improvements in health, including enhanced motor coordination, performance, bone mineral density, and insulin sensitivity[12][13]
SIRT6 Base excision repair, nucleotide excision repair, homologous recombination, non-homologous end joining[14] male, but not female, transgenic mice overexpressing Sirt6 have a significantly longer lifespan than wild-type mice[15]

References

  1. ^ Musich PR, Zou Y (2011). "DNA-damage accumulation and replicative arrest in Hutchinson-Gilford progeria syndrome". Biochem. Soc. Trans. 39 (6): 1764–9. doi:10.1042/BST20110687. PMC 4271832. PMID 22103522.
  2. ^ Dominick G, Bowman J, Li X, Miller RA, Garcia GG (2017). "mTOR regulates the expression of DNA damage response enzymes in long-lived Snell dwarf, GHRKO, and PAPPA-KO mice". Aging Cell. 16 (1): 52–60. doi:10.1111/acel.12525. PMC 5242303. PMID 27618784.
  3. ^ Weiler M, Blaes J, Pusch S, Sahm F, Czabanka M, Luger S, Bunse L, Solecki G, Eichwald V, Jugold M, Hodecker S, Osswald M, Meisner C, Hielscher T, Rübmann P, Pfenning PN, Ronellenfitsch M, Kempf T, Schnölzer M, Abdollahi A, Lang F, Bendszus M, von Deimling A, Winkler F, Weller M, Vajkoczy P, Platten M, Wick W (2014). "mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy". Proc. Natl. Acad. Sci. U.S.A. 111 (1): 409–14. doi:10.1073/pnas.1314469111. PMC 3890826. PMID 24367102.
  4. ^ a b De Luca G, Ventura I, Sanghez V, Russo MT, Ajmone-Cat MA, Cacci E, Martire A, Popoli P, Falcone G, Michelini F, Crescenzi M, Degan P, Minghetti L, Bignami M, Calamandrei G (2013). "Prolonged lifespan with enhanced exploratory behavior in mice overexpressing the oxidized nucleoside triphosphatase hMTH1". Aging Cell. 12 (4): 695–705. doi:10.1111/acel.12094. PMID 23648059.
  5. ^ De Luca G, Russo MT, Degan P, Tiveron C, Zijno A, Meccia E, Ventura I, Mattei E, Nakabeppu Y, Crescenzi M, Pepponi R, Pèzzola A, Popoli P, Bignami M (2008). "A role for oxidized DNA precursors in Huntington's disease-like striatal neurodegeneration". PLoS Genet. 4 (11): e1000266. doi:10.1371/journal.pgen.1000266. PMC 2580033. PMID 19023407.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  6. ^ Almeida KH, Sobol RW (2007). "A unified view of base excision repair: lesion-dependent protein complexes regulated by post-translational modification". DNA Repair (Amst.). 6 (6): 695–711. doi:10.1016/j.dnarep.2007.01.009. PMC 1995033. PMID 17337257.
  7. ^ Pines A, Vrouwe MG, Marteijn JA, Typas D, Luijsterburg MS, Cansoy M, Hensbergen P, Deelder A, de Groot A, Matsumoto S, Sugasawa K, Thoma N, Vermeulen W, Vrieling H, Mullenders L (2012). "PARP1 promotes nucleotide excision repair through DDB2 stabilization and recruitment of ALC1". J. Cell Biol. 199 (2): 235–49. doi:10.1083/jcb.201112132. PMC 3471223. PMID 23045548.
  8. ^ Wang M, Wu W, Wu W, Rosidi B, Zhang L, Wang H, Iliakis G (2006). "PARP-1 and Ku compete for repair of DNA double strand breaks by distinct NHEJ pathways". Nucleic Acids Res. 34 (21): 6170–82. doi:10.1093/nar/gkl840. PMC 1693894. PMID 17088286.
  9. ^ Okano S, Lan L, Caldecott KW, Mori T, Yasui A (2003). "Spatial and temporal cellular responses to single-strand breaks in human cells". Mol. Cell. Biol. 23 (11): 3974–81. PMC 155230. PMID 12748298.
  10. ^ Grube K, Bürkle A (Dec 1992). "Poly(ADP-ribose) polymerase activity in mononuclear leukocytes of 13 mammalian species correlates with species-specific life span". Proceedings of the National Academy of Sciences of the United States of America. 89 (24): 11759–63. Bibcode:1992PNAS...8911759G. doi:10.1073/pnas.89.24.11759. PMC 50636. PMID 1465394.
  11. ^ Mei Z, Zhang X, Yi J, Huang J, He J, Tao Y (2016). "Sirtuins in metabolism, DNA repair and cancer". J. Exp. Clin. Cancer Res. 35 (1): 182. doi:10.1186/s13046-016-0461-5. PMC 5137222. PMID 27916001.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  12. ^ Mercken EM, Mitchell SJ, Martin-Montalvo A, Minor RK, Almeida M, Gomes AP, Scheibye-Knudsen M, Palacios HH, Licata JJ, Zhang Y, Becker KG, Khraiwesh H, González-Reyes JA, Villalba JM, Baur JA, Elliott P, Westphal C, Vlasuk GP, Ellis JL, Sinclair DA, Bernier M, de Cabo R (2014). "SRT2104 extends survival of male mice on a standard diet and preserves bone and muscle mass". Aging Cell. 13 (5): 787–96. doi:10.1111/acel.12220. PMC 4172519. PMID 24931715.
  13. ^ Mitchell SJ, Martin-Montalvo A, Mercken EM, Palacios HH, Ward TM, Abulwerdi G, Minor RK, Vlasuk GP, Ellis JL, Sinclair DA, Dawson J, Allison DB, Zhang Y, Becker KG, Bernier M, de Cabo R (2014). "The SIRT1 activator SRT1720 extends lifespan and improves health of mice fed a standard diet". Cell Rep. 6 (5): 836–43. doi:10.1016/j.celrep.2014.01.031. PMC 4010117. PMID 24582957.
  14. ^ Cite error: The named reference Chalkiadaki was invoked but never defined (see the help page).
  15. ^ Kanfi Y, Naiman S, Amir G, Peshti V, Zinman G, Nahum L, Bar-Joseph Z, Cohen HY (2012). "The sirtuin SIRT6 regulates lifespan in male mice". Nature. 483 (7388): 218–21. doi:10.1038/nature10815. PMID 22367546.

-- Jytdog (talk) 17:34, 7 July 2017 (UTC)[reply]

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