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CS patients display cachectic dwarfism and severe neurological manifestations and have an average life expectancy of 12\u00a0years. The CS proteins are involved in transcription and DNA repair, with the latter including transcription\u2010coupled nucleotide excision repair (TC\u2010NER). However, there is also evidence for mitochondrial dysfunction in CS, which likely contributes to the severe premature aging phenotype of this disease. While damaged mitochondria and impaired mitophagy were characterized in mice with CSB deficiency, such changes in the CS nematode model and CS patients are not fully known. Our cross\u2010species transcriptomic analysis in CS postmortem brain tissue, CS mouse, and nematode models shows that mitochondrial dysfunction is indeed a common feature in CS. Restoration of mitochondrial dysfunction through NAD\n                    <jats:sup>+<\/jats:sup>\n                    supplementation significantly improved lifespan and healthspan in the CS nematodes, highlighting mitochondrial dysfunction as a major driver of the aging features of CS. In cerebellar samples from CS patients, we found molecular signatures of dysfunctional mitochondrial dynamics and impaired mitophagy\/autophagy. In primary cells depleted for CSA or CSB, this dysfunction can be corrected with supplementation of NAD\n                    <jats:sup>+<\/jats:sup>\n                    precursors. Our study provides support for the interconnection between major causative aging theories, DNA damage accumulation, mitochondrial dysfunction, and compromised mitophagy\/autophagy. Together, these three agents contribute to an accelerated aging program that can be averted by cellular NAD\n                    <jats:sup>+<\/jats:sup>\n                    restoration.\n                  <\/jats:p>","DOI":"10.1111\/acel.13268","type":"journal-article","created":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T10:37:04Z","timestamp":1604918224000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":55,"title":["Cockayne syndrome proteins CSA and CSB maintain mitochondrial homeostasis through NAD\n                    <sup>+<\/sup>\n                    signaling"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5724-061X","authenticated-orcid":false,"given":"Mustafa N.","family":"Okur","sequence":"first","affiliation":[{"name":"Laboratory of Molecular Gerontology National Institute on Aging National Institutes of Health  Baltimore MD 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Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,11,9]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-147991"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/dds211"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.dnarep.2014.09.011"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gks565"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gky404"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1093\/genetics\/77.1.71"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07813"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1196371"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2017.11.009"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-13172-8"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41593-018-0332-9"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2016.09.004"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2014.03.026"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1038\/srep46208"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.mad.2020.111208"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1128\/MCB.01037-06"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms9919"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.192138"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.arr.2016.08.002"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2105-6-144"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1004284"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1038\/cdd.2013.126"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.4061\/2011\/542795"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1007\/978-981-15-0602-4_4"},{"key":"e_1_2_10_26_1","first-page":"1473","article-title":"Failure 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